UpToDate Dermatology 2020 Edition

Contents
Cover 1
Overview of dermoscopy 2
Dermoscopic evaluation of skin lesions 11
Dermoscopy of pigmented lesions of the palms and soles 25
Patch testing 83
Evaluation and diagnosis of hair loss 91
Approach to the clinical dermatologic diagnosis 109
Approach to the patient with a scalp disorder 198
Approach to the patient with an intertriginous skin disorder 210
Approach to the patient with annular skin lesions 222
Approach to the patient with cutaneous blisters 235
Approach to the patient with facial erythema 342
Approach to the patient with pustular skin lesions 387
Approach to the patient with retiform (angulated) purpura 446
Approach to the differential diagnosis of leg ulcers 458
Evaluation of adults with cutaneous lesions of vasculitis 471
Office-based dermatologic diagnostic procedures 483
Longitudinal melanonychia 492
Erythroderma in adults 503
Acquired hyperpigmentation disorders 518
Overview of nail disorders 542
Atopic dermatitis 566
allergic contact dermatitis 650
Contact dermatitis in children 677
Irritant contact dermatitis in adults 688
Chronic hand eczema 705
Patch testing 717
Management of allergic contact dermatitis 725
Poison ivy (Toxicodendron) dermatitis 733
Eyelid dermatitis (eczema) 743
Keratosis pilaris 753
Keratosis pilaris atrophicans 758
Cheilitis 763
Acute palmoplantar eczema (dyshidrotic eczema) 774
Cradle cap and seborrheic dermatitis in infants 784
Intertrigo 790
Nummular eczema 798
Overview of dermatitis (eczema) 804
Prurigo nodularis 901
Seborrheic dermatitis in adolescents and adults 912
Stasis dermatitis 925
Vulvar dermatitis 937
Urticarial dermatitis 951
Radiation dermatitis 970
Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris 988
Postadolescent acne in women 1007
Treatment of acne vulgaris 1017
Oral isotretinoin therapy for acne vulgaris 1046
Hormonal therapy for women with acne vulgaris 1060
Light-based, adjunctive, and other therapies for acne vulgaris 1072
Perioral (periorificial) dermatitis 1080
Rosacea Pathogenesis, clinical features, and diagnosis 1092
Management of rosacea 1105
PsoriasisEpidemiology, clinical manifestations, and diagnosis 1124
Pathophysiology of plaque psoriasis 1196
Nail psoriasis 1208
Guttate psoriasis 1245
Treatment of psoriasis in adults 1274
Erythrodermic psoriasis in adults 1318
Treatment selection for moderate to severe plaque psoriasis in special 1343
Psoriasis in children epidemiology clinical manifestation and dianosis 1366
Psoriasis in childrenManagement of chronic plaque psoriasis 1400
Management of psoriasis in pregnancy 1426
Comorbid disease in psoriasis 1444
Patient education Psoriasis (Beyond the Basics) 1463
Pustular psoriasisPathogenesis, clinical manifestations, and diagnosis 1482
Pustular psoriasisManagement 1509
Palmoplantar pustulosisEpidemiology, clinical features, and diagnosis 1531
Palmoplantar pustulosis Treatment 1561
Lichen planus 1583
Lichen Planopilaris 1597
Vulvar lichen planus 1614
Oral lichen planusPathogenesis, clinical features, and diagnosis 1631
Oral lichen planus Management and prognosis 1640
Pityriasis rosea 1651
Pityriasis lichenoides chronica 1683
Pityriasis lichenoides et varioliformis acuta (PLEVA) 1707
Pityriasis rubra pilaris 1739
Confluent and reticulated papillomatosis 1771
Lichen striatus 1799
New-onset urticaria 1827
Chronic spontaneous urticariaClinical manifestations, diagnosis,and natural 1860
Chronic spontaneous urticariaStandard management and patient education 1893
Chronic spontaneous urticaria Treatment of refractory symptoms 1921
An overview of angioedemaPathogenesis and causes 1940
An overview of angioedemaClinical features, diagnosis, and management 1956
Hereditary angioedemaPathogenesis and diagnosis 1986
Hereditary angioedema Epidemiology, clinical manifestations, exacerbating
prognosis 2000
Hereditary angioedema (due to C1 inhibitor deficiency)General care andterm 2011
Hereditary angioedema with normal C1 inhibitor 2037
Hereditary angioedemaAcute treatment of angioedema attacks 2052
Hereditary angioedema Temporary prophylaxis before procedures or stress
angioedema episodes 2077
Acquired C1 inhibitor deficiencyClinical manifestations, epidemiology,and 2090
Acquired C1 inhibitor deficiencyManagement and prognosis 2101
ACE inhibitor-induced angioedema 2115
Physical (inducible) forms of urticaria 2129
Cold urticaria 2167
Urticarial vasculitis 2188
Pathogenesis, clinical manifestations, and diagnosis of pemphigus 2221
Paraneoplastic pemphigus 2236
Initial management of pemphigus vulgaris and pemphigus foliaceus 2249
Management of refractory pemphigus vulgaris and pemphigus foliaceus 2264
Fogo selvagem Brazilian endemic pemphigus foliaceus 2275
Epidemiology and pathogenesis of bullous pemphigoid and mucous
2288
Clinical features and diagnosis of bullous pemphigoid and mucous
2298
Ocular cicatricial pemphigoid 2315
Management and prognosis of bullous pemphigoid 2330
Management of mucous membrane pemphigoid 2345
Dermatitis herpetiformis 2356
Epidermolysis bullosa acquisita 2369
Friction blisters 2383
Linear IgA bullous dermatosis 2390
Evaluation and diagnosis of hair loss 2404
Overview of dermoscopy of the hair and scalp 2422
Alopecia areataClinical manifestations and diagnosis 2435
Alopecia areataManagement 2445
Androgenetic alopecia in menPathogenesis, clinical features, and diagnosis 2460
Treatment of androgenetic alopecia in men 2470
Female pattern hair loss (androgenetic alopecia in women) Pathogenesis,
and diagnosis 2480
Female pattern hair loss (androgenetic alopecia in women)Treatment and 2490
Telogen effluvium 2498
Traction alopecia 2511
Lichen planopilaris 2523
Acne keloidalis nuchae 2540
Central centrifugal cicatricial alopecia 2556
Dissecting cellulitis of the scalp 2571
Erosive pustular dermatosis of the scalp 2580
Folliculitis decalvans 2590
Hair shaft disorders 2605
Pseudofolliculitis barbae 2615
Overview of nail disorders 2625
Overview of dermoscopy 2740
Dermoscopic evaluation of skin lesions 2749
Dermoscopy of facial lesions 2763
Dermoscopy of pigmented lesions of the palms and soles 2826
Dermoscopy of nail pigmentations 2882
Dermoscopy of nonpigmented nail lesions 2920
Dermoscopic algorithms for skin cancer triage 2952
Dermoscopy of mucosal lesions 2988
MelasmaEpidemiology, pathogenesis, clinical presentation, and diagnosis 3009
MelasmaManagement 3020
Acquired melanocytic nevi (moles) 3037
Benign pigmented skin lesions other than melanocytic nevi (moles) 3047
Atypical (dysplastic) nevi 3056
Spitz nevus and atypical Spitz tumors 3071
Congenital melanocytic nevi 3090
Congenital and inherited hyperpigmentation disorders 3100
VitiligoPathogenesis, clinical features, and diagnosis 3116
VitiligoManagement and prognosis 3129
Acquired hypopigmentation disorders other than vitiligo 3145
Lentigo maligna Clinical manifestations, diagnosis, and management 3158
Melanoma Clinical features and diagnosis 3172
Risk factors for the development of melanoma 3190
Screening and early detection of melanoma in adults and adolescents 3207
Melanoma in children 3227
Epidemiology and risk factors for skin cancer in solid organ transplant 3242
Pathologic characteristics of melanoma 3254
Pathologic evaluation of regional lymph nodes in melanoma 3268
Tumor, node, metastasis (TNM) staging system and other prognostic factors
melanoma 3274
Surgical management of primary cutaneous melanoma or melanoma at
sites 3286
Staging work-up and surveillance after treatment of melanoma 3300
Primary prevention of melanoma 3310
Prevention and management of skin cancer in solid organ transplant 3323
Cellulitis and skin abscessClinical manifestations and diagnosis 3340
Cellulitis and skin abscess in adultsTreatment 3351
Erythrasma 3364
Impetigo 3371
Pitted keratolysis 3379
Pseudomonas aeruginosa skin and soft tissue infections 3388
Cutaneous manifestations of tuberculosis 3401
Cutaneous manifestations of gonorrhea 3418
Staphylococcal scalded skin syndrome 3425
Necrotizing soft tissue infections 3438
Trichomycosis (trichobacteriosis) 3454
Botryomycosis 3460
Yaws, bejel, and pinta 3467
Pediculosis capitis 3486
Pediculosis corporis 3500
Pediculosis pubis and pediculosis ciliaris 3516
ScabiesEpidemiology, clinical features, and diagnosis 3524
Scabies Management 3533
Bedbugs 3542
Chigger bites 3552
Jellyfish stings 3557
Lepidopterism Skin disorders secondary to caterpillars and moths 3572
Dermatophyte (tinea) infections 3580
Tinea versicolor (pityriasis versicolor) 3593
Tinea capitis 3602
Tinea nigra 3619
OnychomycosisEpidemiology, clinical features, and diagnosis 3626
OnychomycosisManagement 3637
Candida infections in children 3653
Chromoblastomycosis 3667
Lobomycosis 3679
Piedra 3688
Cutaneous warts (common, plantar, and flat warts) 3695
Condylomata acuminata (anogenital warts) in adults Epidemiology,clinicaland 3710
Condylomata acuminata (anogenital warts) Management of external
in men 3719
Condylomata acuminata (anogenital warts) in children 3734
Epidemiology, clinical manifestations, and diagnosis of genital herpesvirus 3743
Treatment of genital herpes simplex virus infection 3758
Prevention of genital herpes virus infections 3772
Treatment of herpes simplex virus type 1 infection in immunocompeten 3782
Epidemiology, clinical manifestations, and diagnosis of herpes zoster 3792
Treatment of herpes zoster in the immunocompetent host 3807
Molluscum contagiosum 3817
Orf virus infection 3833
HIV-associated eosinophilic folliculitis 3839
Fever and rash in the immunocompetent patient 3849
Gianotti-Crosti syndrome (papular acrodermatitis) 3921
Clinical manifestations, diagnosis, and management of diabetic infections of
etremities 3929
Infectious folliculitis 3944
Soft tissue infections following water exposure 3958
Skin lesions in the returning traveler 3969
Drug eruptions 3978
Exanthematous (maculopapular) drug eruption 3989
Lichenoid drug eruption (drug-induced lichen planus 4000
Acute generalized exanthematous pustulosis (AGEP) 4012
Drug reaction with eosinophilia and systemic symptoms (DRESS) 4020
Fixed drug eruption 4037
Stevens-Johnson syndrome and toxic epidermal necrolysis 4047
Acneiform eruption secondary to epidermal growth factor receptor (EGFR)
inhibitors 4082
Cutaneous side effects of conventional chemotherapy agents 4096
Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors 4118
Cutaneous adverse events of molecularly targeted therapy and otheragents
cancer therapy 4128
Epidemiology, natural history, and diagnosis of actinic keratosis 4142
Treatment of actinic keratosis 4152
Actinic cheilitis 4167
Epidemiology, pathogenesis, and clinical features of basal cell carcinoma 4174
Treatment and prognosis of basal cell carcinoma at low risk of recurrence 4191
Treatment of basal cell carcinomas at high risk for recurrence 4208
Evaluation for locoregional and distant metastases in cutaneous squamous
basal cell carcinoma 4218
Systemic treatment of advanced cutaneous squamous and basal cell 4227
Nevoid basal cell carcinoma syndrome (Gorlin syndrome) 4237
Cutaneous adnexal tumors 4253
Microcystic adnexal carcinoma 4347
Epidemiology and risk factors for cutaneous squamous cell carcinoma 4357
Cutaneous squamous cell carcinoma (cSCC) Clinical features and diagnosis 4372
Treatment and prognosis of low-risk cutaneous squamous cell carcinoma 4380
Recognition and management of high-risk (aggressive) cutaneous squamous
4397
Evaluation for locoregional and distant metastases in cutaneous squamous
basal cell carcinoma 4416
Systemic treatment of advanced cutaneous squamous and basal cell 4425
Keratoacanthoma 4435
Merkel cell (neuroendocrine) carcinoma 4455
Epidemiology and risk factors for skin cancer in solid organ transplant 4486
Prevention and management of skin cancer in solid organ transplant 4498
Sebaceous carcinoma 4515
Atypical fibroxanthoma 4524
Porokeratosis 4532
Overview of cutaneous lupus erythematosus 4548
Initial management of discoid lupus and subacute cutaneous lupus 4599
Management of refractory discoid lupus and subacute cutaneous lupus 4621
Tumid lupus erythematosus 4642
Bullous systemic lupus erythematosus 4672
Cutaneous dermatomyositis in adultsOverview and initial management 4694
Initial treatment of dermatomyositis and polymyositis in adults 4725
Management of refractory cutaneous dermatomyositis in adults 4745
Treatment of recurrent and resistant dermatomyositis and polymyositis in 4762
Malignancy in dermatomyositis and polymyositis 4775
Juvenile dermatomyositis and polymyositis Epidemiology, pathogenesis, and
4784
Juvenile dermatomyositis and polymyositis Diagnosis 4797
Juvenile dermatomyositis and polymyositisTreatment, complications, and 4815
Clinical manifestations, pathologic features, and diagnosis of Langerhans
4833
Treatment of Langerhans cell histiocytosis 4865
Necrobiotic xanthogranuloma 4887
Juvenile xanthogranuloma (JXG) 4907
Pathology and pathogenesis of sarcoidosis 4933
Cutaneous manifestations of sarcoidosis 4953
Clinical manifestations and diagnosis of pulmonary sarcoidosis 4999
Cutaneous sarcoidosisManagement 5039
Pathogenesis of systemic sclerosis (scleroderma) 5065
Risk factors for and possible causes of systemic sclerosis (scleroderma) 5089
Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in 5098
Pretreatment evaluation of adults with systemic sclerosis (scleroderma) 5132
Overview of the treatment and prognosis of systemic sclerosis (scleroderma)
5141
Juvenile systemic sclerosis (scleroderma)Classification, clinicaland diagnosis 5158
Juvenile systemic sclerosis (scleroderma)Assessment and approaches to 5181
Pathogenesis, clinical manifestations, and diagnosis of morphea (localizedin 5203
Treatment of morphea (localized scleroderma) in adults 5238
Localized scleroderma in childhood 5248
Scleredema 5291
Scleromyxedema 5312
Nephrogenic systemic fibrosis-nephrogenic fibrosing dermopathy inkidney 5340
Evaluation of adults with cutaneous lesions of vasculitis 5367
Overview of cutaneous small vessel vasculitis 5400
Management of adults with idiopathic cutaneous small vessel vasculitis 5407
Urticarial vasculitis 5420
Livedoid vasculopathy 5453
IgA vasculitis (Henoch-Schönlein purpura)Clinical manifestations and 5472
IgA vasculitis (Henoch-Schönlein purpura)Management 5496
Erythema induratum (nodular vasculitis) 5505
Erythema elevatum diutinum 5523
Acanthosis nigricans 5545
Anetoderma 5578
Cutaneous polyarteritis nodosa 5596
Cutaneous xanthomas 5615
Erythema annulare centrifugum 5658
Erythema nodosum 5689
Erythromelalgia 5713
Localized lichen myxedematosus 5729
Palisaded neutrophilic and granulomatous dermatitis 5746
Necrobiosis lipoidica 5759
Panniculitis Recognition and diagnosis 5791
Pathogenesis of Raynaud phenomenon 5826
Perforating dermatoses 5837
Pernio (chilblains) 5878
Pigmented purpuric dermatoses (capillaritis) 5896
Calcinosis cutis Etiology and patient evaluation 5942
Calcinosis cutisManagement 5984
Neutrophilic dermatoses 5991
Pyoderma gangrenosum Pathogenesis, clinical features, and diagnosis 6055
Pyoderma gangrenosum Treatment and prognosis 6082
Sweet syndrome 6098
Cutaneous manifestations of amyloidosis 6138
Cutaneous manifestations of graft-versus-host disease (GVHD) 6181
Cutaneous manifestations of internal malignancy 6241
Parapsoriasis (small plaque and large plaque parapsoriasis) 6306
Classification of primary cutaneous lymphomas 6316
Approach to the patient with a diagnosis of atypical lymphocytic infiltrate of
6324
Variants of mycosis fungoides 6332
Primary cutaneous T cell lymphomas, rare subtypes 6346
Clinical manifestations, pathologic features, and diagnosis of peripheral T
not otherwise specified 6358
Treatment of early stage (IA to IIA) mycosis fungoides 6367
Treatment of advanced stage (IIB to IV) mycosis fungoides 6382
Treatment of Sézary syndrome 6402
Primary cutaneous anaplastic large cell lymphoma 6423
Clinical manifestations, pathologic features, and diagnosis of systemiclarge
6435
Jessner's lymphocytic infiltrate 6448
Cutaneous B cell pseudolymphomas 6453
Cutaneous T cell pseudolymphomas 6460
Eosinophilic cellulitis (Wells syndrome) 6470
Lymphomatoid papulosis 6480
Primary cutaneous follicle center lymphoma 6498
Primary cutaneous large B cell lymphoma, leg type 6509
Primary cutaneous marginal zone lymphoma 6518
Angiolymphoid hyperplasia with eosinophilia and Kimura disease 6531
Overview of benign lesions of the skin 6542
PruritusEtiology and patient evaluation 6561
Pruritus Overview of management 6577
Oral lesions 6589
Recurrent aphthous stomatitis 6612
Oral lichen planus Pathogenesis, clinical features, and diagnosis 6626
Oral lichen planusManagement and prognosis 6635
Oral leukoplakia 6646
Vulvar dermatitis 6653
Vulvar lichen sclerosus 6667
Extragenital lichen sclerosus 6686
Primary focal hyperhidrosis 6697
Bromhidrosis 6713
Chromhidrosis 6721
Fox-Fordyce disease (apocrine miliaria) 6728
Miliaria 6737
Granular parakeratosis 6746
Granuloma annulare 6754
Granuloma faciale 6771
Dermatoses of pregnancy 6781
Erythema multiformePathogenesis, clinical features, and diagnosis 6796
Erythema multiforme Management 6807
Grover's disease (transient and persistent acantholytic dermatosis) 6817
Hidradenitis suppurativaPathogenesis, clinical features, and diagnosis 6822
Hidradenitis suppurativa Treatment 6835
Surgical management of hidradenitis suppurativa 6854
Keloids and hypertrophic scars 6864
Laser therapy for hypertrophic scars and keloids 6878
Mastocytosis (cutaneous and systemic)Epidemiology, pathogenesis, and
6892
Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in children 6906
Mastocytosis (cutaneous and systemic)Evaluation and diagnosis in adults 6918
Treatment and prognosis of cutaneous mastocytosis 6936
Systemic mastocytosisDetermining the subtype of disease 6946
Indolent and smoldering systemic mastocytosis Management and prognosis 6957
Advanced systemic mastocytosisManagement and prognosis 6971
Cutaneous manifestations of amyloidosis 6989
Necrobiosis lipoidica 7001
Atrophoderma of Pasini and Pierini 7015
Paronychia 7022
Pernio (chilblains) 7032
Skin picking (excoriation) disorder and related disorders 7041
Skin biopsy techniques 7058
Subcorneal pustular dermatosis 7073
Technique of incision and drainage for skin abscess 7084
Management of ingrown toenails 7101
Office-based dermatologic diagnostic procedures 7115
Intralesional corticosteroid injection 7124
Topical corticosteroidsUse and adverse effects 7131
Pyogenic granuloma (lobular capillary hemangioma) 7143
Acute genital ulceration (Lipschutz ulcer) 7191
Vesicular, pustular, and bullous lesions in the newborn and infant 7209
Aplasia cutis congenita 7283
Approach to the patient with a scalp disorder 7306
Approach to the patient with pustular skin lesions 7395
Atypical exanthems in children 7457
Candida infections in children 7486
Capillary malformations (port wine stains) and associated syndromes 7521
Condylomata acuminata (anogenital warts) in children 7553
Contact dermatitis in children 7572
Cradle cap and seborrheic dermatitis in infants 7600
Cutaneous developmental anomalies in the newborn and infant 7627
Diaper dermatitis 7656
Epidermal nevus and epidermal nevus syndrome 7702
Evaluation of purpura in children 7734
Gianotti-Crosti syndrome (papular acrodermatitis) 7769
IgA vasculitis (Henoch-Schonlein purpura)Clinical manifestations and 7796
IgA vasculitis (Henoch-Schonlein purpura)Management 7820
Infantile hemangiomasEpidemiology, pathogenesis, clinical features, and 7829
Infantile hemangiomasEvaluation and diagnosis 7858
Infantile hemangiomasManagement 7879
Juvenile dermatomyositis and polymyositisEpidemiology, pathogenesis, and
7907
Juvenile dermatomyositis and polymyositisDiagnosis 7920
Juvenile dermatomyositis and polymyositisTreatment, complications, and 7938
Juvenile systemic sclerosis (scleroderma)Classification, clinicaland diagnosis 7956
Juvenile systemic sclerosis (scleroderma)Assessment and approaches to 7979
Juvenile xanthogranuloma (JXG) 8001
Klippel-Trenaunay syndromeClinical manifestations, diagnosis, and 8027
Localized scleroderma in childhood 8049
Melanoma in children 8092
Mycoplasma pneumoniae-induced rash and mucositis (MIRM) 8120
Neonatal and infantile erythroderma 8146
Nevus sebaceus and nevus sebaceus syndrome 8189
Overview of vulvovaginal complaints in the prepubertal child 8217
PHACE syndrome 8248
Rapidly involuting congenital hemangioma (RICH) and noninvoluting
NICH) 8265
Sclerema neonatorum 8290
Skin lesions in the newborn and infant 8301
Skin nodules in newborns and infants 8338
Sturge-Weber syndrome 8371
Subcutaneous fat necrosis of the newborn 8387
Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-
8397
Vascular lesions in the newborn 8424
Vasculitis in children Evaluation overview 8458
Venous malformations 8488
Overview of cutaneous photosensitivityPhotobiology, patient evaluation, and 8513
Photosensitivity disorders (photodermatoses)Clinical manifestations,and 8522
Polymorphous light eruption 8552
PorphyriasAn overview 8571
Porphyria cutanea tarda and hepatoerythropoietic porphyriaPathogenesis,
and diagnosis 8598
Porphyria cutanea tarda and hepatoerythropoietic porphyria Management
8618
Congenital erythropoietic porphyria 8630
Variegate porphyria 8646
Erythropoietic protoporphyria and X-linked protoporphyria 8666
Hereditary coproporphyria 8687
Pseudoporphyria 8712
Sunburn 8741
Selection of sunscreen and sun-protective measures 8778
Targeted phototherapy 8794
UVB therapy (broadband and narrowband) 8804
UVA1 phototherapy 8822
Psoralen plus ultraviolet A (PUVA) photochemotherapy 8829
The genodermatoses An overview 8851
Epidemiology, pathogenesis, classification, and clinical features ofbullosa 8863
Diagnosis of epidermolysis bullosa 8882
Overview of the management of epidermolysis bullosa 8892
Overview and classification of the inherited ichthyoses 8910
Ichthyosis vulgaris 8921
Autosomal recessive congenital ichthyosis 8929
Recessive X-linked ichthyosis 8941
The dyschromatoses 8952
Birt-Hogg-Dube syndrome 8960
Brooke-Spiegler syndrome (CYLD cutaneous syndrome) 8971
Buschke-Ollendorff syndrome 8980
Carney complex 8990
Cutaneous leiomyomatosis 8999
Cutis verticis gyrata 9007
Darier disease 9013
Ectodermal dysplasias 9025
Epidermodysplasia verruciformis 9062
Focal dermal hypoplasia (Goltz syndrome) 9070
Hailey-Hailey disease (benign familial pemphigus) 9077
Hereditary palmoplantar keratodermas 9087
Hermansky-Pudlak syndrome 9106
Hutchinson-Gilford progeria syndrome 9114
Incontinentia pigmenti 9122
Keratinopathic ichthyoses 9132
Kindler syndrome 9140
Lipoid proteinosis 9150
Muir-Torre syndrome 9159
Netherton syndrome 9165
Nevoid basal cell carcinoma syndrome (Gorlin syndrome) 9177
Oculocutaneous albinism 9193
Pachyonychia congenita 9208
Peeling skin syndromes 9217
Piebaldism 9228
Pigmentary mosaicism (hypomelanosis of Ito) 9237
Tumor protein p63-related disorders 9248
Xeroderma pigmentosum 9254
Skin biopsy techniques 9267
Fusiform - elliptical excision - UpToDate.pdf (p.16-24) 9282
Minor dermatologic procedures 9291
Skin surgeryPrevention and treatment of complications 9307
Mohs surgery 9318
Anatomic danger zones in cutaneous surgery of the head and neck 9332
Nail biopsy Indications and techniques 9341
Principles and overview of nail surgery 9348
Nail avulsion and chemical matricectomy 9362
Overview of botulinum toxin for cosmetic indications 9371
Botulinum toxin for cosmetic indications Treatment of specific sites 9386
Injectable soft tissue fillersOverview of clinical use 9398
Injectable soft tissue fillers Permanent agents 9409
Injectable soft tissue fillersTemporary agents 9417
Anatomic danger zones for facial injection of soft tissue fillers 9428
Chemical peels Principles 9438
Chemical peels Procedures and complications 9446
Principles of laser and intense pulsed light for cutaneous lesions 9459
Laser and light therapy for cutaneous hyperpigmentation 9470
Laser and light therapy for cutaneous vascular lesions 9485
Ablative laser resurfacing 9503
Nonablative skin resurfacing 9518
Photodynamic therapy 9533
Laser therapy of lower extremity telangiectasias, reticular veins, and small
9547
sclerotherapy techniques for lower extremity veins 9555
Topical skin-lightening agents Complications associated with misuse 9573
Management of acne scars 9580
Photoaging 9598
Postinflammatory hyperpigmentation 9611
Removal of unwanted hair 9623
Striae distensae (stretch marks) 9631
Tattoo removal 9647
What's new in dermatology 9657
Overview of dermoscopy - UpToDate
uptodate.com/contents/overview-of-dermoscopy/print
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2020. | This topic last updated: Sep 09, 2019.
INTRODUCTION Dermoscopy is a noninvasive, in vivo technique

primarily used for the examination of pigmented skin lesions; however, it can also assist observers
in assessing lesions with little to no pigment [1]. Dermatoscopy, epiluminescence microscopy,
incident light microscopy, and skin-surface microscopy are synonyms.
Dermoscopy is performed with a handheld instrument called a dermatoscope. The procedure allows
for the visualization of subsurface skin structures in the epidermis, at the dermoepidermal junction,
and in the upper dermis; these structures are usually not visible to the naked eye [2-4]. The
dermoscopic images may be photographed or recorded digitally for storage or sequential analysis.
The basic principles of dermoscopy will be discussed in this topic. The dermoscopic diagnosis of
skin lesions, including those in special anatomic areas (eg, face, volar surfaces of palms and soles,
mucosal surfaces, and glabrous skin in genital area), dermoscopy of nail pigmentation, and
algorithms used for skin cancer triage are discussed separately.
●(See "Dermoscopic evaluation of skin lesions".)
●(See "Dermoscopy of pigmented lesions of the palms and soles".)
●(See "Dermoscopy of facial lesions".)
●(See "Dermoscopy of mucosal lesions".)
●(See "Dermoscopy of nail pigmentations".)
●(See "Overview of dermoscopy of the hair and scalp".)
●(See "Dermoscopic algorithms for skin cancer triage".)
2
DERMOSCOPY PHYSICS Ambient light is reflected,
scattered, or absorbed by objects. Under normal conditions, most of the light is reflected by the skin
surface because of the higher refractive index (RI) of the stratum corneum (1.55) compared with that
of the air (1.0).
Reduction of skin surface reflection allows for the visualization of deeper epidermal and dermal
structures. This reduction can be achieved by affixing a glass plate (RI: 1.52) to the stratum corneum
(RI: 1.55) and using an RI-matched immersion fluid as an interface or by using polarizing filters [5-7].
Several immersion fluids have been used, including water, alcohols (ethanol and isopropanol), oils
(mineral oil, immersion oil, and olive oil), and water-soluble gels (ultrasound gel, cosmetic gels).
Alcohols (in particular ethanol 70%) are the preferred immersion liquid due to their low viscosity,
amphiphilic properties (ie, both water and lipid soluble), disinfectant capabilities, and image clarity.
However, on some specific sites such as the mucosae and areas around the eyes and nails, water-
soluble gels are preferred over alcohol since they are noncaustic and have higher viscosity [6].
Alternatively, reduction of the skin surface reflection can be achieved by using polarized light [8].
Polarized light dermoscopy utilizes two orthogonally placed filters in a process called cross-
polarization (figure 1). After reaching the skin surface, part of the polarized light is reflected by the
stratum corneum maintaining its polarization, whereas part enters the skin and is scattered back
from the deeper layers, losing its polarization. The light reflected by the skin surface, responsible for
the glare of the skin, is blocked by the cross-polarized filter, since this light maintains its polarization.
The backscattered light from the deeper layers passes through the cross-polarized filter since some
of the polarized light has lost its angle of polarization. This makes the subsurface structures visible
to the eye [7-9].
TYPES OF DERMATOSCOPES Dermatoscopes

consist of a transilluminating light source and magnifying optics. The most commonly used
dermatoscopes have a 10-fold magnification [4].
Three types of dermatoscopes are available:
●Nonpolarized light, contact
●Polarized light, contact
●Polarized light, noncontact
Nonpolarized and polarized light dermoscopy provide complementary information (table 1)

[5,7,9,10]. Deeper structures are more conspicuous with polarized dermoscopy; in contrast,
superficial structures are more conspicuous with nonpolarized dermoscopy. For example, epidermal
structures (eg, milia cysts and comedo-like openings in seborrheic keratoses and blue-white veil due
to orthokeratosis) are more conspicuous with nonpolarized dermoscopy, whereas blood vessels and
3
shiny, white structures (shiny, white lines; shiny, white blotches; and strands and rosettes) are better
visualized with polarized light dermoscopy [5,7,11]. Structures visible in one mode and not in the
other will blink when viewed with dermatoscopes that can toggle between polarized and
nonpolarized light [12].
COLORS AND STRUCTURES The visualization of

colors and structures in the epidermis and papillary dermis has generated a new terminology for the
morphologic description of skin lesions [13]. A histologic correlation has been established for most
of the structures seen with dermoscopy [14-17].
Colors — The colors seen with dermoscopy include yellow, red, brown, blue, gray, black, and
white (figure 2D) [18,19]. Melanin is the most important chromophore in pigmented lesions. The
color of melanin as seen on the surface of the skin depends upon its concentration and its
localization in the skin; it usually appears black if located in the stratum corneum, brown if in the
epidermis and superficial dermis, and gray/blue to blue if in the dermis. The color red is determined
by vascularity; a thrombus will appear black. White color is associated with collagen/fibrosis, and
yellow is associated with keratin or sebum.
Structures — The structures visualized in skin lesions are determined by the distribution
and amount of melanin, keratin, collagen, and vascularity [10,13,18,20-22].
●Pigment network, negative network, angulated lines, streaks, aggregated or peripheral rim of
globules, and homogeneous blue pigmentation are the hallmark of melanocytic lesions (picture 1A-
C).
●Arborizing vessels, leaf-like structures, spoke wheel-like structures, concentric structures, large
blue/gray ovoid nests, multiple blue/gray nonaggregated globules, shiny white blotches and strands,
ulceration, and multiple erosions are features of basal cell carcinomas (BCCs) (picture 2).
●Glomerular vessels, white circles, rosettes, white/yellow scale, brown circles, and brown
dots/globules aligned radially are structures of squamous cell carcinomas (picture 3).
●Milia-like cysts, comedo-like openings, finger print-like structures, moth-eaten borders, gyri and
sulci, and sharp demarcation are characteristic of seborrheic keratoses (picture 4).
Red or blue/purple/black lagoons are seen in cherry angiomas or angiokeratomas (picture 5). (See
"Dermoscopic evaluation of skin lesions", section on 'First step: Melanocytic versus
nonmelanocytic'.)
●Atypical pigment network, blue-white veil, atypical vascular pattern, irregular streaks, atypical dots
or globules, angulated lines creating a zigzag pattern or polygons, and regression structures are
some of the features associated with melanoma (picture 6A-C). (See "Dermoscopic evaluation of
skin lesions", section on 'Second step: Nevus versus suspicious lesion or melanoma'.)
4
A detailed description of the dermoscopic structures visualized in melanocytic and nonmelanocytic
lesions and their histologic correlates is provided in the figures (figure 2A-C).
The diagnostic criteria for benign and malignant melanocytic and nonmelanocytic skin lesions are
discussed separately. (See "Dermoscopic evaluation of skin lesions".)
Vascular structures — In amelanotic and hypomelanotic lesions, the vascular

structures (morphology, distribution, and arrangement) may provide the only clues to the diagnosis.
In pigmented lesions, the pigmented structures provide the primary clue to the diagnosis, and
vascular morphology provides additional secondary clues to the diagnosis [23,24].
Noncontact polarized light is the preferred type of dermatoscope for the visualization of blood
vessels. However, if a contact dermatoscope is utilized, an ultrasound gel should be used as a liquid
interface since the gel acts as a cushion and reduces the need for pressure being applied to the skin,
preventing the blanching of the vessels.
The dermoscopic evaluation of vascular structures includes morphology (dotted, serpentine,

comma, corkscrew, looped or hairpin, glomerular or coiled, arborizing or branched, and branched
vessels with rounded endings), distribution (focal, diffuse, central, peripheral, or random),
arrangement (crown, string of pearls, clustered, or radial), and presence of a white or pink halo (table
2A-B) [21,23,25-30].
Although some vessel morphologies are most commonly associated with certain types of lesions
(eg, arborizing vessels are common in BCC), the presence of a given vessel morphology is not
exclusive to a particular diagnosis. For example, dotted vessels can be seen in melanocytic tumors,
squamous cell carcinoma (picture 3), BCC, porokeratosis, clear cell acanthoma, and psoriasis
[25,28,29,31,32]. Similarly, glomerular vessels are most commonly associated with squamous cell
carcinoma/Bowen disease (picture 3), but they can also be seen in clear cell acanthoma.
Polymorphous vessels are typically associated with melanoma but can also be seen in BCC [28].
Arborizing vessels are commonly seen in BCC, but they can also be seen in melanoma and
intradermal nevi. Hairpin vessels are commonly associated with seborrheic keratoses, although they
can also be seen in melanoma. Despite this overlap, the positive predictive value for a given vessel
morphology can guide the clinician to the correct diagnosis if the clinical context is carefully
considered (table 2A-B). (See "Dermoscopic evaluation of skin lesions", section on 'Second step:
Nevus versus suspicious lesion or melanoma'.)
CLINICAL ROLE OF DERMOSCOPY The

importance of dermoscopy in the in vivo diagnosis of melanoma is well recognized [33], following
the identification of a large set of dermoscopic features in benign and malignant lesions together
with their histopathologic correlates [16-18,34].
5
Dermoscopy requires some formal training to be effectively practiced. Online tutorials on
dermoscopy can be found at www.dermnetnz.org/doctors/dermoscopy-course/introduction.html,
www.dermoscopy-ids.org/index.php/education/podcasts, www.genomel.org/dermoscopy, or
www.dermoscopedia.org.
Cross-sectional studies, randomized trials, meta-analyses, and a 2018 Cochrane systematic review
have indicated that dermoscopic examination has a higher discriminatory power than naked-eye
examination to detect skin cancer, including melanoma either in experimental or real-life clinical
settings [13,33,35-43]. For clinicians with at least minimal training in dermoscopy, the addition of this
procedure to the clinical examination increases the accuracy of the in vivo diagnosis of skin cancer
and reduces the number of unnecessary biopsies [36] (see "Evaluating diagnostic tests"). In fact, 86
percent of dermoscopy users from 32 European countries reported that dermoscopy increased their
melanoma detection rate, and 70 percent reported that dermoscopy decreased the number of
unnecessary biopsies of benign lesions they performed [44].
Diagnostic accuracy for melanoma — Three meta-analyses

and a 2018 Cochrane systematic review have shown that dermoscopy improves diagnostic
accuracy for melanoma over naked-eye examination [33,37-39]. In one of these meta-analyses
including nine studies performed in clinical settings, the authors reported an odds ratio for the
diagnosis of melanoma of 9 (95% CI 1.5-54.6) for dermoscopy plus clinical examination, compared
with clinical examination alone [38]. The summary sensitivity was 90 percent (95% CI 80-95) and the
specificity was 90 percent (95% CI 57-98) for dermoscopy plus clinical examination; sensitivity was
71 percent (95% CI 59-82) and specificity was 81 percent (95% CI 48-95) for clinical examination
alone. Sensitivity improved without a decrease in specificity, meaning that the higher rate of
melanoma detection was not associated with a concomitant increase in the number of unnecessary
excisions of benign lesions.
Several factors may affect the diagnostic performance of dermoscopy:
●Experience of the examiner
●Diagnostic algorithm and threshold for a positive test
●Prevalence of melanoma in the patient population examined
●Clinical context and patient-related factors [45,46]
In a systematic review of 27 studies performed in clinical and experimental settings, the diagnostic
accuracy of dermoscopy was lower for inexperienced examiners compared with experts, and was
inversely proportional to the prevalence of melanoma in the sample [39]. The degree of experience
improved the diagnostic accuracy of complex algorithms, such as pattern analysis, whereas it did
not affect the performance of simpler algorithms such as the ABCD rule of dermoscopy.
6
Two clinical trials performed in primary care settings have shown that a short training in
dermoscopy enables nondermatologists to use simplified diagnostic algorithms and improve their
accuracy in the diagnosis of melanoma [36,47]. In one trial, 73 primary care physicians received one-
day training in skin cancer detection and dermoscopy and were subsequently randomly assigned to
use a polarized light handheld dermatoscope or the naked eye to assess the pigmented lesions of
their patients for a period of 16-months [36]. All patients were also independently evaluated by
expert dermatologists. The sensitivity for the referral of suspicious lesions was significantly higher
in the dermoscopy group, compared with the naked-eye examination group (79 and 54 percent,
respectively), without difference in specificity (71 and 72 percent, respectively).
A 2019 systematic review of 23 randomized and observational studies performed in primary care
settings confirmed that dermoscopy, with appropriate training, was associated with improved
diagnostic accuracy for melanoma and benign lesions and reduced unnecessary excisions and
referrals [48]. However, the minimal amount of training required to achieve competence in
dermoscopy has not been determined.
Indications — Dermoscopy aids in the evaluation of pigmented and nonpigmented skin

lesions and helps in the decision-making process as to whether or not a biopsy is warranted to rule
out skin cancer. Dermoscopic examination is especially useful for patients with multiple common
and/or atypical nevi who are at increased risk of melanoma. In those patients, dermoscopic
examination of their nevi helps identify suspicious lesions not found with naked-eye preselection
[49].
Although it will be beneficial to examine as many lesions as possible in patients with multiple nevi,
special attention should be paid to the following [50]:
●Any new or changing lesion
●Any lesions that are a concern (including symptomatically) for the patient
●Outlier skin lesions that are clinically different from the other lesions (the "ugly duckling" sign)
●Lesions that appear clinically suspicious for skin cancer
In addition, dermoscopy has been shown to be a useful tool in the evaluation of other dermatologic
entities, such as inflammatory and infectious diseases and hair and nail disorders. (See
"Dermoscopy of nail pigmentations" and "Dermoscopy of nonpigmented nail lesions".)
Purposes — Dermoscopy may have different purposes depending upon the clinical
setting in which it is used.
In general dermatology and in primary care practices, the primary purpose of dermoscopy is the
evaluation of pigmented and nonpigmented skin lesions to decide whether or not a lesion should be
biopsied or referred. For this purpose, a minimal amount of training is needed [36,51-53].
7
In specialized dermatologic settings, which include management of high-risk patients (eg, patients
with the dysplastic/atypical nevus syndrome), the main purposes of dermoscopy are to differentiate
early melanoma from benign skin lesions and to minimize the unnecessary excision of benign nevi.
Subtle signs of melanoma may be detected on dermoscopy by experienced clinicians before they
become clinically evident to the naked eye.
Digital dermoscopy may also be useful for long- or short-term follow-up of patients with multiple
common and atypical nevi [54-59]. Sequential digital dermoscopy imaging (SDDI) involves the
capture and comparison of sequential dermoscopic images of one or more melanocytic lesions for
short-term (three to four months) or long-term (6 to 12 months) surveillance. Several studies have
indicated that SDDI has high sensitivity and specificity for detecting in situ or thin invasive
melanomas that are difficult to diagnose otherwise [56-58,60]. One study showed that in the primary
care setting the combination of dermoscopy and short-term digital monitoring reduced the excision
or referral of benign pigmented skin lesions by 56 percent and increased the sensitivity for
diagnosing melanoma from 38 to 72 percent [53].
In addition to its conventional use, dermoscopy has also been shown to improve the clinical
diagnosis in other fields of dermatology, including infections/infestations as well as inflammatory
skin diseases and hair diseases [61].
Benefits
●Dermoscopy improves the diagnosis of melanocytic lesions in clinical practice. Several meta-
analyses of studies performed in experimental and clinical settings have indicated that dermoscopy
increases the sensitivity for the diagnosis of melanoma without decreasing the specificity, compared
with the naked-eye examination [33,37-39].
●Dermoscopy improves the confidence in the diagnosis of benign pigmented lesions, reducing the
number of unnecessary biopsies. In a randomized trial, dermatologists using dermoscopy,
compared with those using naked-eye examination, referred fewer patients for excision of benign
lesions (9 versus 16 percent) without missing malignant lesions [40]. Several retrospective studies
examined the numbers of excised benign and malignant lesions in dermatologic practices before
and after the introduction of dermoscopy [62,63]. In one study, the ratio between benign and
malignant excised lesions decreased from 18:1 to 4:1 over a three-year period [62].
●Dermoscopy allows digital surveillance and monitoring of melanocytic lesions in patients with
multiple common or atypical nevi [54-59].
●Dermoscopy is useful in the diagnosis and differentiation of nonmelanocytic benign and malignant
tumors such as basal cell carcinoma, dermatofibroma, seborrheic keratosis, and hemangioma
[10,21,25,27].
Limitations
8
●The diagnostic accuracy of dermoscopy may be poorer than naked-eye examination when
performed by individuals with limited experience in the interpretation of dermoscopy [39].
Dermoscopy requires at least a minimal amount of training to provide advantage over the clinical
examination [64]. The correct interpretation of dermoscopic images depends upon knowledge of the
significance of colors and structures manifested by a lesion. In addition, examining a lesion with
reference to the clinical context and comparison to surrounding lesions is also important for
rendering a correct diagnosis [45].
●Even in expert hands, dermoscopy may fail to recognize melanomas that lack specific dermoscopic
criteria (featureless melanomas) or melanomas masquerading as inflammatory or benign lesions,
such as Spitzoid melanomas, amelanotic melanomas, nodular melanomas, nevoid melanomas,
desmoplastic melanomas, or verrucous melanomas [65,66].
●Although digital dermoscopic images are suitable for distance consultation, interpretation of
dermoscopic photographs may be slightly less accurate than in-vivo dermoscopy [67,68].
SOCIETY GUIDELINE LINKS Links to society and

government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Dermoscopy".)
SUMMARY AND
RECOMMENDATIONS
●Dermoscopy is a noninvasive, in vivo technique primarily used for the examination of skin lesions.
A handheld instrument called a dermatoscope, consisting of a light source and magnifying optics,
allows the visualization of subsurface skin structures that are usually not visible to the naked eye.
(See 'Dermoscopy physics' above and 'Types of dermatoscopes' above.)
●Colors and structures visualized in skin lesions are mainly related to the amount, distribution, and
localization of melanin, vasculature structures, collagen, and keratin (figure 2A-D and table 2A-B).
●Pigment network, negative network, angulated lines, streaks, aggregated globules or peripheral rim
of globules, and homogeneous, blue pigmentation are the hallmark of melanocytic lesions (picture
1A-C). Arborizing vessels, leaf-like structures, spoke wheel-like structures/concentric globules, ovoid
or round blue/gray nonaggregated areas, and shiny white blotches and strands are features of basal
cell carcinomas (picture 2). Glomerular vessels, white circles, rosettes, white/yellow scale crust,
brown circles, and brown dots/globules aligned radially are structures of squamous cell carcinomas.
Milia-like cysts, comedo-like openings, and gyri and sulci are characteristic of seborrheic keratoses
(picture 4), whereas red or blue/purple/black lagoons are seen in cherry angiomas or
angiokeratomas (picture 5). (See "Dermoscopic evaluation of skin lesions", section on 'First step:
Melanocytic versus nonmelanocytic'.)
9
●Atypical pigment network, negative network, atypical vascular pattern, irregular streaks, atypical
dots or globules, regression structures, blue-white veil, angulated lines forming a zigzag pattern or
polygons (such as rhomboids), and peripheral tan structureless areas are some of the features
associated with melanoma (picture 6A-C). (See "Dermoscopic evaluation of skin lesions", section on
'Second step: Nevus versus suspicious lesion or melanoma'.)
●For clinicians who have been formally trained, the addition of dermoscopy to clinical examination
improves the sensitivity and specificity of the in vivo diagnosis of skin cancer, including melanoma.
In particular, dermoscopy improves the confidence in the diagnosis of benign lesions and reduces
the number of unnecessary biopsies. However, even in expert hands, dermoscopy may fail to
recognize melanomas lacking specific dermoscopic features. (See 'Diagnostic accuracy for
melanoma' above and 'Benefits' above and 'Limitations' above.)
●Dermoscopy may be useful in patients with multiple common or atypical nevi who are at increased
risk for melanoma. Special attention should be paid to lesions with reported history of change and
lesions appearing clinically different from the other lesions (the "ugly duckling" sign) or clinically
suspicious of melanoma. (See 'Indications' above.)
10
Dermoscopic evaluation of skin lesions
uptodate.com/contents/dermoscopic-evaluation-of-skin-lesions/print
INTRODUCTION Dermoscopy is a noninvasive, in vivo technique

primarily used for the examination of pigmented and nonpigmented skin lesions. Dermatoscopy,
epiluminescence microscopy, incident light microscopy, and skin-surface microscopy are synonyms.
Dermoscopy is performed with a handheld instrument called a dermatoscope. The procedure allows
for the visualization of subsurface skin structures in the epidermis, dermoepidermal junction, and
superficial dermis; these structures are not visible to the naked eye [1-3].
Dermoscopic diagnosis involves the recognition of specific structures, or their absence, to rule out
or confirm a given diagnosis. From a cognitive perspective, this task may be accomplished using a
bottom-up or a top-down strategy. In the bottom-up approach, the observer performs a visual search
for salient details (individual features) to arrive at a diagnosis, whereas in the top-down strategy the
observer recognizes the general context, generates a hypothesis of the likely clinical diagnosis, and
performs a targeted dermoscopic search for specific features to confirm the presumed clinical
diagnosis [4].
This topic will review several algorithms and scoring systems that use mainly a top-down strategy to
help clinicians distinguish melanocytic lesions from nonmelanocytic lesions (First Step) and
differentiate nevus from melanoma or lesions suspicious for melanoma (Second Step). The general
principles of dermoscopy, dermoscopic structure terminology, dermoscopic evaluation of skin
lesions, and the dermoscopic evaluation of facial, mucosal, and acral volar skin lesions are
discussed separately. Dermoscopy of nail pigmentation and dermoscopic algorithms for skin cancer
triage are also discussed separately.
●(See "Overview of dermoscopy".)
11
●(See "Dermoscopy of pigmented lesions of the palms and soles".)
THE TWO-STEP ALGORITHM FOR

SKIN LESION EVALUATION The two-step dermoscopy
algorithm forms the foundation for the dermoscopic evaluation of skin lesions. It was introduced by
the panel of the Consensus Internet Meeting on Dermoscopy in 2003 and has since undergone
several modifications (algorithm 1) [5-7].
In the first step, the observer decides whether a lesion is melanocytic or nonmelanocytic by looking
for the presence or absence of specific features. In addition to differentiating melanocytic lesions
from nonmelanocytic lesions, the first step of the two-step algorithm also serves as an aid to
correctly sub-classify the nonmelanocytic lesions [5,6]. (See "Overview of dermoscopy".)
The second step is intended only for lesions classified as melanocytic. Melanocytic lesions are
further evaluated to differentiate nevi from suspicious lesions or melanoma by using one of several
algorithms created for this purpose [8-12]. (See 'Second step: Nevus versus suspicious lesion or
melanoma' below.)
FIRST STEP: MELANOCYTIC

VERSUS NONMELANOCYTIC One approach to
differentiate melanocytic from nonmelanocytic lesions is based on an eight-level criterion ladder [6].
In this approach the observer evaluates the lesion for the presence or absence of specific
dermoscopy criteria in an ordered sequence (figure 1).
The lesion is first examined for the presence of structures that are typical of melanocytic lesions. If
none of those structures are found, the lesion is examined for the presence of features of
dermatofibroma, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, or
angioma/hemangioma/angiokeratoma.
Lesions lacking features to classify them as one of the aforementioned categories are evaluated for
the presence of blood vessels. The morphology, distribution, and arrangement of blood vessels can
assist in classifying these lesions into melanocytic or nonmelanocytic tumors.
12
Lesions lacking features that would allow their characterization as melanocytic or nonmelanocytic
lesions are classified as featureless (feature poor, nonspecific, nonclassifiable, or structureless)
lesions. Melanoma needs to be ruled out for all featureless lesions. (See 'Featureless lesions
(feature poor, nonspecific, nonclassifiable, or structureless)' below and 'Vascular structures in skin
lesions' below.)
Criteria for melanocytic lesions — The structures that

characterize melanocytic lesions include (figure 2 and picture 1A-C) [6,13] (see "Overview of
dermoscopy", section on 'Colors and structures'):
●Pigment network
●Angulated lines
●Negative network
●Aggregated (three or more) or peripheral rim of globules
●Streaks (pseudopods and radial streaming)
●Homogeneous blue pigmentation
●Parallel pattern (for lesions on palm and soles)
●Pseudonetwork (facial skin)
Lesions presenting with any of the above structures are classified as melanocytic and will proceed
to the second step to differentiate nevi from suspicious lesions or melanoma. (See 'Second step:
Nevus versus suspicious lesion or melanoma' below.)
Dermatofibroma — While the presence of a network is indicative of a melanocytic

lesion, there are exceptions. One such exception is exemplified by dermatofibroma, which is a
nonmelanocytic lesion displaying a delicate pigment network at its perimeter with central scar-like
area containing shiny white lines when seen with polarized light (picture 2) [14,15]. The delicate grid-
like network in dermatofibroma often takes on the appearance of ring-like globules as it moves
towards the central scar-like area. An additional clue to the diagnosis of dermatofibroma can be
obtained by palpation, which will reveal a firm lesion that dimples inward when lateral pressure,
directed towards the lesion, is applied at the lesion's edge (picture 3). (See "Overview of benign
lesions of the skin", section on 'Dermatofibroma'.)
Criteria for basal cell carcinoma — The diagnostic criteria for

basal cell carcinoma (BCC) include the lack of a pigment network and the presence of at least one
positive feature for BCC (figure 3 and picture 4) [16]:
13
●Arborizing vessels
●Leaf-like areas
●Large blue-gray ovoid nests
●Multiple blue-gray, nonaggregated globules
●Spoke-wheel structures, including concentric globules
●Ulceration and small erosions
●Shiny white blotches and strands (seen with polarized dermoscopy) [17]
Additional clues in BCC are the presence of multiple in-focus, fine brown to gray dots and fine short
superficial telangiectasia.
Criteria for squamous cell carcinoma — The diagnostic

criteria for squamous cell carcinoma (SCC) include (figure 4 and picture 5A-B) [18-20]:
●Glomerular vessels, usually focally distributed
●Rosettes
●White circles or keratin pearls
●Yellow scale
●Brown dots/globules aligned in straight, radially oriented lines, usually located towards the
periphery
●Brown circles
Criteria for seborrheic keratoses — Most of the dermoscopic

features of seborrheic keratoses are related to the papillomatous growth of the epidermis and the
abundance of keratin in these tumors, and include (figure 5 and picture 6) [21]:
●Multiple milia-like cysts (three or more).
●Comedo-like openings.
●Moth-eaten borders.
●Gyri and sulci (also known as fissures and ridges) creating a cerebriform pattern. At times, these
gyri and sulci can create a pattern resembling a network.
●Fingerprint-like structures.
14
●Hairpin vessels surrounded by a white halo.
Milia-like cysts can also be seen occasionally in other lesions such as BCCs and in melanocytic nevi,
particularly in congenital nevi. Additional clues for seborrheic keratosis include sharp demarcation,
network-like structure (due to pigment surrounding comedo-like and ostial openings), and a negative
"wobble sign" [22]. The wobble sign allows differentiation of an epidermal keratinocytic lesion from a
lesion with a dermal component such as a compound or intradermal nevus.
Criteria for hemangioma/angioma and

angiokeratoma — Red, purple, or blue-black lagoons are the diagnostic criteria for
hemangiomas/angiomas and angiokeratomas. They are small, well demarcated areas, often
separated by septa, corresponding to dilated blood vessels in the dermis (picture 7).
Vascular structures in skin lesions — Both melanocytic and

nonmelanocytic lesions can present as hypomelanotic or amelanotic lesions ("pink lesions") (picture
8A-B) [23]. The dermoscopic differentiation of such lesions can be challenging. Acknowledging the
context of the lesion together with evaluating the morphology and architectural arrangement of
vascular structures (picture 9) can provide clues to the correct diagnosis [24,25].
Comma-shaped, dotted, and linear irregular or serpentine vessels are usually seen in melanocytic
lesions (table 1) [24]. Serpentine, dotted, or polymorphous vessels (two or more morphologies within
the same lesion) are often seen in amelanotic melanomas. Dotted vessels can on occasion be seen
in dysplastic and congenital nevi [26]. Thicker amelanotic melanomas may present a combination of
dotted, serpentine, corkscrew, or arborizing vessels.
Regularly distributed hairpin vessels with a white halo are characteristic of seborrheic keratoses
(picture 6), whereas arborizing vessels are typically seen in basal cell carcinomas (table 2 and
picture 4).
Amelanotic or hypomelanotic lesions with atypical vascular morphology and/or arrangement should
be biopsied to rule out amelanotic melanoma or other skin neoplasms (picture 9).
Featureless lesions (feature poor, nonspecific,

nonclassifiable, or structureless) — Some skin lesions may
not show any of the above criteria for melanocytic and nonmelanocytic lesions or may not display
any vascular structures to assist in diagnosis. These lesions are defined as featureless (feature poor,
nonspecific, nonclassifiable, or structureless) lesions (picture 10). Since a subgroup of melanomas
may lack any recognizable dermoscopic structures, nonclassifiable lesions, especially if changing or
symptomatic, should be biopsied to rule out melanoma.
15
SECOND STEP: NEVUS VERSUS
SUSPICIOUS LESION OR
MELANOMA Once a lesion is classified as melanocytic, the observer proceeds
to the second step, intended to differentiate nevus from suspicious lesions or melanoma [5]. The
decision whether to reassure the patient, monitor the lesion, or perform a biopsy is based upon this
second step. A small percentage of nonmelanocytic lesions may be misclassified as melanocytic in
the first step. For example, some pigmented basal cell carcinomas may exhibit a dermoscopic
pattern that raises suspicion of melanoma and a biopsy will be performed.
There are different algorithms and methods that aid the observer in the second step, including [2,8-
12]:
●ABCD rule of dermoscopy (table 3)
●Menzies method (table 4)
●The seven-point checklist (table 5)
●Color, architectural disorder, symmetry, homogeneity/heterogeneity of dermoscopic structures

(CASH) algorithm (table 6)
●Pattern analysis (table 7)
Although all methods have a similar sensitivity, pattern analysis has a superior specificity compared
with the other quantitative scoring systems and is the method preferred by most experienced
clinicians (table 8) [5,27]. Novices in dermoscopy will benefit from quantitative methods such as the
dermoscopy ABCD rule, Menzies method, and the seven-point checklist, which are relatively simple,
accurate, and reproducible [10,28,29].
Online tutorials on dermoscopy can be found at www.dermoscopedia.org,

www.dermnetnz.org/doctors/dermoscopy-course/introduction.html, www.dermoscopy-
ids.org/index.php/education/podcasts, or www.genomel.org/dermoscopy. Also, information
regarding the two-step algorithm can be found in an app called Dermoscopy Two Step Algorithm.
ABCD rule of dermoscopy — The ABCD rule of dermoscopy is a semi-

quantitative scoring system that employs four dermoscopic criteria to evaluate a pigmented lesion:
asymmetry, border sharpness, colors, and dermoscopic structures (table 3) [8].
●Asymmetry: Asymmetry refers to the contour and distribution of colors and structures within the
lesion, in none, one, or two perpendicular axes (figure 6). The score for asymmetry ranges between
zero and two points. The ABCD rule of dermoscopy and the CASH algorithm are the only algorithms
16
that take into account both contour and distribution of colors and structures.
●Border sharpness: The border is evaluated for the presence of abrupt cutoffs between the lesion
and the normal skin. The lesion is divided into a virtual pie with eight sections. For each segment
presenting with an abrupt cutoff of pigment, a score of 1 is assigned. Hence, the border scoring
ranges between zero and eight points.
●Colors: Presence of any of six colors within the lesion: white, red, light brown, dark brown, blue-gray,
and black. The score for color ranges from one to six points.
●Differential dermoscopic structure: Presence of any of five structures including pigment network,
homogeneous/structureless areas greater than 10 percent of the lesion (ie, hypopigmented or
hyperpigmented blotches and depigmented or scar-like areas), branched streaks, dots, and globules.
The score for dermoscopic structures ranges between one and five points.
The scores assigned to each feature are multiplied by a weighted factor and summed up in a final
dermoscopy score. Sensitivity ranges from 78 to 90 percent and specificity from 45 to 90 percent
among experts and non-experts [5,7,8,10,11,29-34].
Menzies method — The Menzies method was originally developed to

differentiate invasive melanomas from other pigmented lesions (table 4) [35]. The method is based
upon the evaluation of two negative features with a low sensitivity (0 percent) for melanoma, and
nine positive features with a high specificity for melanoma (>85 percent).
"Negative features" are:
●Symmetry of the pigmentation pattern
●Presence of only one color (black, gray, blue, red, dark brown, or tan)
"Positive features" are:
●Blue-white veil
●Multiple brown dots
●Pseudopods
●Radial streaming
●Scar-like depigmentation
●Peripheral black dots/globules
●Broadened network
●Multiple blue/gray dots
17
●Multiple (five to six) colors
The presence of both negative features virtually excludes the diagnosis of melanoma. For all other
lesions, the presence of any one of the positive features raises the suspicion for melanoma. Menzies
method has a sensitivity of 85 to 92 percent and a specificity of 38 to 78 percent among examiners
with various degrees of experience [5,7,11,30,33,35,36].
The seven-point check list — The seven-point checklist is based upon

seven dermoscopic features frequently associated with melanoma (table 5) [10]:
Major criteria:
●Atypical pigment network
●Blue-whitish veil
●Atypical vascular pattern
Minor criteria:
●Irregular streaks
●Irregular dots/globules
●Irregular blotches
●Regression structures
A score is calculated by summing points allotted as two points for each of the major three criteria
and one point for each of the four minor criteria. A final score of three or more suggests melanoma
[10]. The seven-point checklist has a sensitivity of 62 to 95 percent and a specificity of 35 to 97
percent among experts and non-experts [5,7,10,30-32,34,35,37].
The presence of any one of the criteria has been proposed as sufficient to warrant a biopsy in a
revised version of this check list [37]. This revised seven-point checklist lowered the threshold for
biopsy, using a total score of one instead of three as sufficient to warrant a biopsy. Although this
revision increases the sensitivity of the criteria, the authors acknowledge that the most sensitive and
specific method to diagnose melanoma requires supportive evidence based on clinical
characteristics, follow-up, and the comparative approach [38].
CASH algorithm — CASH is an acronym for Color, Architectural disorder,

Symmetry, and Homogeneity/Heterogeneity of dermoscopic structures (table 6) [11].
This method is based upon evaluating a pigmented lesion for the following:
●Presence of few versus many colors
18
●Architectural order versus disorder
●Symmetry of shape and pattern versus asymmetry
●Homogeneity versus heterogeneity of dermoscopic structures
The scoring system for the CASH algorithm is shown in a table (table 6). A total CASH score of eight
or more is suspicious of melanoma (range 2 to 17) [11]. A score of eight was chosen as a threshold
that optimizes sensitivity and specificity for individuals with all levels of experience. However, a
lower threshold for lesion excision may be appropriate for novices. The CASH algorithm has a
sensitivity of 87 to 98 percent and a specificity of 67 to 68 percent [11,39].
Pattern analysis — Pattern analysis is based upon the association of an image

with a recognition template developed from previous experience (table 7) [40,41]. It therefore
requires the knowledge and recognition of the global and local patterns of nevi and melanoma
[9,42,43]. For experienced clinicians, pattern analysis is a sensitive and specific method, whereas for
nonexperts, it may have a worse diagnostic accuracy than the unaided eye [31,44].
In analyzing a melanocytic lesion using the pattern analysis method, it should be determined
whether or not the lesion manifests one of the global patterns encountered in nevi. In broad terms,
benign lesions have an organized distribution of dermoscopic structures, one or a few colors, and a
symmetric pattern. In contrast, melanomas often have a disorganized distribution of structures,
multiple colors, and an asymmetric pattern (figure 7).
Nevi: Global and local features — Nevi tend to manifest 1 of the 10

following benign global patterns (figure 8):
●Reticular diffuse: A diffuse pigment network composed of lines that have minimal variation in their
color and thickness. The holes of the network also appear relatively homogeneous in size. The
network tends to fade toward the periphery. This pattern is commonly seen in melanocytic nevi with
a prominent junctional component (ie, junctional nevi, superficial congenital nevi) (picture 11).
●Reticular patchy: A subclassification of reticular diffuse and represents a reticular network similar
to that described above presenting in focal patches that are distributed in a symmetric and
organized manner. The patches are separated by homogeneous structureless areas, which are of the
same color or slightly darker than the background skin. This pattern is commonly seen in acquired
melanocytic nevi and superficial congenital nevi (picture 12).
●Peripheral reticular with central hypopigmentation:Auniform network at the periphery of the lesion
with a central homogeneous and hypopigmented structureless area. The structureless area has the
same color, or slightly darker as compared to the background skin. This pattern is commonly seen in
acquired melanocytic nevi, especially in individuals with fair skin (picture 13).
19
●Peripheral reticular with central hyperpigmentation:A uniform network at the periphery of the
lesion with a central homogeneous and hyperpigmented structureless area or blotch. This pattern is
commonly seen in acquired melanocytic nevi, especially in individuals with darker skin (picture 14).
●Homogeneous pattern: A diffuse homogeneous structureless pattern in a stable and non-changing

lesion. It may appear as gray-blue as seen in blue nevi, brown as seen in congenital nevi, or tan-pink
as seen in acquired nevi in individuals with fair skin (picture 15).
●Peripheral reticular with central globules:Auniform network at the periphery of the lesion with
central globules. This pattern is commonly seen in congenital nevi (picture 16).
●Peripheral globules with central network or homogeneous area, including the starburst pattern:
The central component consists of a reticular or homogeneous pattern. The peripheral component
can manifest in one of three ways: a single row of globules as seen in some actively growing nevi;
more than one row of globules (ie, tiered globules) creating a starburst pattern as commonly seen in
Spitz nevi; and streaks (classic starburst pattern) giving the appearance of an exploding star, as
seen in Spitz/Reed nevi (picture 17).
●Globular pattern: Globules of similar shape, size, and color are distributed throughout the lesion.
Globules may be large and angulated, creating a cobblestone pattern as seen in dermal nevi and
some congenital nevi (picture 18).
●Two-component pattern: A combination of two patterns with one half of the lesion manifesting one
pattern and the other half another pattern. The most common two-component pattern is the
reticular-globular pattern (picture 19).
●Multicomponent pattern: A combination of three or more patterns distributed symmetrically in at

least one axis (picture 20).
Nevi on volar surfaces present a parallel furrow pattern, characterized by the presence of pigment
along the sulci (furrows) of palms and soles (picture 21). (See "Dermoscopy of pigmented lesions of
the palms and soles".)
After determining whether or not the lesion adheres to 1 of the 10 benign global patterns, the
observer proceeds to analyze the lesion's local features. A description of the typical and atypical
variants of the local features with their diagnostic associations is provided in the table (table 7).
Melanoma: Global and local features — The melanoma specific

structures are, by convention, termed atypical/irregular. Many of these atypical/irregular structures
have a typical/regular counterpart that is associated with nevi (table 7).
Global features of melanoma are:
●Deviation from the benign patterns and at least 1 of the 10 melanoma specific structures.
20
●Multicomponent pattern: A combination of three or more patterns (eg, reticular, globular, and
homogeneous), asymmetrically distributed in the lesion. It has also been defined as a lesion with
three or more dermoscopic structures distributed asymmetrically.
●Nonspecific pattern: Lack of any recognizable global pattern of pigmentation.
●Volar skin patterns: Melanomas on palms and soles (ie, volar surfaces) can present with a
multicomponent pattern, nonspecific pattern, or a parallel ridge pattern, which is characterized by
the presence of pigment along the cristae (ridges) of palms or soles. (See "Dermoscopy of
pigmented lesions of the palms and soles".)
●Facial skin patterns: Lesions on facial skin can present with a multicomponent pattern, nonspecific
pattern, asymmetric follicular openings, perifollicular granularity, circle within a circle, angulated
lines creating zigzag lines or coalescing to form polygons such as rhomboidal structures, and
blotches obliterating follicular openings.
Lesions displaying a multicomponent or nonspecific pattern are further examined for the following
10 melanoma specific structures (picture 22A-D):
●Atypical network, including angulated lines.
●Peripheral streaks (pseudopods and radial streaming).
●Negative network.
●Off-centered blotch.
●Atypical dots and/or globules.
●Regression structures, including granularity (also known as peppering), and scar-like areas. The
presence of granularity and scar-like areas within the same lesion result in the appearance of a blue-
white coloration, usually overlying macular areas.
●Blue-white veil overlying raised areas.
●Atypical vascular structures.
●Shiny white lines (also known as crystalline structures).
●Tan peripheral structureless areas.
The sensitivity, specificity, and predictive value of melanoma specific structures are provided in the
table (table 9).
A lesion is considered malignant if it deviates from the benign patterns, and has at least 1 of the 10
melanoma-specific structures. Lesions are considered suspicious if they have a benign pattern and
reveal a melanoma specific structure, or if they do not adhere to one of the benign global patterns
21
and lack a specific feature of melanoma.
DERMOSCOPY FROM A
MANAGEMENT PERSPECTIVE The primary
purpose of examining a skin lesion with a dermatoscope is to determine whether the lesion should
be biopsied or not [45]. The decision to biopsy a suspicious lesion should be based upon the
combination of clinical and dermoscopic examination of the lesion in question as well as
surrounding lesions (comparative approach) and other relevant information, including history of
change, associated symptoms, and personal and family history of melanoma and other skin
cancers.
In patients with multiple nevi, it is useful to identify the "signature nevus" pattern (the predominant
type of nevus) as well as lesions that deviate from the predominant pattern ("ugly duckling" lesions),
both clinically and dermoscopically [46,47]. A comparative dermoscopic approach to the patient with
multiple nevi reduces the number of excisions of benign nevi [48]. (See "Melanoma: Clinical features
and diagnosis", section on 'The "ugly duckling" sign'.)
After a complete clinical and dermoscopic examination utilizing the two-step dermoscopy algorithm,
a management decision can be rendered (algorithm 1).
●If the lesion is considered to be benign, the patient can be reassured, educated on the importance
of self-skin examination, and instructed to return if changes are detected [49,50].
●If the lesion is considered to be a melanoma, it should undergo excisional biopsy [51-54].
●If the lesion is considered suspicious, there are two options: perform a biopsy or refer the patient to
an expert clinician for further evaluation.
The management decision will depend on several factors such as the pretest probability of the
diagnosis of the lesion. For example, a lesion with a spitzoid morphology in a child is less likely to be
a melanoma than a similar lesion in an adult. Based on the pretest probability, the clinician may be
more likely to biopsy spitzoid lesions in adults than in children. Other factors that may influence the
management decision include whether or not the lesion is an isolated lesion or one in a sea of many
nevi, and whether or not the lesion is a clinical or dermoscopic outlier lesion.
Lesions referred to an expert for further evaluation may be deemed benign, biopsied, or subjected to
short-term monitoring. The rationale behind short-term monitoring is that stable lesions are
biologically indolent and represent nevi, whereas changing lesions are biologically dynamic and may
be atypical nevi or melanoma [55,56].
Short-term dermoscopic monitoring, which consists of comparing digital dermoscopic images of the
same lesion taken approximately three to four months apart, should ideally be performed in
specialized centers by experienced clinicians [55-57]. This type of monitoring is only suitable for
22
macular (nonpalpable) lesions; suspicious or atypical nodular (palpable) lesions should be biopsied.
Short-term dermoscopic monitoring is a safe and accepted approach to monitor these flat
(nonpalpable) atypical lesions. In one study, 19 percent of 318 nevi showed a change during this
time period (2.5 to 4.5 months) and 11 percent of those changing lesions were found to be early
melanomas [55].

INFORMATION FOR PATIENTS UpToDate offers

two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer
the four or five key questions a patient might have about a given condition. These articles are best
for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Seborrheic keratosis (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●The two-step dermoscopy algorithm forms the foundation of the dermoscopic evaluation of skin
lesions. It is based upon the systematic search and recognition of specific dermoscopic structures
to distinguish melanocytic and nonmelanocytic lesions, diagnose common benign and malignant
nonmelanocytic lesions, and decide whether a melanocytic lesion is benign, suspicious, or
malignant. (See "Overview of dermoscopy", section on 'Colors and structures'.)
●In the first step the observer decides whether a lesion is melanocytic or nonmelanocytic by looking
for the presence or absence of specific features. (See 'Criteria for melanocytic lesions' above.)
●Nonmelanocytic lesions are further examined for the presence of features of dermatofibroma,
basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, angioma, or other benign or
malignant nonmelanocytic lesions. The possibility of a featureless or amelanotic melanoma should
23
be kept in mind. (See 'Criteria for basal cell carcinoma' above and 'Criteria for seborrheic keratoses'
above and 'Criteria for hemangioma/angioma and angiokeratoma' above and 'Vascular structures in
skin lesions' above.)
●In the second step of the two-step algorithm, melanocytic lesions are further evaluated to
differentiate benign nevi from suspicious lesions or melanoma. The decision whether to reassure
the patient, monitor the lesion, or perform a biopsy is based upon this second step. (See 'Second
step: Nevus versus suspicious lesion or melanoma' above.)
●The second step is performed using one of several algorithms. Clinicians with limited experience in
dermoscopy may benefit from quantitative methods, such as the ABCD rule, Menzies method, and
the seven-point checklist. These methods are relatively simple, accurate, and reproducible. (See
'ABCD rule of dermoscopy' above and 'Menzies method' above and 'The seven-point check list' above
and 'CASH algorithm' above and 'Pattern analysis' above.)
●If a lesion is considered to be benign after a thorough clinical and dermoscopic examination, the
patient can be reassured and educated on the importance of self-skin examination and instructed to
return if changes occur. If the lesion is considered suspicious, there are two options: perform a
biopsy or refer the patient to an expert clinician for further evaluation. Lesions referred to an expert
for further evaluation may be deemed benign, biopsied, or subjected to short-term dermoscopic
monitoring. (See 'Dermoscopy from a management perspective' above.)
●If the lesion is considered to be a melanoma, it should undergo excisional biopsy. (See "Melanoma:
Clinical features and diagnosis", section on 'Biopsy'.)
24
Dermoscopy of pigmented lesions of the palms and soles
uptodate.com/contents/dermoscopy-of-pigmented-lesions-of-the-palms-and-soles/print
Dermoscopy of pigmented lesions of the palms and soles
Authors:
Toshiaki Saida, MD, PhD
Hiroshi Koga, MD
Section Editor:
Hensin Tsao, MD, PhD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Apr 2020. | This topic last updated: May 31, 2018.
INTRODUCTION In populations with darker skin, melanoma occurs most

frequently in acral areas, with a particular predilection for the soles of the feet. In Japanese, almost
one-half of cutaneous melanomas occur in acral areas and approximately 30 percent affect the sole
[1]. The prognosis of acral melanoma is generally poor, mainly as a consequence of a delay in
diagnosis [2,3]. Dermoscopy, a noninvasive technique performed by a handheld instrument called a
dermatoscope, increases the clinician's diagnostic accuracy for pigmented lesions of the palms and
soles and may help in the recognition of acral melanoma at an early, curable stage [4,5].
This topic will review the dermoscopic features of melanocytic and nonmelanocytic pigmented
lesions of the palms and soles and the dermoscopic criteria for differentiating benign melanocytic
nevi from early melanoma. The principles of dermoscopy and the use of dermoscopy for the
evaluation of lesions located on the nonglabrous skin, face, mucosal surfaces, and nails are
discussed separately. Dermoscopic algorithms for skin cancer triage are also discussed separately.
●(See "Dermoscopic evaluation of skin lesions".)
●(See "Dermoscopy of nonpigmented nail lesions".)
25
HISTOLOGIC FEATURES OF
PALMOPLANTAR SKIN The palmoplantar skin is
anatomically and histologically unique. It is characterized by a thick, compact, cornified layer and by
the presence of dermatoglyphics, consisting of ridges and furrows (sulci) that run on the surface in a
parallel fashion and form loops, whorls, and arches in highly individualized patterns. Hair follicles
are absent, but eccrine sweat glands, whose ducts open in the center of surface ridges, are well
developed.
The pattern of the epidermal rete ridge is characteristic. In a tissue section cut perpendicularly to the
surface skin markings, two types of rete ridges can be identified: the crista profunda limitans,
situated under the surface furrow, and the crista profunda intermedia, situated under the surface
ridge (picture 1) [4]. On scanning electron microscopy, these rete ridges appear as longitudinal
parallel rows protruding into the dermis (picture 2) [6]. Transverse ridges bridging the longitudinal
ridges also may be seen; they are generally short and thin but are more prominent in the peripheral
areas of the palms and soles and in the foot arch.
The assessment of the distribution of melanin granules and melanocytes in relation to the rete
ridges is critical to differentiate acral nevi from early acral melanoma [7-9]. In acral nevi,
melanocytes arranged in nests are predominantly located in the crista profunda limitans, although
some melanocytes may be detected also in the crista profunda intermedia [9]. Melanin granules
appear as regular columns situated in the cornified layer underneath the surface furrows, but they
are usually absent under the surface ridges (picture 3). In contrast, in early acral melanoma,
melanocytes arranged as solitary units are present mainly in the crista profunda intermedia
underlying the surface ridges, although a few melanocytes can be seen also in the crista profunda
limitans (picture 4).
DERMOSCOPIC FEATURES OF
ACRAL MELANOCYTIC LESIONS
Overview — Melanocytic lesions of the palms and soles exhibit unique dermoscopic
patterns that are significantly different from those seen in nonglabrous skin, due to the distinctive
histologic characteristics of the acral skin (picture 1). (See 'Histologic features of palmoplantar skin'
above.)
The main pigmentation patterns of acral melanocytic lesions are as follows (figure 1) [4,10,11]:
●Parallel furrow pattern – Linear pigmentation along the furrows of the skin markings
●Lattice-like pattern – Pigmented lines along and across the furrows
26
●Fibrillar pattern – Fine fibrillar or filamentous pigmentation usually arranged in the direction
crossing the parallel skin markings
●Parallel ridge pattern – Band-like pigmentation located on the ridges of the skin markings
The first three patterns are typically seen in benign acquired nevi, whereas the parallel ridge pattern
is the hallmark of acral melanoma. Since early melanoma and benign melanocytic nevi on the palms
and soles may have a similar appearance on naked eye examination, the recognition of these
specific pigmentation patterns by dermoscopy is of great help for the clinician in determining
whether a lesion should be biopsied or not.
Acquired melanocytic nevi — Most melanocytic nevi detected on the

palms and soles are acquired [12,13]. Approximately two-thirds of acquired acral nevi show one or
combinations of the three major benign dermoscopic patterns: the parallel furrow pattern, the lattice-
like pattern, and the fibrillar pattern (figure 1) [4,10,11,13-18].
Parallel furrow pattern and its variants — The parallel furrow

pattern results from a linear distribution of the pigment along the furrows of the skin markings,
which run on the skin surface in a parallel fashion (figure 1). The basic type of parallel furrow pattern
shows a single solid line of pigmentation in the furrows. Variants include the double solid line, single
dotted line, and double dotted line (picture 5) [18].
The parallel furrow pattern is seen in approximately 50 percent of acral nevi in any ethnic group
[5,19] and is occasionally associated with a light brown background pigmentation [18]. Orderly
combinations of the parallel furrow pattern with the two other major dermoscopic patterns (lattice-
like and fibrillar) are also common in acral nevi (picture 6A-B) [5,18,20].
Rarely, the parallel furrow pattern may be detected in acral melanoma. However, in melanoma, this
pattern is present focally or unevenly within the lesion, whereas in melanocytic nevi it is regularly
distributed across the lesion. (See 'Melanoma' below.)
Lattice-like pattern — The lattice-like pattern is formed by pigmented lines along

and across the furrows of the skin markings (figure 1 and picture 7). A light brown background
pigmentation may be present. This pattern is detected in approximately 15 percent of acral nevi,
most often in those located on the arch of the foot or in peripheral areas of the palms and soles,
where the skin markings lose the typical parallel pattern [5,6,20]. The lattice-like pattern can be
regarded as an anatomical modification of the parallel furrow pattern [18].
Fibrillar pattern — The fibrillar pattern consists of a densely packed, fine, fibrillar or
filamentous pigmentation arranged perpendicularly or obliquely to the parallel skin markings (picture
8 and figure 1). It is detected in 10 to 20 percent of plantar nevi and rarely in palmar nevi. The
27
pigment fibrils typically cover at least the whole width of one surface ridge (picture 8); if the fibrils
starting on a furrow do not reach the neighboring furrow, the pattern is classified as parallel furrow
pattern (picture 9).
The fibrillar pattern results from the oblique arrangement of the thick, cornified layer of the plantar
skin, due to the mechanical pressure exerted by the body weight, and may be considered an
artifactual modification of the parallel furrow pattern [5,18,20]. In some cases, particularly in young
individuals, a regular fibrillar pattern can be visualized as a parallel furrow pattern by advancing the
cornified layer horizontally with the probe of a contact dermatoscope or by oblique view dermoscopy
performed with a noncontact dermatoscope (picture 10) [21].
Regular versus irregular fibrillar pattern — The regular fibrillar pattern

typically seen in melanocytic nevi should be differentiated from the irregular fibrillar pattern
occasionally detected in acral melanomas. Criteria for regular fibrillar pattern are [5]:
●Regular and symmetrical overall arrangement of the fibrillar pigmentation
●Even thickness and length of each fibril
●Alignment of the starting points of the fibrils on a surface furrow
In contrast, in the irregular fibrillar pattern, the overall arrangement of the pigmentation is
asymmetrical and patchy, the fibrils vary in thickness and color, and their starting points do not line-
up on a straight line in most cases (picture 11).
Minor (nontypical) patterns — In addition to the three major dermoscopic

patterns (ie, parallel furrow pattern, lattice-like pattern, fibrillar pattern), minor patterns, formerly
collectively called nontypical patterns, can be detected in approximately one-third of acquired
melanocytic nevi of the palms and soles [16-18,22]. Minor patterns include:
●Globular pattern – Dots and globules arranged in a nonparallel fashion, often accompanied by
diffuse light brown background (picture 12A)
●Acral reticular pattern – Reticulated pigmentation similar to the pigment network of the
nonglabrous skin (picture 12A)
●Homogeneous pattern – Light brown, mostly structureless pigmentation with no other distinctive
feature
●Globulo-streak-like pattern – Brown globules attached to linear or curvilinear streaks without

relation to the skin markings (picture 12B)
●Transition pattern – Pigment network on the nonglabrous side and parallel furrow pattern or
lattice-like pattern on the glabrous side of the lesion (picture 13)
28
Congenital melanocytic nevi — Small congenital melanocytic nevi
(≤1.5 cm) may occur on the palms and soles, but their prevalence is not known. Dermoscopic
features typically detected in congenital melanocytic nevus of the palms and soles include the
parallel furrow pattern, crista dotted pattern, and peas-in-a-pod pattern, as described below [23].
Parallel furrow pattern — The parallel furrow pattern, a major dermoscopic

pattern most frequently detected in acquired acral nevi, is frequently also seen in acral congenital
melanocytic nevi. In a dermoscopic study of 24 congenital nevi, 6 showed the parallel furrow pattern
[23]. (See 'Parallel furrow pattern and its variants' above.)
Crista dotted pattern — The crista dotted pattern consists of dots/globules of

pigment regularly distributed on the ridges of the skin markings (picture 14). In a series of congenital
acral nevi described by the author, this pattern was observed in 3 of 24 lesions [23]. The crista dotted
pattern results from the adnexocentric distribution of nevus cells, which is one of the
histopathologic characteristics of congenital nevi. The dots/globules on the ridges correspond to
nests of nevus cells surrounding the upper portion of eccrine ducts opening in the center of the
surface ridges.
Peas-in-a-pod pattern — The peas-in-a-pod pattern is a combination of the

parallel furrow and the crista dotted patterns (picture 15). This pattern, seen in 8 of 24 nevi in the
author's series, is the most prevalent dermoscopic pattern of acral congenital melanocytic nevi [23].
Other findings — Congenital nevi of the palms and soles may also show [5,23-25]:
●Combinations of the three major dermoscopic patterns seen in acquired melanocytic nevi (ie,
parallel furrow pattern, lattice-like pattern, and fibrillar pattern)
●Features similar to the parallel ridge pattern found in melanoma (picture 16) or other minor
(nontypical) patterns, such as the globular and globulo-streak-like pattern (picture 12A-B)
●A blue-gray background pigmentation mostly seen in the central areas of the lesions, reflecting the
presence of pigmented nevus cells in the dermis (picture 17)
●Enlarged pink ridges, seen in central areas of the lesions [26]
The symmetric distribution of dermoscopic features and an even pigmentation support the
diagnosis of congenital nevus. Elements of the clinical history (eg, presence since infancy, stable
course over time) may be additional clues to the diagnosis. However, lesions with equivocal or
suspicious dermoscopic features should be biopsied for histopathologic evaluation.
29
Influence of age on dermoscopic
patterns — Several studies indicate that the prevalence of specific dermoscopic patterns
of melanocytic nevi on the palms and soles varies with age [27-29]. The crista dotted pattern and the
peas-in-a-pod pattern are commonly detected in acquired acral nevi of children and adolescents.
In one study, evaluating the dermoscopic images of 75 acral nevi in 69 patients younger than 18
years, the parallel furrow pattern and the crista dotted pattern were the most common patterns,
detected in 71 and 21 percent of nevi, respectively [27]. Digital follow-up dermoscopic images
obtained after a median follow-up time of 32 months showed a change in global pattern (from
parallel furrow to lattice-like or fibrillar) in 5 of 31 nevi and a decrease or increase in local criteria (eg,
pigmentation, size, and number of globules/dots) in 20.
In another study, the peas-in-a pod pattern was observed in 20 percent of acral nevi seen in persons
younger than 20 years but only in less than 1 percent of individuals older than 59 years [28]. An
opposite trend was seen for nontypical patterns, detected in 36 percent of older individuals and in
less than 10 percent of those younger than 20 years.
Nevi of the glabrous/nonglabrous skin

transition zone — Melanocytic nevi located on the transitional zones between
glabrous and nonglabrous skin (ie, peripheral areas of the palms and soles, lateral aspects of fingers
and toes) (picture 18) may show unusual dermoscopic features. One of these is the so-called
transition pattern, consisting of a typical pigment network in the nonglabrous portion of the lesion
and a parallel furrow pattern or lattice-like pattern in the glabrous portion (picture 13) [17]. Nevi
situated in the interdigital web spaces or on the lateral aspects of fingers or toes may show another
unusual dermoscopic pattern composed of a densely arranged reticular or branched pigmentation
(picture 19).
On histology, melanocytic nevi located on transition zones often show a prominent proliferation of
melanocytes arranged as solitary units within the epidermis that mimics melanoma in situ (picture
20) [30]. However, the symmetric, orderly intraepidermal distribution of melanocytes and the
absence of nuclear atypias differentiate a benign nevus from melanoma.
Melanoma — The parallel ridge pattern and an irregular, diffuse pigmentation are highly
sensitive and specific features of early and advanced acral melanoma, respectively. Advanced
melanoma of the palms and soles may also show dermoscopic features characteristic of melanoma
of nonglabrous skin, including irregular dots/globules, irregular streaks, blue-white veil, regression
structures, and polymorphous vessels (picture 21) [4,11]. (See "Dermoscopic evaluation of skin
lesions", section on 'Melanoma: Global and local features'.)
30
Parallel ridge pattern — The parallel ridge pattern consists of a band-like
pigmentation, tan to black in color, located on the ridges of the skin markings (figure 1 and picture
22A). It is highly characteristic of melanoma of the palms and soles and reflects the preferential
proliferation of melanocytes in the crista profunda intermedia during the early horizontal growth
phase (picture 4) [4,10,11,14,15].
In early melanoma, the parallel ridge pattern is evenly detected within the lesion, whereas in
advanced melanoma it is focally distributed (picture 22A-B). Sensitivity and specificity of the parallel
ridge pattern for the diagnosis of melanoma, including melanoma in situ, are 86 and 99 percent,
respectively [14].
Occasionally, the parallel ridge pattern is detected in a variety of benign pigmented lesions of palms
and soles, such as drug-induced pigmentations, Peutz-Jeghers syndrome, or pigmented warts.
However, in most cases, these lesions can be correctly diagnosed based upon clinical findings and
additional dermoscopic characteristics. (See 'Dermoscopic features of acral nonmelanocytic
pigmented lesions' below.)
Irregular diffuse pigmentation — Irregular diffuse pigmentation is defined

as a structureless pigmented area, tan to black in color, which is highly characteristic of acral
melanoma (picture 22C) [11,14,31]. Sensitivity and specificity of irregular diffuse pigmentation are 85
and 97 percent, respectively. As expected, sensitivity is lower for melanoma in situ (69 percent),
since the diffuse pigmentation reflects the florid proliferation of melanocytes in more advanced
lesions [14].
Other features — Advanced melanoma of the palms and soles may show the same
dermoscopic features of advanced melanoma of nonglabrous skin, including irregular dots/globules,
irregular streaks, blue-white veil, regression structures, and polymorphous vessels (picture 21) [4,11].
However, the atypical pigment network, which is a major feature of melanoma of nonglabrous skin,
is extremely rare in melanomas of the palms and soles [32]. Brown globules irregularly distributed
on the ridges, reflecting transepidermal elimination of melanoma cell nests, can be a characteristic
dermoscopic pattern of acral melanoma [33]. Of note, brown globules are regularly distributed on the
ridges in congenital nevus [23] and Spitz nevus on the palms and soles [34]. (See "Dermoscopic
evaluation of skin lesions", section on 'Melanoma: Global and local features'.)
Occasionally, dermoscopic patterns typically seen in acral melanocytic nevi (eg, parallel furrow,
lattice-like, and fibrillar patterns) can also be seen in advanced acral melanoma [35]. However, in
melanoma these patterns usually have a focal or irregular distribution within the lesion (picture 22B).
Acral melanoma may be amelanotic or hypomelanotic. In a series of 126 acral lentiginous

melanomas, 34 (28 percent) were unpigmented [36]. In amelanotic or hypomelanotic melanomas,
the presence of microscopic remnants of pigmentation and atypical vascular structures are
31
important clues to the diagnosis [37]. Lesions with these dermoscopic findings should always be
biopsied and sent for histopathologic examination. (See "Dermoscopic evaluation of skin lesions",
section on 'Vascular structures in skin lesions'.)
Atypical melanosis of the foot — Atypical melanosis of the foot is

an unusual plantar pigmented lesion that has clinical and dermoscopic, but not histologic, features
of early acral lentiginous melanoma [38-41]. These lesions present as large macules with irregular
borders and variegated colors (picture 23). On dermoscopy, they usually show the parallel ridge
pattern typical of melanoma (picture 24) [40,41]. Although the clinical and dermoscopic features
suggest melanoma, on histologic examination only a slightly increased number of melanocytes
without cytologic atypias is detected in the crista profunda intermedia (picture 25). It has been
hypothesized that these lesions may represent early or slowly evolving acral melanoma in situ
[8,42,43].
THE THREE-STEP DERMOSCOPIC

ALGORITHM The three-step algorithm for the diagnosis and management of
melanocytic lesions on the palms and soles was originally proposed in 2007. Step 1 of this
algorithm is based upon the high sensitivity, specificity, and positive predictive value (86, 99, and 94
percent, respectively) of the parallel ridge pattern for early acral melanoma [14,18]. Sensitivity,
specificity, and positive predictive value of the parallel furrow pattern/lattice-like pattern for
melanocytic nevi are 67, 93, and 98 percent, respectively [14]. A revised version of the three-step
algorithm was published in 2011 and is presented here (algorithm 1) [44]:
●Step 1 – The lesion is examined for the presence of the parallel ridge pattern. If the parallel ridge
pattern is found in any part of the lesion, the lesion should be biopsied regardless of the size. If the
lesion does not show the parallel ridge pattern, proceed to Step 2.
●Step 2 – The lesion is examined for the presence of one or an orderly combination of the typical
benign dermoscopic patterns (ie, typical parallel furrow pattern, typical lattice-like pattern, regular
fibrillar pattern). If the whole area of the lesion shows one or a combination of two or three typical
benign patterns, further dermoscopic follow-up is not needed. If the lesion shows equivocal
dermoscopic features (ie, part or total absence of any typical/regular patterns) (picture 26), proceed
to Step 3.
●Step 3 – The maximum diameter of lesions that do not show typical benign patterns is measured.
Lesions >7 mm should be excised or biopsied for histopathologic evaluation [45]. Lesions ≤7 mm
should be monitored clinically and dermoscopically at three- to six-month intervals.
For the correct use of the three-step algorithm, it is important to keep in mind the following:
32
●The algorithm has been developed for the differentiation of acquired melanocytic nevi from acral
melanoma of the palms and soles and may not be appropriate for the evaluation of congenital nevi
in those locations. In most cases, congenital nevi can be identified on the basis of their
characteristic dermoscopic features (see 'Congenital melanocytic nevi' above). However, the three-
step algorithm can be used to evaluate acral nevi whose type (acquired or congenital) cannot be
determined.
●In the first step, it is crucial to correctly identify the furrows and ridges of the skin markings. Their
recognition can be greatly facilitated by performing the "furrow ink test" before examining the lesion
under the dermatoscope [46,47]. The periphery of the lesion is marked with liquid ink (eg, from a
fountain pen) or with a whiteboard marker pen, preferably blue or green in color; the skin surface is
then gently wiped with a dry paper towel. The surface furrows retain the blue or green ink and
become clearly visible on dermoscopic examination as thin inked lines. The test will allow the
clinician to assess whether the melanin pigmentation follows the ink lines as in the parallel furrow
pattern (picture 27) or is located between the ink lines, thus representing a parallel ridge pattern
(picture 28). Once the examination is completed, the marker pen ink in the furrows can be easily
removed by wiping the skin with a wet paper towel.
●In the second step, the clinician must assess whether the benign patterns are typical or regular.
Typical parallel furrow or lattice-like patterns are symmetrically and evenly distributed across the
lesion. The criteria for classifying a fibrillar pattern as regular are described above (see 'Regular
versus irregular fibrillar pattern' above). Orderly combinations of benign patterns are also considered
as benign. If there is any uncertainty in classifying a pattern as benign, the lesion should be biopsied
or monitored as described in Step 3. The decision not to follow-up lesions that are judged
unequivocally benign in Step 2 is based upon the observation that the risk of acral melanoma
developing in a preexisting nevus is extremely low [48,49]. In digital follow-up studies of acral
melanocytic nevi, a change from a benign to a malignant pattern has not been reported [18,22,50].
However, changes within benign patterns have been observed in 20 to 70 percent of cases [22,50].
Lesions that cannot be unequivocally classified as benign should be biopsied for histopathologic
evaluation if they are larger than 7 mm.
THE BRAAFF CHECKLIST Based upon the dermoscopic

examination of 603 acral lesions (472 nevi and 131 acral melanomas, including 42 in situ lesions), a
new six-variable scoring system has been developed for the diagnosis of acral melanoma [51]. This
system, called the BRAAFF checklist, consists of six variables, each with a positive or negative
value:
●Irregular blotch (+1)
●Parallel ridge pattern (+3)
●Asymmetry of structures (+1)
●Asymmetry of colors (+1)
33
●Parallel furrow pattern (-1)
●Fibrillar pattern (-1)
A total score of ≥1 is needed for a diagnosis of melanoma. The threshold of one point provided a
sensitivity of 93 percent and a specificity of 87 percent [51].
DERMOSCOPIC FEATURES OF
ACRAL NONMELANOCYTIC
PIGMENTED LESIONS Dermoscopy is helpful in the diagnosis
of a variety of benign pigmented lesions of the palms and soles, some of which may mimic acral
melanoma [52]. In most cases, the correct diagnosis can be made based upon clinical history and/or
associated signs and symptoms. A biopsy for histopathologic evaluation may be warranted when
the diagnosis is uncertain.
Hemorrhage, hematoma, and

hemangioma — Dermoscopic features of hemorrhage/hematoma and hemangioma
of the palms and soles are similar to those seen in nonglabrous skin. However, due to the unique
anatomical structure of the acral volar skin, some hemorrhagic lesions show characteristic
dermoscopic patterns, as described below. (See "Dermoscopic evaluation of skin lesions", section on
'Criteria for hemangioma/angioma and angiokeratoma'.)
Black heel (calcaneal petechiae) — Black heel, also called calcaneal

petechiae or talon noir, is an asymptomatic pigmentation of the heel secondary to intraepidermal
extravasation of red blood cells, caused by shear-force injuries (eg, during vigorous sports) [53]. On
naked-eye examination, black heel appears as a black macule or plaque that mimics melanoma
(picture 29A-B).
On dermoscopic examination, black heel shows a unique dermoscopic pattern called the "pebbles
on the ridges," in which a reddish-black, pebble-like pigmentation is distributed on the ridge of the
skin markings (picture 30) [4,10]. The pebble-like pigmentation corresponds to aggregation of
hemosiderin in the superficial skin layers, mostly in the stratum corneum.
With more abundant blood extravasations, the pebble-like pigmentation becomes confluent and
forms a band-like pigmentation (picture 31) that mimics the parallel ridge pattern seen in melanoma
[54]. However, the reddish tone, sharp demarcation, and subtle segmentation of the pigmented
bands differentiate black heel from melanoma.
34
PlayStation purpura/PlayStation fingertip — The so-called
PlayStation purpura or PlayStation fingertip presents as brownish macules on the index or middle
fingers, which result from subcorneal hemorrhages caused by a prolonged use of the handheld
game controller device. On dermoscopy, these macules show a parallel ridge pattern [55,56].
However, the symmetric location on the index or middle fingers, the rusty/reddish hue of the color,
and a history of prolonged video gaming are clues to the correct diagnosis.
Drug-induced acral pigmentation — Several anticancer drugs

(eg, topical fluorouracil, doxorubicin, cyclophosphamide) may induce focal acral hyperpigmentation,
such as pigmented macules and melanonychia [57-59]. Multiple small, brownish macules may
develop on the hands or feet and are often accompanied by a linear pigmentation of the palmar and
plantar creases. On dermoscopy, the hyperpigmented macules show a parallel ridge pattern similar
to that seen in early acral melanoma (picture 32). Histology shows increased melanin in the basal
layer of the epidermis and melanophages in the papillary dermis [57].
Peutz-Jeghers syndrome and Laugier-

Hunziker syndrome — Peutz-Jeghers syndrome is a rare autosomal dominant
disorder characterized by gastrointestinal polyposis in association with multiple small,
hyperpigmented, mucocutaneous macules most often located on the lips and buccal mucosa
(picture 33) and on the dorsal and volar aspect of hands and feet (picture 34A-B). On dermoscopy,
the pigmented macules located on the volar skin show the parallel ridge pattern [60]. The diagnosis
is based upon the characteristic distribution of the macules, family history, and demonstration of
colonic hamartomas. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and
management".)
Laugier-Hunziker syndrome is a rare, acquired, macular hyperpigmentation of the lips, oral mucosa,
and acral skin frequently associated with longitudinal melanonychia. In contrast with Peutz-Jeghers
syndrome, Laugier-Hunziker syndrome is not associated with systemic disorders. On dermoscopy,
the pigmented macules typically show the parallel ridge pattern, but cases with a parallel furrow
pattern have been reported [61,62]. Histology shows increased melanin in basal keratinocytes,
particularly in those located in the crista profunda intermedia, corresponding to the epidermal rete
ridges underlying the surface ridges [62].
Volar melanotic macules — Volar melanotic macules are solitary or

multiple brownish macules found on the palms and soles of individuals with darker skin types [63-
65]. On dermoscopy, they may show a parallel ridge pattern (picture 35). Histologically, volar
melanotic macules are characterized by increased deposition of melanin in all epidermal layers,
hyperpigmented solitary dendritic melanocytes scattered along the basal layer, and melanophages
in the dermis [64].
35
Pigmented ridged wart — The pigmented ridged wart is an uncommon
type of plantar wart associated with a cystic component, caused by the human papillomavirus type
60 [66]. On dermoscopy, it shows a parallel ridge pattern and may mimic a verrucous type of acral
melanoma [67-69]. When the clinical diagnosis is unclear, a biopsy is necessary to exclude
melanoma. Histology reveals hyperkeratosis, acanthosis, large vacuolated cells in the malpighian
and granular layers, and absence of abnormal melanocyte proliferation.
Tinea nigra — Tinea nigra is a superficial fungal infection of the palms and soles that
presents as a large, brownish macule (picture 36). Dermoscopy reveals light brown, fine strands
arranged in a reticular pattern [70]. The pigmentation does not follow the furrow or ridges of the skin
markings. The diagnosis is confirmed by potassium hydroxide (KOH) examination of scrapings from
the lesion.
Pigmentation due to chemicals — Accidental staining of the

plantar skin with paraphenylenediamine, a derivative of aniline used in hair dyes and rubber
products, can display the parallel ridge pattern on dermoscopy [52,71,72]. Palmar or plantar
pigmentation caused by self-tanning products can also show the parallel ridge pattern. A detailed
history, including the patient's occupation and hobbies, is important for a correct diagnosis. The
pigment can be removed by shaving the superficial cornified layer with a scalpel.
SUMMARY AND
RECOMMENDATIONS
●Dermoscopy, a noninvasive diagnostic technique performed by a handheld instrument called a
dermatoscope, is of great value in the diagnosis and management of pigmented lesions of the palms
and soles. (See 'Introduction' above.)
●Most acral acquired melanocytic nevi show one of three major dermoscopic patterns (figure 1): the
parallel furrow pattern (picture 5), the lattice-like pattern (picture 7), and the fibrillar pattern (picture
8). (See 'Acquired melanocytic nevi' above.)
●Major dermoscopic patterns seen in acral congenital melanocytic nevi are the parallel furrow
pattern (picture 17), the crista dotted pattern (picture 14), and the peas-in-a-pod pattern (picture 15).
In addition, congenital nevus may exhibit variegated dermoscopic features mimicking those seen in
melanoma. (See 'Congenital melanocytic nevi' above.)
●The parallel ridge pattern (figure 1 and picture 22A) is highly characteristic of early melanoma of
the palms and soles. Advanced melanoma typically shows irregular diffuse pigmentation (picture
22B-C) but may also show dermoscopic features seen in melanoma of nonglabrous skin (eg,
36
irregular dots/globules, irregular streaks, blue-white veil, regression structures, and polymorphous
vessels). (See 'Melanoma' above.)
●A three-step algorithm (algorithm 1) has been proposed for the diagnosis and management of
acquired melanocytic lesions on the palms and soles. (See 'The three-step dermoscopic algorithm'
above.)
●Pigmented lesions other than melanoma and melanocytic nevus that can be found on the palms
and soles include the so-called black heel and other hemorrhagic conditions, drug-induced
pigmentations, Peutz-Jeghers and Laugier-Hunziker syndrome, pigmented ridged wart, and tinea
nigra. Dermoscopy is useful in the diagnosis of these conditions. (See 'Hemorrhage, hematoma, and
hemangioma' above and 'Dermoscopic features of acral nonmelanocytic pigmented lesions' above.)
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Topic 16551 Version 11.0
GRAPHICS
37
Histopathology of the volar skin
This tissue section was cut perpendicularly to the parallel skin markings. The ridges (orange bars)
and furrows (arrows) are recognized on the surface. Under the epidermis, two kinds of epidermal
rete ridges are recognized: the crista profunda intermedia (dashed arrows) underlying the surface
ridges and the crista profunda limitans (arrowheads) underlying the surface furrows. The crista
profunda intermedia is passed through by an intraepidermal eccrine duct.
Graphic 89394 Version 2.0
38
Surface electron microscopy of plantar skin
On the undersurface of the epidermis, two kinds of main longitudinal ridges, the crista profunda
limitans and the crista profunda intermedia, are observed as parallel rows. Eccrine ducts are
recognized as tube-like projections from the crista profunda intermedia. The short transverse ridges
are also detected, bridging the main longitudinal ridges.
Courtesy of Tetsuya Tsuchida, MD, PhD.
39
Histopathologic features of acral nevi
Histopathologic features of acral nevus of the junctional type. The cornified layer slants slightly.
(A) Nevus cells arranged in nests are predominantly located in the crista profunda limitans (arrows),
and only a few melanocytes are detected in the crista profunda intermedia (asterisks) (hematoxylin-
eosin stain).
(B) Melanin granules in the cornified layer are detected as parallel columns regularly situated under
the surface furrows (arrows), whereas they are mostly absent in the cornified layer under the surface
ridges (asterisks) (Fontana-Masson stain).
Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of
melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic
differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI:
10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology.
Unauthorized reproduction of this material is prohibited.
40
Histopathologic features of early acral melanoma
Histopathologic features of the macular portion of an acral melanoma showing the parallel ridge
pattern on dermoscopy.
(A) Melanocytes arranged as solitary units are mainly observed in the crista profunda intermedia
(asterisks), although a few melanocytes are also detected in the crista profunda limitans (arrows)
(hematoxylin-eosin stain).
(B) Melanin granules in the cornified layer are mostly derived from melanocytes in the crista
profunda intermedia (Fontana-Masson stain). They are detected as broad columns under the
surface ridges (blue bars). Melanin granules are mostly absent in the cornified layer under the
surface furrow, corresponding to the underlying crista profunda limitans (arrows). This distribution
corresponds well to the dermoscopic parallel ridge pattern.
Reproduced with permissiomn from: Saida T, Koga H, Goto Y, Uhara H. Characteristic distribution of
melanin columns in the cornified layer of acquired acral nevus: An important clue for histopathologic
differentiation from early acral melanoma. Am J Dermatopathol 2011; 33:468. DOI:
10.1097/DAD.0b013e318201ac8f. Copyright © 2011 International Society of Dermatopathology.
Unauthorized reproduction of this material is prohibited.
41
Schematic representation of the dermoscopic patterns of melanocytic lesions located on the palms
and soles
The parallel furrow, lattice-like, and fibrillar patterns are major dermoscopic patterns seen in
acquired melanocytic nevus of the palms and soles, whereas the parallel ridge pattern is the most
sensitive and specific dermoscopic pattern detected in acral melanoma.
Reproduced with permission from: Saida T. Textbook of Dermoscopy, Nankodo Co. Ltd, Tokyo, 2011.
Copyright © 2011 Toshiaki Saida, MD, PhD.
42
Dermoscopic images of variants of the parallel furrow pattern in acquired melanocytic nevi of palms
and soles
In the parallel furrow pattern, parallel pigmented lines are detected along the furrows of the skin
markings. Variants of this pattern include: (A) single solid line variant, (B) double solid line variant,
(C) single dotted line variant, and (D) double dotted line variant.
43
Combination of the parallel furrow pattern and other benign dermoscopic patterns in acquired
melanocytic nevi of the palms and soles
(A) In this lesion, the parallel furrow pattern is associated with the lattice-like pattern in the center of
the lesion.
(B) The parallel furrow pattern shows transition to the fibrillar pattern on the right side of this lesion.
Reproduced with permission from: John Wiley & Sons, Inc. Saida T, Koga H, Uhara H. Key points in
dermoscopic differentiation between early acral melanoma and acral nevus. J Dermatol 2011; 38:25.
Copyright © 2011 Japanese Dermatological Association. All rights reserved.
44
Combination of the three major dermoscopic patterns in melanocytic nevi of the palms and soles
In this nevus, the three major benign dermoscopic patterns, the parallel furrow (blue circle), fibrillar
(dashed red circle), and lattice-like pattern (dotted green circle), are detected. Note that they are
arranged in an orderly fashion.
Inset: clinical photograph.
Reproduced with permission from: Saida T, Koga H. Dermoscopic patterns of acral melanocytic nevi:
Their variations, changes, and significance. Arch Dermatol 2007; 143:1423. Copyright © 2007
American Medical Association. All rights reserved.
45
Dermoscopic image of an acquired melanocytic nevus on the palm: The lattice-like pattern
On dermoscopic examination, this acquired melanocytic nevus on the palm shows a pigment
distribution that forms linear lines along and across the surface furrows in a lattice-like fashion.
46
Dermoscopic image of an acquired melanocytic nevus on the sole: The fibrillar pattern
In this regular fibrillar pattern, the starting points of the fibrils align on the lines corresponding to the
surface furrows (arrows).
47
Dermoscopic parallel furrow pattern and fibrillar pattern
Because of the oblique arrangement of the cornified layer, the parallel furrow pattern sometimes
shows features of fibrillar pattern. If the fibrils do not reach the neighboring furrow (A), the pattern is
classified as parallel furrow pattern. If the fibrils reach or cross the neighboring furrow (B) or cover at
least the whole width of one surface ridge, the pattern is classified as fibrillar.
48
Oblique-view dermoscopy of the fibrillar pattern in an acral melanocytic nevus
This melanocytic nevus of the sole shows the regular fibrillar pattern on the ordinary dermoscopy
(A). The green lines correspond to the furrows of the skin marking visualized by the furrow ink test.
Oblique view dermoscopy using a noncontact dermatoscope changes the fibrillar pattern to the
parallel furrow pattern, dotted line variant (B).
49
Dermoscopic features of regular and irregular fibrillar pattern
In the regular fibrillar pattern of benign nevi (A), the overall arrangement of the fibrils is mostly
symmetric and the starting points of the fibrils align on straight lines corresponding to the surface
furrows. In contrast, in the irregular fibrillar pattern seen in melanoma (B), the fibrils are variable in
color and thickness and are arranged in a disorderly, haphazard fashion. Their starting points do not
align on a straight line.
50
Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles
(A) Globular pattern.

(B) Acral reticular pattern.
51
Minor dermoscopic patterns seen in acquired melanocytic nevi of palms and soles: Globulo-streak-
like pattern
Globulo-streak-like pattern seen in two small acquired melanocytic nevi (arrows) affecting the arch
areas.
52
Dermoscopy of acral melanocytic lesions: Transition pattern
On dermoscopy, this nevus located on the inner aspect of the right heel shows the parallel furrow
pattern in the lower portion and the reticular pattern in the upper portion. This pattern is
characteristic of melanocytic nevi of the glabrous/nonglabrous skin transition zone. Inset: clinical
photograph.
53
Dermoscopic features of congenital nevi of the palms and soles: The crista dotted pattern
In the crista dotted pattern, brown globules are regularly distributed on the surface ridges. The
globules correspond to nevus cell nests surrounding the distal portion of the eccrine ducts, which
open in the center of the ridges.
54
Dermoscopic features of congenital nevi of palms and soles: The peas-in-a-pod pattern
The peas-in-a-pod, commonly detected in congenital nevus on the palms and soles, is regarded as a
combination of the parallel furrow pattern and crista dotted pattern.
55
Dermoscopic features of a congenital plantar nevus
In this plantar congenital nevus, the dermoscopic pattern is similar to the parallel ridge pattern.
However, the color is grayish and the pigmented bands are segmented, resembling the crista dotted
pattern. These findings help in differentiating this pattern from the classic parallel ridge pattern seen
in melanoma. Subtle features of the parallel furrow pattern, which is typical of acquired acral
melanocytic nevi, are detected on the left side of this lesion.
56
Dermoscopic features of congenital melanocytic nevus on the palms and soles: The parallel furrow
pattern
In this plantar congenital nevus, the typical parallel furrow pattern is associated with a grayish-
brown background pigmentation. The gray tone reflects the melanin granules in the dermis derived
from the prominent intradermal component of congenital nevi.
57
Clinical and histopathologic features of a melanocytic nevus located on the foot
Melanocytic nevus located in the fourth interdigital space of the right foot of a 23-year-old woman.
This brownish-black macule, 5 mm in diameter, shows virtually no irregularity in shape or color.
Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the
histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008
58
Dermoscopic features of an acral melanocytic nevus located in the transition zone between
glabrous and nonglabrous skin
In this nevus located on the side of a toe, a densely arranged reticular or branched pigmentation is
observed. Inset: clinical photo. Note that the histopathological features of melanocytic nevi located
on the transition zone between glabrous and nonglabrous skin often mimic those of melanoma,
showing prominent proliferation of solitary melanocytes within the epidermis.
Courtesy of Akemi Ishida-Yamamoto, MD, PhD
Histologic features of melanocytic nevi of the glabrous/nonglabrous skin transition zone
59
Clinical and histopathologic features of a melanocytic nevus located on a transition area (the fourth
interdigital area of the right foot) of a 23-year-old woman.
(A-C) In all of the histopathologic photographs (hematoxylin-eosin), we see that melanocytes
proliferate mainly as solitary units within the epidermis, and many of them are situated above the
dermoepidermal junction, mimicking histopathologic features of melanoma in situ. However, overall
distribution of melanocytes within the lesion is mostly symmetrical and orderly. The nuclei of
melanocytes are relatively large but not hyperchromatic; instead, they are vesicular. In addition, there
is virtually no inflammatory cell infiltrate in the dermis. The original magnifications are x12, x38, and
x84 for panels A, B, and C, respectively.
Reproduced with permission from: Saida T, Kawachi S, Koga H. Anatomic transitions and the
histopathologic features of melanocytic nevi. Arch Dermatol 2008; 144:1232. Copyright © 2008
60
Dermoscopic features of advanced melanoma of the sole
There is an ulcerated nodule on the right, surrounded by a blue white veil (star). The parallel ridge
pattern (square) as well as the irregular fibrillar pattern (circle) are also detected.
61
Parallel ridge pattern seen on dermoscopic examination of melanoma of palms and soles
The parallel ridge pattern represents band-like pigmentation on the ridges of the skin markings. In
this melanoma in situ (A), the pattern covers almost all the lesion. In an early invasive melanoma of
the sole (B), the parallel ridge pattern is detected only in the lower portion of the lesion (circle) and
irregular diffuse pigmentation is observed in the upper portion.
62
Dermoscopic features of macular areas of melanoma on the sole
In the macular areas of this advanced melanoma, the parallel ridge pattern is detected focally (red
rectangle). An irregular fibrillar pattern (blue circle) and the parallel furrow pattern (green rounded
rectangle) are also focally detected.
63
Dermoscopic image of irregular diffuse pigmentation in a melanoma on the sole
In this advanced melanoma, irregular diffuse, structureless pigmentation of variable shades from tan
to brownish black, predominates. Hints of the parallel ridge pattern also can be recognized.
64
Clinical image of atypical melanosis of the foot
A 45 x 25 mm brownish macule with irregular shape and color on the volar aspect of the great toe.
65
Dermoscopic image of atypical melanosis of the foot
On dermoscopic examination, atypical melanosis of the foot shows a typical parallel ridge pattern.
66
Histopathologic characteristic of atypical melanosis of the foot
The melanocytes in the crista profunda intermedia are slightly increased in number. Eccrine ducts
run through the epidermal rete ridges.
67
The 3-step dermoscopic algorithm for the diagnosis and management of acquired melanocytic
lesions of the palms and soles
68
Acral melanocytic lesion with equivocal dermoscopic features
A brown macule 6.5 mm in maximum diameter is present on the right fifth toe of a 63-year-old
woman. On dermoscopic examination, the lesion does not show any typical/regular patterns.
69
The furrow ink test: Parallel furrow pattern
In this acral lesion, the pigmented lines correspond to the furrows of the skin markings. The parallel
furrow pattern is typical of acquired acral nevi.
70
The furrow ink test: Parallel ridge pattern
In this acral melanocytic lesion, the band-like pigmentation is detected between the furrows, on the
ridges of the skin markings. The parallel ridge pattern is typical of acral melanoma.
71
Black heel (calcaneal petechiae)
The black specks on the heel result from intradermal hemorrhage due to trauma (eg, friction against
shoes during vigorous sports).
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
72
Black heel (calcaneal petechiae)
Aggregated black specks on the heel resulting from intraepidermal hemorrhage caused by shear-
force injuries (eg, during vigorous sports).
73
Dermoscopic features of the "black heel"
The "black heel" results from the formation of tiny petechiae in the superficial skin tissue of the heel
caused in most cases by friction with tight, ill-fitted sport shoes. Reddish to black, globular
pigmentation on the ridges (the pebbles on the ridges) is characteristic. Inset: clinical photograph.
74
Dermoscopic features of superficial hematoma in the plantar skin
On dermoscopy, a superficial hematoma in the plantar skin shows a pigment distribution

reminiscent of the parallel ridge pattern. However, the reddish tone and demarcation of the lesion
and the presence of reddish black globules are helpful in differentiating hematomas from
melanocytic lesions.
75
Dermoscopic features of pigmentation induced by 5-fluorouracil
The drug-induced light brown pigmentation is accentuated on the surface ridges, resembling the
parallel ridge pattern. This pigmentation can be differentiated from melanoma based upon the
presence of multiple brown macules bilaterally on the palms and soles and history of drug intake.
76
Peutz-Jeghers syndrome
Multiple pigmented macules are present on the lips.
77
Peutz-Jeghers syndrome
Multiple hyperpigmented macules on the dorsum of the hand of a patient with Peutz-Jeghers
syndrome.
78
Cutaneous hyperpigmentation in Peutz-Jeghers syndrome
Multiple hyperpigmented macules on the volar aspect of the thumb in a patient with Peutz-Jeghers
syndrome.
79
Volar melanotic macule
The picture shows one of several light-brown macules noted on the soles of a middle-aged Japanese
man. The macule has regular borders and even pigmentation. On dermoscopy, it shows a typical
parallel ridge pattern.
80
Tinea nigra
A well-dermarcated brown patch on the palm of a three-year-old boy with tinea nigra. The patch had
been slowly expanding for six months. A potassium hydroxide preparation revealed grayish brown
branching hyphae typical of tinea nigra which is caused by a dermatiaceous fungus
Phaeoannellomyces werneckii.
Copyright © Samuel Freire da Silva, MD, Dermatlas; http://www.dermatlas.org.
Contributor Disclosures
Toshiaki Saida, MD, PhDNothing to discloseHiroshi Koga, MDNothing to discloseHensin Tsao, MD,
PhDGrant/Research/Clinical Trial Support: Relay Therapeutics; Asana BioSciences [Melanoma (Dual
BRAF/PI3K inhibitor, ERK 1/2 inhibitor)]. Consultant/Advisory Boards: Epiphany Dermatology [Basal
cell carcinoma, melanoma, nevi, skin cancer screening]; World Care Clinical; Ortho Dermatologics
[Melanoma (Imaging services)]. Consultant/Advisory Boards (Spouse): Ortho Dermatologics
[Melanoma].Rosamaria Corona, MD, DScNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
81
82
Patch testing - UpToDate
uptodate.com/contents/patch-testing/print
INTRODUCTION Patch testing is an essential investigation to identify

specific allergens in allergic contact dermatitis (ACD) or, in some cases, to make the diagnosis of
ACD. Patch testing is based upon the principle that in sensitized individuals, primed antigen-specific
T lymphocytes of the Th1 phenotype circulate throughout the body and are able to recreate a
delayed-type hypersensitivity reaction when nonirritating concentrations of the antigen are applied
to normal skin.
This topic will discuss indications, techniques, and interpretation of patch testing. The basic
mechanisms, clinical manifestations, diagnosis, and management of ACD are discussed separately.
(See "Basic mechanisms and pathophysiology of allergic contact dermatitis" and "Clinical features
and diagnosis of allergic contact dermatitis" and "Management of allergic contact dermatitis".)
INDICATIONS FOR PATCH

TESTING Indications for patch testing may include:
●Persistent eczematous eruptions when contact allergy is suspected [1]
●Any chronic dermatitis, especially when involving the hands, feet, face, or eyelids
●Eczematous dermatitis in individuals involved in high-risk occupations for contact dermatitis (eg,
health care workers, dental assistants, cosmetologists, machinists, or rubber and plastic workers)
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●Dermatitis of unknown etiology
●Worsening of a previously stable dermatitis
Patch testing also may be indicated when allergic contact dermatitis (ACD) is suspected as a
complication of:
●Atopic dermatitis
●Stasis dermatitis
●Seborrheic dermatitis
●Nummular eczema
●Asteatotic eczema
●Psoriasis
SELECTION OF ALLERGENS Observational studies

have identified more than 4350 chemicals as contact allergens with varying potential to cause
allergic contact dermatitis (ACD) [2]. However, a high proportion of ACD are caused by a relatively
small number of allergens commonly found in the environment.
Standard (baseline) series of allergens — Standard

(baseline) or screening series of contact allergens, which are designed to include the most common
sensitizers responsible for ACD in a given region, are recommended as the initial battery for patients
undergoing patch testing. The standard series are revised on a regular basis, as new allergens are
identified as a cause of ACD.
There are several baseline series throughout the world, including the North American Contact
Dermatitis Group and the European standard series of approximately 35 allergens (determined by
consensus of the European Society of Contact Dermatitis and the European Environmental and
Contact Dermatitis Research Group). Details on the standard series most commonly used can be
found at www.dermnetnz.org/dermatitis/standard-patch.html. The American Contact Dermatitis
Society (ACDS) (www.contactderm.org) has developed a recommended core series of 80 allergens
divided into eight panels [3].
The thin-layer rapid-use epicutaneous (TRUE) test, which includes 35 allergens and one control, is a
commercially available ready-to-use test widely used in basic standard patch testing among
dermatologists and allergists. Although it is easy to apply, it may have lower sensitivity than other
standard series [4].
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Additional series of patch testing — Supplemental series of
patch tests suitable for specific exposures, including workplace exposures, are available to
complement the standard series (eg, hairdressers, dental, or cosmetic series). The patient's clinical
presentation and history help to determine whether testing with supplemental series and/or
products provided by the patient is necessary [5]. (See "Clinical features and diagnosis of allergic
contact dermatitis", section on 'History'.)
Individualized patch testing — In the event that a standard series

and supplemental series do not identify an offending antigen, patients may be patch tested with their
own products. As a general rule, when patch testing patients with their own products, it is
acceptable to use products that are left on the skin (eg, lotions, creams). However, products that
typically are rinsed off the skin (eg, soap) should not be patch tested; when left on the skin these
products may act as irritants. Rinse-off products may be tested with open testing. (See 'Open test'
below.)
Specific allergens can also be customized [6].
PATCH TEST PROCEDURE

Preparing the patient — Patients need to be informed that patch testing is a
time consuming process that requires at least three visits during a specified week. Patients should
avoid showering, exercising, and extremes of heat and humidity, and should be alerted that positive
reactions can result in itching and discomfort.
Patch testing is usually performed on the back. If the back is excessively hairy it may be difficult to
achieve adequate skin contact with the patches. To avoid irritation it is advisable to clip the hair from
the back one or two days before patch testing.
Effect of systemic immunosuppression — The effect of systemic

immunosuppression on the accuracy of patch testing has not been well established. Potent topical
corticosteroids applied to the test site or oral corticosteroids ideally should be discontinued at least
two weeks before patch testing [7,8]. Topical treatment with potent corticosteroids or systemic
treatment with corticosteroids or other immunosuppressant drugs may cause weak or negative
reactions [1,7]. Studies on poison ivy, which usually induces strong positive reactions, have indicated
that it may be acceptable to perform patch testing with doses of prednisone up to 20 mg per day.
However, this practice may be suboptimal for allergens that are weaker than poison ivy, and
generally should be discouraged [9,10]. In two small studies, positive patch test reactions were seen
in patients taking prednisone, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil,
infliximab, adalimumab, and etanercept [11,12]. An additional study found no difference in the
prevalence or intensity of positive patch test reactions in psoriasis patients on etanercept, infliximab,
85
adalimumab, and ustekinumab [13]. A small case series and a few case reports suggest a variable
and potentially allergen-specific effect of dupilumab on patch testing results [14-16]. This suggests
that it may be preferable to patch test patients prior to the initiation of dupilumab.
Effect of oral antihistamines — Oral antihistamines may be continued

during patch testing, as they have minimal if any effect on the mechanisms of delayed
hypersensitivity. Since a positive patch test reaction is not a histamine mediated process, there is no
pathophysiologic rationale to discontinue antihistamines prior to patch testing.
Effect of ultraviolet radiation — Patients should avoid irradiation from both

artificial and natural (sunlight) sources of ultraviolet (UV) radiation before patch testing. Irradiation
with UVB can reduce the number of antigen presenting cells in the skin and the intensity of patch
test reactions. Patch testing should be deferred in heavily tanned patients, and a minimum of four
weeks after significant sun exposure should be allowed before patch testing.
Patch test site — The optimal site for patch testing is the upper back. The outer
aspect of the upper arms is an alternative. Placing patches on other skin areas may result in a higher
degree of false-negative results. If the skin is oily, gentle degreasing can be performed with ethanol
or another mild solvent. The sites of patch application are then marked with a suitable marker to
identify the test sites.
Patch testing should be performed on intact skin without dermatitis to minimize the risk of
nonspecific inflammatory responses with numerous false-positive tests ("angry back" syndrome).
(See 'The "angry back"' below.)
Types of tests
Closed test — The most commonly accepted technique for patch testing involves the
application of test allergens under occlusion onto the skin of the upper back for two days. Allergens
are applied in standard amounts to aluminum or synthetic material chambers mounted on non-
occlusive tape strips. Commercially available patch test units are described in the table (table 1).
Open test — Open test may be used to test products with a potential to create irritation on
the skin, which include paints, soluble oils, soaps, glues, and other cleansing agents. Unlike
traditional patch testing, the area is kept open. After 30 minutes the materials are gently removed
and readings are performed in a delayed fashion similar to closed patch testing. If the reaction is
negative but contact allergy is still suspected, closed patch testing with single ingredients in
appropriate concentration and vehicle should be performed.
Semi-open test — The semi-open or semi-occlusive test is used for products with a
slight irritant potential, including [17,18]:
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●Pharmaceutical products – Products containing antiseptic agents such as mercurial compounds
(eg, phenylmercuriborate), quaternary ammonium salts such as benzalkonium chloride and iodine;
antiseptics containing emulsifiers such as lauraminoxyde and nonoxynol; products containing
solvents such as propylene glycol in high concentrations; creams based on the emulsifier sodium
laurylsulfate.
●Cosmetic products – Products containing emulsifiers, solvents, or other potentially irritant

substances such as mascara, nail lacquers, hair dyes, shampoos, permanent-wave solutions, liquid
soaps, and peels.
●Household and industrial products – Paints, resins, varnish, glue, ink, wax, and soluble oils (after
having verified that the pH is >3 and <11 or that a corrosive material is not involved).
For a semi-open test, minute amounts of allergens (1 to 2 microL) are applied to the skin and allowed
to dry (water-soluble products can be tested as 1% or 2% solution). After complete drying, the test
site is covered with a non-occlusive tape for two days and read at two and four days in a fashion
similar to closed patch testing.
Repeated open application test — The repeated open application test

(ROAT) may be useful to evaluate the clinical relevance of doubtful positive patch test reaction to
preparations in which the putative allergen is present in a low concentration [19,20].
The ROAT is performed by applying 0.1 mL of the test substance to a specified area twice daily for
up to 28 days or until an eczematous reaction develops. The antecubital fossa and the outer aspect
of the upper arm are the most suitable areas for ROAT, as patients can easily perform the test and
observe any reactions. A positive reaction may establish the clinical relevance of the product for the
patient and confirm the source of the allergy.
Usage test — If a closed patch test or open test is negative despite a history suggestive of
allergic contact dermatitis (ACD), the patient is asked to use the product under real world conditions.
This method reproduces all the factors associated with the original dermatitis, for example sweating,
friction, or application of allergen on damaged or presensitized skin and is especially helpful in
suspected clothing and cosmetic dermatitis. However, usage tests may fail to differentiate irritative
from allergic dermatitis.
Patch test reading

Initial reading — The patches typically are left in place for a period of two days (48
hours), which allows adequate penetration of the allergen into the skin. To reduce the number of
false-positive readings, the initial evaluation is generally performed between 15 and 60 minutes after
the patches are removed, when the transient erythema has resolved. Patients should avoid removing
the skin marks before the second reading is performed.
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Second reading — A second reading is critically important to distinguish irritant
reactions (which fade) from true allergic reactions (which persist) and to identify allergic reactions
that do not appear at the time of patch removal [21]. The time of the second reading varies among
different patch testing centers, but generally is on day four or five. Day four readings appear to be
associated with a low number of false-negative reactions [22]. Performing the second reading too
soon may miss some delayed reactions, whereas performing the second reading too late may result
in missing some positive reactions that fade rapidly, such as those due to fragrances. An additional
reading at day six or seven may be useful to identify a small number of late, positive reactions, in
particular to nickel, neomycin, and corticosteroids [23].
PATCH TEST
INTERPRETATION Correctreading and interpretation of patch test
reactions require the skills of a trained clinician. The International Contact Dermatitis Research
Group has developed a scoring system for evaluating patch test reactions that has been accepted by
the North American Contact Dermatitis Group (table 2) [24].
Strong positive allergic reactions are erythematous and infiltrated, often with minute papules or
vesicles that may coalesce into bullae (picture 1A-B). The reaction may extend beyond the margins
of the patch and is usually associated with pruritus. In all cases, positive reactions should be
evaluated within the clinical context to establish their relevance. (See 'Determining the clinical
relevance' below.)
It may be difficult to distinguish true-positive weak reactions from irritant (false-positive) reactions.
In addition, a variety of morphologic patterns can be seen in irritant patch test reactions, depending
upon the nature and/or concentration of irritants (table 3) [25].
DETERMINING THE CLINICAL

RELEVANCE The relevance of a positive reaction in the diagnosis of allergic
contact dermatitis (ACD) is established by examining the patient's clinical manifestations and
history. (See "Clinical features and diagnosis of allergic contact dermatitis", section on 'Diagnosis'.)
In many cases, relevance to the current problem can be clearly established and avoidance advice
given. In some cases the relevance is found to a past episode or may be uncertain. Some individuals
may have a positive patch test reaction but still tolerate the contact with the allergen.
If the relevance of the positive patch test is not easily apparent, it is important to reexamine in
greater detail the history of exposure to the allergen or cross-reacting substances, and evaluate the
outcome after the patient avoids the allergen.
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A detailed exposure history must include occupational exposure, hobbies, personal care products,
topical medications, and protective measures (table 4). (See "Clinical features and diagnosis of
allergic contact dermatitis", section on 'History'.)
In some cases of occupational ACD, history must be supplemented with a detailed environmental
evaluation. This might include a workplace visit, assessment of materials contacted in the
workplace, evaluation of the physicochemical properties of a substance, and evaluating the
exposure parameters. The exposure parameters include the route and site of exposure, dose,
duration, frequency, and surrounding environmental conditions.
Sometimes provocation with the allergen in the form of a usage test or repeated open application
test (ROAT) may be required to determine the clinical relevance. (See 'Usage test' above and
'Repeated open application test' above.)
There is no consensus regarding the definition, scoring, and determination of clinical relevance
[26,27]. One set of criteria for scoring clinical relevance is provided in the table (table 5) [28]. The
most reliable "test" of relevance is the finding of clearance of the dermatitis with avoidance of
identified allergens.
COMPLICATIONS OF PATCH
TESTING Although generally safe, patch testing may cause adverse reactions (table
6).
Active sensitization — Patch testing is associated with a small risk of

sensitization. A late reaction appearing 10 to 20 days after the test may indicate active sensitization
from the patch test, although some "normal" patch test reactions may be observed at this late time.
However, the risk of active sensitization from patch testing appears to be very low [29-33].
The "angry back" — The "angry back" or "excited skin syndrome" occurs when a
few strong positive reactions cause a chain of multiple reactions to other patch tests that would
otherwise be negative [34]. In most cases, one or two strong reactions create an array of false-
positive reactions. The cause of this phenomenon is not known. One hypothesis is that some
individuals who have an active dermatitis at other body sites or exhibit a strong patch test reaction
develop a nonspecific hyperreactivity of the skin [34]. Another hypothesis is that placing substances
with a similar chemical affinity in the same area induces multiple positive reactions [35]. Patients
with the "angry back" should be retested with the positive allergens separately and sequentially.
Additional validation of positive reactions can be performed by using repeated open application
tests. (See 'Repeated open application test' above.)
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Other — Patients undergoing patch testing may develop a flare of dermatitis, which provides
additional validation of a positive test result. Occasionally, a positive reaction may persist for several
weeks. Other uncommon adverse reactions are summarized in the table (table 6).

provided separately. (See "Society guideline links: Contact dermatitis".)
SUMMARY
●Patch testing is an essential investigation to identify specific allergens in allergic contact dermatitis
(ACD). (See 'Introduction' above.)
●Indications for patch testing include persistent eczematous dermatitis; chronic dermatitis,
especially of the hands, feet, face, or eyelids; eczematous dermatitis in individuals in high risk
occupations; and suspicion of ACD as a complication of other forms of dermatitis. (See 'Indications
for patch testing' above.)
●Standard series of contact allergens, which are designed to include the most common sensitizers
responsible for ACD in a given region, are recommended as the initial battery for patients undergoing
patch testing. Additional series may be used to complement the standard series (eg, hairdressers,
dental, or cosmetic series). (See 'Selection of allergens' above.)
●The most commonly accepted technique for patch testing involves the application of test allergens
to the skin of the upper back under occlusion for two days (closed test). Alternative methods,
including open or usage tests, may be useful for irritant allergens, pharmaceutical products, or
cosmetics. (See 'Types of tests' above.)
●Correct reading and interpretation of patch test reactions require the skills of a trained clinician
(table 2). Strong positive reactions are erythematous and infiltrated, often with minute papules or
vesicles (picture 1A-B). It may be difficult to distinguish true-positive weak reactions from irritant
reactions (table 3). (See 'Patch test interpretation' above.)
●The clinical relevance of a positive patch test is established by reexamining the patient's clinical
manifestations and history. (See 'Patch test interpretation' above.)
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Evaluation and diagnosis of hair loss
uptodate.com/contents/evaluation-and-diagnosis-of-hair-loss/print
Literature review current through: Apr 2020. | This topic last updated: Apr 17, 2019.
INTRODUCTION "Hair loss" is a common clinical complaint that is a

manifestation of a wide variety of disorders. Although the cause of hair loss is easily diagnosed in
some cases, such as in patients who present with classic male pattern hair loss or patchy hair loss
due to alopecia areata, the diagnosis of hair loss also can be challenging.
An overview of the basic principles of hair biology, potential causes of hair loss, and the assessment
of patients who present with a complaint of hair loss is provided here. Specific types of hair
disorders are reviewed in greater detail separately.
●(See "Acne keloidalis nuchae".)
91
●(See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis".)
●(See "Central centrifugal cicatricial alopecia".)
●(See "Alopecia related to systemic cancer therapy".)
●(See "Alopecia areata: Clinical manifestations and diagnosis".)
●(See "Dissecting cellulitis of the scalp".)
●(See "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical features,
and diagnosis".)
●(See "Folliculitis decalvans".)
●(See "Lichen planopilaris".)
●(See "Telogen effluvium".)
●(See "Tinea capitis".)
●(See "Traction alopecia".)
HAIR BIOLOGY
Anatomy — The human scalp contains approximately 100,000 to 150,000 hair follicles [1].
Each hair follicle sits above a dermal papilla, a collection of mesenchymal tissue with inductive
properties (figure 1). The dermal papilla induces the development of hair follicles in the fetus and
appears to play an important role in follicular cycling and hair growth [2]. (See 'Hair cycle' below.)
Hair follicles consist of four segments: the bulb, suprabulbar region, isthmus, and infundibulum
(figure 1) [3]. The bulb, the lowest portion of the hair follicle, is the site of the hair matrix, a group of
rapidly proliferating keratinocytes responsible for the production of hair [2]. The suprabulbar region
of the follicle extends from the bulb to the isthmus, which is the portion of the follicle between the
insertion of the arrector pili muscle and the insertion of the sebaceous gland. The uppermost portion
of the follicle, the infundibulum, extends from the insertion of the sebaceous gland to the
interfollicular epithelium.
The hair shaft is a layered structure that consists of three major components. The medulla, the
innermost layer, is surrounded by the cortex and cuticle. Between the hair bulb and the isthmus, the
hair shaft is surrounded by the inner root sheath, a structure that is composed of the cuticle of the
inner root sheath, Huxley layer, Henle layer, and companion layer. The inner root sheath plays an
important role in the shaping of the hair shaft [2]. The outer root sheath surrounds both the inner
root sheath and the hair shaft and extends from the hair bulb to the epidermis. The outer root sheath
and each of the components of the hair shaft and inner root sheath have distinct keratin profiles [4].
92
A region near the insertion of the arrector pili muscle, referred to as the bulge region of the hair
follicle, has been identified as a site that harbors hair follicle stem cells that are essential for
follicular cycling and hair growth [5]. The loss of the hair follicle stem cells in the bulge is postulated
to contribute to permanent loss of hair in cicatricial alopecias (see 'Cicatricial alopecia' below) [5,6].
Mouse studies have demonstrated that hair follicle stem cells may also support wound healing by
contributing to repopulation of interfollicular epithelial cells [7].
Hair types — The two major types of hair follicles on the human body are terminal hair
follicles and vellus hair follicles. Terminal hair follicles are larger than vellus hair follicles and extend
into the subcutaneous fat (2 to 5 mm from the skin surface) during hair growth. In contrast, the
lowest portions of vellus hair follicles generally extend only into the reticular dermis. Hairs produced
by terminal hair follicles are usually at least 0.06 mm in diameter while vellus hairs are short, fine,
and usually less than 0.03 mm in diameter [8]. The term "intermediate hairs" has been used to
describe hairs with characteristics that are between vellus and terminal hairs (0.03 to 0.06 mm)
[9,10].
At birth, terminal hairs are found on the scalp, eyebrows, and eyelashes, and vellus hairs populate
the remaining hair-bearing areas. During puberty, vellus hairs in certain areas, such as the genital
area and axilla, are stimulated to become terminal hairs. Transitioning between terminal and vellus
hair follicles may also occur in pathologic states. Abnormal transitioning of vellus hairs to terminal
hairs occurs in hirsutism in women, and transitioning of terminal hairs to vellus hairs (follicular
miniaturization) is a classic feature of androgenetic alopecia. (See "Pathophysiology and causes of
hirsutism" and "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis" and
"Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical features, and
diagnosis".)
Hair cycle — Once formed, hair follicles undergo lifelong cycling characterized by periods
of growth (anagen), transformation (catagen), and rest (telogen). In humans, hair cycling is not
synchronous, meaning that individual follicles cycle independently, preventing en mass shedding of
hair. Although the lower portion of the hair follicle undergoes growth and regression during cycling,
the isthmus and infundibulum remain stable.
●Anagen – At any given time, approximately 90 percent of scalp hair follicles are in the anagen
phase [11]. The rate of hair growth and the duration of anagen vary with the type of hair and location.
On the scalp, the growth rate of terminal hair is approximately 0.3 mm per day and the duration of
anagen ranges from two to six years [9,11]. In contrast, eyebrow hair grows only at a rate of 0.1 mm
per day and has an anagen phase of two to three months [2,9]. The abbreviated anagen phase
accounts for the relatively short maximum length of eyebrow hair. Similarly, a short anagen phase is
responsible for the short maximum length of vellus hairs (typically less than 20 mm) [8].
●Catagen –During catagen, the lower portion of the hair follicle regresses and hair production
ceases. The deepest part of the hair follicle tracts upward toward the isthmus, and the dermal papilla
migrates from within the subcutaneous fat into the reticular dermis. The duration of catagen on the
93
scalp is usually around three weeks [9]. Less than 1 percent of follicles on the scalp are in catagen
[11].
●Telogen – The telogen phase, also known as the resting phase, follows catagen and lasts for two
to three months on the scalp [11]. Normally, up to 10 percent of scalp follicles are in telogen [11].
Telogen is characterized by the presence of a club hair (a fully keratinized hair with a club-shaped
proximal end) that is ready for shedding from the hair follicle (figure 2) [2]. The term "exogen" has
been used to describe the exact time point at which the hair is shed. Normally, between 50 and 150
telogen hairs are shed per day [2].
Anagen follows the telogen phase, resulting in the production of a new hair. Prolongation of the
telogen phase, as may occur in telogen effluvium, can result in a reduction in hair density due to a
failure of follicles to reenter anagen following shedding. The term "kenogen" has been used to
describe a delay in the entry into anagen following shedding of a telogen hair [12].
CLASSIFICATION Hair loss disorders are a large, heterogenous group

of conditions that have various clinical features, pathologic findings, and etiologies. Hair loss may
occur due to disorders of hair cycling, inflammatory conditions that damage hair follicles, or
inherited or acquired abnormalities in hair shafts.
The major dividing lines for the various forms of hair loss are the distinction between cicatricial
(scarring) alopecia, nonscarring alopecia, and structural hair disorders. Cicatricial alopecias are
conditions that lead to the irreversible cessation of hair cycling and permanent hair loss. As noted
above, the loss of hair follicle stem cells in the bulge region of the hair follicle is thought to
contribute to the development of cicatricial alopecia (see 'Anatomy' above). In nonscarring
alopecias, the hair follicle is not permanently damaged, making spontaneous or treatment-induced
regrowth a possibility. Structural hair disorders that lead to hair loss demonstrate abnormalities
within the hair shafts that result in hair fragility. (See 'Scalp and hair examination' below.)
Cicatricial alopecia — Primary cicatricial alopecias are inflammatory disorders

of the scalp that lead to permanent hair loss. The primary cicatricial alopecias are subdivided by the
type of inflammation detected on histologic examination. The three major classes are lymphocytic
primary cicatricial alopecias, neutrophilic primary cicatricial alopecias, and mixed primary cicatricial
alopecias [13].
Examples of the primary cicatricial alopecias are provided below. A summary of the clinical and
histologic features of the cicatricial alopecias is provided in a table (table 1A).
●Lymphocytic primary cicatricial alopecia
•Alopecia mucinosa –Alopecia mucinosa (also known as follicular mucinosis) may result in scarring
or nonscarring alopecia. Permanent hair loss results from the replacement of hair follicles by mucin,
rather than from fibrosis. Patients usually present with erythematous or skin-colored indurated
94
plaques of alopecia on the face or scalp (picture 1). Follicular papules may also be present.
Two types of alopecia mucinosa have been described, idiopathic alopecia mucinosa and alopecia
mucinosa that occurs as a manifestation of mycosis fungoides or cutaneous T cell lymphoma.
However, some authors believe that these disorders may represent aspects of a single disease
spectrum [14]. Whether all cases designated as idiopathic alopecia mucinosa are actually indolent
forms of mycosis fungoides remains uncertain [15]. (See "Clinical manifestations, pathologic
features, and diagnosis of mycosis fungoides".)
•Central centrifugal cicatricial alopecia – Central centrifugal cicatricial alopecia is a form of

cicatricial alopecia that primarily affects women of African descent. Alopecia occurs on the crown of
the scalp and gradually progresses in a centrifugal manner to the parietal areas (picture 2).
Perifollicular hyperpigmentation and the emergence of multiple hairs from a single follicle may be
present. Symptoms may include itching, tenderness, or prickling sensations [14]. (See "Central
centrifugal cicatricial alopecia".)
•Discoid lupus erythematosus – Discoid lupus erythematosus (also known as a form of chronic
cutaneous lupus erythematosus) may occur in the absence of systemic disease but may also occur
in the setting of systemic lupus erythematosus. Patients typically present with well-demarcated
inflammatory plaques that develop into atrophic scars (picture 3A-B). Follicular hyperkeratosis
(follicular plugging, aka patulous follicles), telangiectasias, hypopigmentation, and
hyperpigmentation are common clinical features [16]. When the scalp seems to be the primary site
of involvement, examination of the conchal bowls for patulous follicles can aid in differentiating
discoid lupus erythematosus from other forms of scarring alopecia. (See "Overview of cutaneous
lupus erythematosus", section on 'Discoid lupus erythematosus'.)
•Keratosis follicularis spinulosa decalvans (KFSD) –Keratosis follicularis spinulosa decalvans is a

rare genetic disorder that commonly is associated with a mutation in the membrane-bound
transcription factor protease site 2 (MBTPS2) gene on the X-chromosome (MIM #308800) [17].
Familial cases of KFSD that demonstrate an autosomal dominant inheritance pattern have also been
reported (MIM #612843) [18,19]. Patients first present in infancy with follicular papules with
keratotic spines on the scalp. Eyebrow, eyelash, and other involvement of hair-bearing skin may
develop (picture 4A-B). Photophobia is common [18]. Progression of the disease improves during
puberty, leaving atrophic scars. (See "Keratosis pilaris atrophicans", section on 'Keratosis follicularis
spinulosa decalvans'.)
•Lichen planopilaris – Lichen planopilaris is a follicular variant of lichen planus that typically
manifests with perifollicular erythema and follicular hyperkeratosis (picture 5A-B) [20]. The areas of
alopecia may be discrete or confluent, especially on the crown. Itching, burning, pain, or skin
sensitivity are often present. (See "Lichen planopilaris".)
•Frontal fibrosing alopecia – In this disorder, patients present with band-like alopecia affecting the
frontal scalp. Follicular hyperkeratosis and perifollicular erythema may be seen. Concomitant
eyebrow involvement is common and may precede the hair loss [21]. Facial involvement may
95
manifest as small rough follicular papules that have a predilection for the temporal area [22]. (See
"Lichen planopilaris", section on 'Frontal fibrosing alopecia'.)
•Pseudopelade of Brocq –Pseudopelade of Brocq is an idiopathic cicatricial alopecia that presents

with small, skin-colored patches of alopecia on the scalp [16]. The pattern of the disorder has been
described as "footprints in the snow" [23]. Follicular hyperkeratosis and erythema are minimal or
absent. Some clinicians believe pseudopelade of Brocq is a late stage of lichen planopilaris.
●Neutrophilic primary cicatricial alopecia
•Dissecting cellulitis of the scalp – Dissecting cellulitis of the scalp (also known as perifolliculitis
capitis abscedens et suffodiens of Hoffman or dissecting folliculitis) is a form of cicatricial alopecia
that may occur independently or in association with acne conglobata and hidradenitis suppurativa
as part of the "follicular occlusion triad." The condition most commonly occurs in young black men
[24]. Patients develop follicular papules, pustules, fluctuant nodules, and abscesses on the scalp
(picture 6A-B). Purulent drainage is common. Over time, hypertrophic or keloidal scars may develop.
•Folliculitis decalvans – Folliculitis decalvans often begins on the vertex of the scalp. Patches of
alopecia, inflamed papules, pustules, and follicular hyperkeratosis are common features (picture 7A-
B) [25]. Tufted folliculitis (multiple hairs emerging from a single inflamed follicle) is a characteristic
feature, but is not exclusive to this disorder. Pain, itching, and burning are common. Staphylococcus
aureus colonization and a defect in host cell-mediated immunity may be contributing factors [25].
(See "Folliculitis decalvans".)
●Mixed
•Acne keloidalis nuchae – Acne keloidalis nuchae primarily occurs in young black men [26]. Affected
patients present with dome-shaped follicular papules, pustules, and plaques on the occipital scalp
(picture 8). Keloid-like plaques also may develop. (See "Acne keloidalis nuchae".)
•Acne necrotica –Acne necrotica is a rare form of cicatricial alopecia that is characterized by the
development of umbilicated papules on the scalp that undergo central necrosis. Patients usually
experience pruritus or pain. Individual lesions resolve with small varioliform or pox-like scars [27,28].
•Erosive pustular dermatosis of the scalp –Erosive pustular dermatosis of the scalp is a rare
disorder that primarily occurs in older adults. The condition often develops after trauma or surgery
on the scalp [29,30]. It may also develop after treatment of actinic keratoses with topical agents or
photodynamic therapy [31]. Patients develop sterile pustules, erosions, and crusted plaques on the
scalp that lead to scarring (picture 9) [29,30].
A wide variety of conditions or events may cause secondary cicatricial alopecia. Inflammation from
a condition that is not a primary scalp disease and physical trauma are potential causes. Examples
include tinea capitis, neoplasms, radiation therapy, and surgical scars. (See "Tinea capitis".)
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Nonscarring alopecia — In nonscarring alopecias, clinical signs of
inflammation are usually mild or absent and destruction of the hair follicle does not occur.
Recognition of the distribution of nonscarring alopecia is useful for narrowing the differential
diagnosis (table 1B).
●Focal hair loss
•Alopecia areata – Alopecia areata is a relatively common form of nonscarring alopecia in which an
autoimmune process contributes to the loss of hair on the scalp or other areas. Most frequently, hair
loss occurs in patches (picture 10A-B). Another common pattern is loss at the occipital scalp
margin, called ophiasis. Occasionally, alopecia areata progresses to loss of all scalp or body hair. A
diffuse variant of alopecia areata that manifests with diffuse hair thinning also occurs. (See
"Alopecia areata: Clinical manifestations and diagnosis".)
•Alopecia syphilitica – Secondary syphilis can present with patchy hair loss on the scalp, which has
been described as "moth-eaten" alopecia (picture 11). Hair loss may also occur in other sites. (See
"Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected patients",
section on 'Clinical manifestations'.)
•Pressure-induced (postoperative) alopecia –Pressure-induced alopecia describes transient hair

loss that occurs in areas of prolonged pressure on the scalp, as may occur during general
anesthesia for long operative procedures [32,33]. Hair loss usually develops a few weeks after the
event. Regrowth occurs in most patients.
•Temporal triangular alopecia –Temporal triangular alopecia (also known as congenital triangular
alopecia) is a lifelong condition that is usually first noted in infancy or childhood as a triangular or
oval patch of alopecia in the temporal area (picture 12) [34,35]. The area of involvement is usually
only a few centimeters in diameter. Most cases are unilateral, though bilateral involvement may also
occur. Fine vellus hairs are visible in the affected area with close inspection. Hair transplantation is
an effective treatment [36,37].
•Traction alopecia – Traction alopecia results from prolonged pull or tension on the hair follicle,
usually due to hairstyles such as tight ponytails or braids. Traction alopecia from braids or hair
weaves is most commonly detected along the frontal and temporal hair lines (picture 13).
Longstanding traction can result in a transition to cicatricial alopecia with permanent hair loss. (See
"Traction alopecia".)
●Patterned
•Androgenetic alopecia in men (male pattern hair loss) – Androgenetic alopecia in men is
characterized by the slow, progressive loss of hair in a characteristic distribution (picture 14A-C).
The condition is mediated by the action of androgens on androgen-sensitive hair follicles in
genetically susceptible males. (See "Androgenetic alopecia in men: Pathogenesis, clinical features,
and diagnosis".)
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•Female pattern hair loss – Female pattern hair loss most frequently presents as hair thinning on the
frontal and crown areas of the scalp with relative sparing of the occipital scalp (picture 15A-B). The
frequency of this condition increases with age. (See "Female pattern hair loss (androgenetic
alopecia in women): Pathogenesis, clinical features, and diagnosis".)
•Trichotillomania –Trichotillomania is a disorder in which individuals repeatedly pluck hairs from the
scalp or other hair-bearing areas (picture 16A-C) [38]. The areas of alopecia may have irregular,
bizarre shapes.
●Diffuse
•Anagen effluvium –Anagen effluvium occurs as a result of an acute interruption of the anagen
phase and leads to extensive hair loss without transition of follicles into the catagen or telogen
phase. Hair loss typically occurs within two weeks of an inciting event. Chemotherapeutic agents are
a major cause of anagen effluvium. (See "Alopecia related to systemic cancer therapy".)
•Loose anagen syndrome –Loose anagen syndrome usually presents in young children (ages two to
five years) as slowly growing hair that can easily be pulled out without pain [39]. The hair density
may appear normal or reduced (picture 17). Affected children are often females with blond hair.
Loose anagen syndrome is characterized by the light microscopic finding of anagen hairs with a
ruffled cuticle and an absent inner root sheath (picture 18). The condition often improves with age
and may be sporadic or familial.
•Telogen effluvium –Telogen effluvium is a common cause of diffuse hair loss that usually presents
with acute or chronic loss of hair due to an abrupt shift of numerous hair follicles in anagen to the
telogen phase (picture 19A-B). Chronic telogen effluvium may also occur. Examples of factors that
may stimulate acute telogen effluvium include major physical or psychologic stressors, childbirth,
dietary restriction, and medications. Hair loss usually occurs two to three months after the inciting
event. Arsenic, thallium, or mercury poisoning can also result in telogen effluvium [40]. (See 'Medical
and family history' below.)
•Other –Alopecia areata and female pattern hair loss may present with diffuse hair thinning.
Additional rare causes of diffuse nonscarring hair loss include atrichia with papular lesions (MIM
#209500), a condition caused by a mutation in the hairless gene that results in hair loss within the
first year of life (picture 20) [41], and hypotrichosis simplex. Hypotrichosis simplex consists of a
group of hereditary alopecias in which diffuse hair loss usually begins in early childhood and
progresses until adulthood [42]. Multiple gene mutations have been linked to this condition [42].
Nonscarring alopecia may also occur as a direct consequence of scalp involvement with acute or
chronic inflammatory skin diseases. As examples, psoriasis, atopic dermatitis, seborrheic dermatitis,
and contact dermatitis may result in focal or diffuse hair loss. In addition, patients with systemic
lupus erythematosus may develop "lupus hair," which is described by dry, coarse hair along the
frontal hair line that usually occurs in association with disease flares [43]. Patients with systemic
lupus erythematosus may also develop telogen effluvium as a consequence of disease
exacerbations or medical treatments [43].
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Inherited and acquired structural hair
disorders — Structural hair abnormalities that result in brittle or fragile hair can lead to
hair breakage or the appearance of a failure of hair to grow. The hair fragility may result from
abnormal hair formation or external insults that damage the hair shaft. The most common structural
hair abnormalities are acquired trichorrhexis nodosa and trichoptilosis, both of which may occur as
a result of harmful hair care practices, such as chemical processing, excessive brushing or teasing
of hair, or the application of excessive heat. Trichorrhexis nodosa is characterized by disruption of
the protective cuticle and fraying of the hair shaft (picture 21A). Trichoptilosis is a term that
describes splitting and fraying of the distal end of the hair shaft, which is commonly referred to as
"split ends." Bubble hair (bubble-like structures within the hair shaft) is another microscopic finding
that may be seen in heat-damaged hair.
Examples of genetic conditions that cause hair fragility and excessive hair breakage include:
●Menkes disease –Patients with Menkes disease (MIM #309400), an X-linked disorder associated
with a defect in copper transport, develop hair fragility that is most prominent during childhood. The
mutation is in the gene encoding a copper transporting ATPase (ATP7A) [44]. Sparse, short, and
brittle hair with a kinky or steel wool-like quality is present (picture 22). Microscopic examination of
the hair shaft reveals pili torti (flattened, twisted hair) (picture 21C). Pili torti may also be seen as an
isolated congenital disorder or a manifestation of other genetic conditions.(See "Overview of dietary
trace elements", section on 'Menkes disease'.)
●Monilethrix –Monilethrix (MIM #158000) is a genetic condition that is usually associated with an
autosomal dominant pattern of inheritance. Most cases occur due to mutations in the hair cortex
keratin genes, KRT81, KRT83, or KRT86 [45]. Patients present with short, brittle hair (picture 23).
Microscopic examination of the hair shaft reveals elliptical nodes, resulting in a beaded appearance
(picture 21D). Examples of other potential findings in monilethrix include brittle nails, keratosis
pilaris, cataracts, and tooth abnormalities.
●Trichothiodystrophy –Trichothiodystrophy (MIM #601675) is an autosomal recessive disorder that

manifests with sulfur-deficient, short, brittle hair (picture 24). Microscopic examination of the hair
reveals trichoschisis (transverse fractures of hair) (picture 21B). Examination of the hair shaft under
polarized light demonstrates alternating light and dark bands that resemble a "tiger tail" pattern.
Patients may have accompanying features such as photosensitivity, ichthyosis, intellectual
impairment, decreased fertility, and short stature. Mutations in the XPD, XPB, and p8/TTDA subunits
of the transcription/repair factor TFIIH have been linked to trichothiodystrophy with photosensitivity
[46].
●Trichorrhexis invaginata –Trichorrhexis invaginata (also known as "bamboo hair" or "ball and
socket" deformity) is a hair shaft disorder that results from intussusception within the hair shaft
(picture 21E). Trichorrhexis invaginata is a pathognomonic finding of Netherton syndrome (OMIM
#256500), but may also occur as a sporadic disorder or in combination with other hair shaft
disorders. (See "Netherton syndrome".)
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Individuals with Netherton syndrome (OMIM #256500), an autosomal recessive disorder, develop
atopy, ichthyosis (ichthyosis linearis circumflexa), and short, sparse hair (picture 25A-B). Mutations
in the SPINK5 gene encoding the serine protease inhibitor lymphoepithelial Kazal-type related
inhibitor (LEKTI) lead to this disorder [47]. Clinicians should be aware that trichorrhexis invaginata is
not evident in every hair. Multiple hairs may need to be examined before trichorrhexis invaginata is
detected.
Examples of other rare inherited conditions that may result in hair fragility include inherited
trichorrhexis nodosa, Björnstad syndrome, ectodermal dysplasias, and argininosuccinic aciduria.
Structural hair disorders may also occur without associated hair fragility. Examples include pili
annulati, uncombable hair syndrome (picture 26), and woolly hair.
PATIENT INTERVIEW The patient interview, if performed

carefully, can provide valuable clues for diagnosis. In general, the interview should include an
assessment of the nature of hair loss, the patient's medical history (including medication and
supplement use), the patient's hair care practices, and the patient's family history as it relates to hair
loss and potential causes of hair loss.
Description of hair loss — Questioning about the nature of hair loss

consists of an assessment of the course and pattern of hair loss, as well as associated symptoms.
This can be particularly helpful for narrowing the differential diagnosis in patients with physical
findings that suggest nonscarring alopecia.
●Duration and rate of progression of hair loss – Knowledge of the duration and progression of hair
loss is useful for differentiating between congenital and acquired disorders, and between acute,
chronic, or transient conditions.
●Location and pattern of hair loss –In conjunction with the physical examination, the patient's
description of the distribution of hair loss may help to distinguish focal, patterned, and diffuse hair
loss (see 'Nonscarring alopecia' above). Since some disorders characterized by scalp hair loss may
involve other hair-bearing areas, patients should also be asked about the presence of additional sites
of hair loss.
●Extent of hair loss –When evaluating patients with a complaint of diffuse hair loss, the knowledge
that normal hair loss ranges from 50 to 150 hairs per day is useful for comprehending the magnitude
of the patient's complaint [2]. Of note, for patients who shampoo hair infrequently, marked increases
in hair loss may be noted on shampoo days due to the manual dislodging of telogen hairs that would
have been progressively shed with more frequent manipulation of the hair.
Patient descriptions of physical changes noted (eg, a thinning ponytail or increased visibility of the
scalp through hair) and review of prior photographs also may be useful for assessing the degree of
hair loss. On average, a 30 percent decrease in hair density occurs before hair loss is easily
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appreciated by individuals other than the affected patients [43]. In particular, patients with thick,
coarse hair at baseline may not appear to have clinically concerning hair loss until a major reduction
in hair density has occurred.
●Associated symptoms –Although symptoms such as pain, tenderness, pruritus, or burning

sensations are not always consistently detected in specific types of hair loss, the recognition of
associated symptoms can be useful for supporting a diagnosis. In addition, in patients who appear
to have a form of hair loss that is typically asymptomatic, the presence of symptoms may indicate
the presence of an additional disorder (eg, pruritus from seborrheic dermatitis in a patient with
androgenetic alopecia).
●Differentiation of hair shedding from hair breakage –Patients who are focused on their hair loss
may be able to communicate information that helps to distinguish hair shed from the follicle from
hair breakage. Patients with disorders associated with shedding of telogen hairs from follicles may
describe the hair loss as occurring from "the roots," meaning that they have noticed a small white
bulb at the proximal end of lost hairs (figure 2). In contrast, the follicular portion of the hair shaft is
absent in broken hairs.
●Hair care practices – Questions about hair care practices are particularly relevant in patients with
features suggestive of hair breakage or traction alopecia. Hair care practices that damage the hair
shaft are a common cause of hair breakage and prolonged traction of hair by tight braids, ponytails,
or other means can lead to traction alopecia.
Medical and family history — Questions about the patient's medical

and family history may be useful for diagnosis. As an example, for women with clinical features
suggestive of patterned hair loss, questions about irregular menses, hirsutism, infertility, and signs
of virilization may provide clues about an underlying hormonal disorder as a contributor to the
condition. (See "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical
features, and diagnosis", section on 'Diagnosis' and "Evaluation of premenopausal women with
hirsutism" and "Diagnosis of polycystic ovary syndrome in adults".)
In addition, telogen effluvium, one of the most common causes of nonscarring hair loss, may be
induced by factors that can be detected via a medical history (see "Telogen effluvium"). Potential
contributing factors include [40]:
●Drugs(table 2)
●Poor diet (caloric or protein restriction)
●Medical disorders and medical events
•Major illness or surgeries
•Major psychologic stress
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•Significant weight loss
•Chronic iron deficiency
•Thyroid disorders
•Childbirth
•Poisoning from arsenic, mercury, or thallium
The clinical history may also be useful when a diagnosis that may present with associated clinical
findings is being considered. Examples of questions that may be useful include inquiries about a
history of lichen planus in a patient with lichen planopilaris and questions about a history of
hidradenitis suppurativa or severe acne in a patient with folliculitis decalvans. (See "Lichen planus",
section on 'Clinical features' and "Hidradenitis suppurativa: Pathogenesis, clinical features, and
diagnosis".)
Obtaining a family history of similar hair loss can be useful because genetics play a role in
susceptibility to multiple hair diseases. Sometimes patients will deny a family history of hair loss
because their parents were not fully bald. Asking about both hair thinning and balding is helpful for
identifying a family history of alopecia.
PHYSICAL EXAMINATION The physical examination of

the patient with a complaint of scalp hair loss involves the examination of the scalp, hair, and other
body sites.
Scalp and hair examination — Ideally, the scalp and hair

examination should be performed with the patient in a position that allows the clinician to examine
the scalp from above comfortably, such as the clinician in a standing position and the patient seated
in a chair. Good lighting is essential. Examination techniques such as trichoscopy and the hair pull
test may be helpful.
Visual inspection — The first step of the physical examination consists of inspection
of the entire scalp for physical clues that may aid with diagnosis, such as erythema, scales, papules,
pustules, erosions, or excoriations. The presence or absence of follicular ostia (the pinpoint
openings from which hair emerges from the scalp) within affected areas also should be noted; a lack
of follicular ostia suggests a scarring alopecia. Among the primary cicatricial alopecias, pustules
are most likely to be seen in neutrophilic or mixed cicatricial alopecias.
The examination of the hair should include an assessment of the distribution and density of hair on
the scalp to identify the pattern and degree of hair loss. Hair density is best assessed by parting the
hair and noting the amount of space between the parts [48]. Comparing the frontal hair density to the
occipital hair density is particularly useful for female pattern hair loss. In female pattern hair loss,
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hair density on the frontal and vertex scalp is reduced, while hair on the occipital scalp is relatively
spared. A Christmas-tree-like pattern of hair loss (with a wider part at the frontal hairline) is often
evident in the involved area (picture 15A-B). (See "Female pattern hair loss (androgenetic alopecia in
women): Pathogenesis, clinical features, and diagnosis", section on 'Physical examination'.)
The hair shafts are then evaluated for caliber, length, shape, fragility, and texture. Distinguishing
between terminal and vellus hairs is particularly helpful for the diagnosis of male and female pattern
hair loss, disorders in which terminal hairs transition to vellus hairs. Broken hairs, which suggest a
structural hair disorder, may also be noted during this step. Hair fragility can be further assessed by
grasping a cluster of hair fibers in two places and tugging in opposite directions [48].
Features associated with certain forms of hair loss may also be detected during examination of the
hair and may aid in diagnosis. Examples include exclamation point hairs in alopecia areata (picture
27), tufted folliculitis in folliculitis decalvans and other cicatricial alopecias (picture 7B), follicular
plugging in discoid lupus erythematosus (picture 3A), and keratotic follicular papules in lichen
planopilaris (picture 5B).
A tool that can be helpful during the hair examination is a small piece of white or black paper. The
color should contrast with the color of the patient's hair (eg, white paper for a patient with dark hair).
Placing the paper behind the hairs being examined facilitates visualization of the hairs [48]. This
procedure also is helpful for differentiating the tapered tips of regrowing hairs from the blunt tips of
broken or cut hairs.
Trichoscopy — Dermoscopy, a technique in which a handheld magnifier is used to

visualize skin structures, can aid in the examination of patients with hair loss. Some devices are
equipped for photography. (See "Overview of dermoscopy".)
Dermoscopy of the hair and scalp (trichoscopy) facilitates the examination of the epidermis,
follicular ostia, hair shafts, perifollicular scale and erythema, and blood vessels [49]. Certain
dermoscopic findings have been linked to particular forms of hair loss [49-54]. (See "Overview of
dermoscopy of the hair and scalp".)
Examples of trichoscopic features of follicular ostia that may aid in diagnosis include [49]:
●Absence of follicular ostia (suggests cicatricial alopecia)
●Black dots (indicates hairs broken or destroyed at the level of the scalp as may occur in alopecia
areata, dissecting cellulitis, tinea capitis, and some other disorders)
●Yellow dots (indicates accumulation of keratotic material or sebum, as may occur in alopecia
areata, discoid lupus erythematosus, male or female pattern hair loss, and some other disorders)
●Fibrotic white dots (indicates fibrosis as may occur in primary cicatricial alopecias)
Examples of hair shaft abnormalities that may be detected with trichoscopy include [49]:
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●Exclamation point hairs (as may occur in alopecia areata, trichotillomania, or chemotherapy-
induced alopecia) (picture 27)
●Comma or corkscrew hairs (as may occur in tinea capitis) (picture 28)
●Pohl-Pinkus constrictions (thinning of the hair shaft), as may occur in alopecia areata;
chemotherapy-induced alopecia; blood loss; malnutrition; or chronic intoxication
●Increased proportion of vellus hairs (as may occur in male or female pattern hair loss or alopecia
areata)
●Hair shaft changes correlating with genetic hair shaft disorders
Hair pull test — A hair pull test identifies active hair loss and should be performed on
every patient who presents with a complaint of hair loss. It is important to consider that patients
with hair loss may have concerns about pulling out additional hair; therefore, good communication is
essential.
To perform the test, 50 to 60 hair fibers are grasped close to the skin surface and tugged from the
proximal to the distal end. The easy extraction of more than six hair fibers suggests the presence of
active hair loss. The proximal ends of hairs obtained by the hair pull test can be microscopically
examined to determine the type of hairs removed (eg, telogen, anagen, dystrophic, or broken hairs)
(figure 2).
Examination of other sites — Some hair loss disorders are associated

with abnormalities in areas other than the scalp. Depending on the disorder, additional hair, nail, skin,
tooth, or other abnormalities may be seen. Examining the entire skin surface, nails, and teeth at the
time of the initial evaluation is useful for identifying additional sites of involvement and associated
features.
DIAGNOSTIC TECHNIQUES If the cause of hair loss

remains uncertain following the patient history and physical examination, additional tests may
assist with diagnosis. Microscopic examination of hair shafts and scalp biopsies are commonly
performed in clinical practice.
Microscopic examination — When patients present with diffuse hair

shedding, microscopic evaluation of the proximal ends of shed hairs is useful for determining the
type of hairs that are being shed (eg, telogen, anagen, or dystrophic anagen hairs). For patients with
hair breakage, microscopic examination of the hair shaft may identify structural abnormalities that
contribute to hair fragility (picture 21A-E); this is done by cutting hairs close to the scalp surface.
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The use of 1 to 2 drops of a mounting medium (eg, Permount) when placing the hair shafts between
a glass slide and a coverslip optimizes the examination [48]. Examinations for pili torti are an
exception; the shadows and twists of pili torti are best visualized when the hair is examined dry,
without a mounting medium [48].
Of note, microscopic examination under polarized light is necessary for visualization of the "tiger-
tail" pattern seen in patients with trichothiodystrophy. (See 'Inherited and acquired structural hair
disorders' above.)
Scalp biopsies — Scalp biopsies can be a useful tool for the evaluation of hair loss
when the diagnosis is uncertain. Scalp biopsies can distinguish scarring from nonscarring alopecia,
and can provide information that further narrows the differential diagnosis. We perform scalp
biopsies to confirm the diagnosis in all patients with cicatricial alopecia. Scalp biopsies are not
usually performed for the diagnosis of hair shaft disorders due to the ability to diagnose these
disorders with light microscopic examination of the hair shaft. However, in genetic structural hair
disorders, abnormalities also may be evident when the intrafollicular portion of the hair shaft is seen
on histologic examination.
Cicatricial alopecia — In patients with suspected cicatricial alopecia, scalp biopsies

for diagnosis should be performed in sites of active disease. Features that suggest sites of active
disease include the presence of primary lesions, symptoms, or a positive pull test [14]. The
peripheral margin of an area of alopecia usually is the preferred site for a biopsy. Some hair should
remain in the biopsy site; areas of end-stage, complete balding should be avoided.
Many dermatopathologists prefer to receive two punch biopsy specimens, since this allows for
evaluation of the tissue in both vertical and transverse sections [14]. We usually perform two 4 mm
punch biopsies. If only one biopsy can be performed, transverse sections are preferred [13,14]. The
punch biopsies should be performed at an angle that mimics the direction of hair growth. (See "Skin
biopsy techniques", section on 'Punch biopsy'.)
The vascular nature of the scalp can lead to significant bleeding during surgical procedures. To
decrease bleeding, we inject 1% lidocaine with epinephrine for anesthesia and wait up to 10 minutes
prior to performing the biopsy.
Nonscarring alopecia — Scalp biopsies are less frequently performed in patients

with nonscarring alopecias, since the clinical picture and patient history often provide the diagnosis.
However, when the diagnosis remains uncertain, scalp biopsies can be useful for ruling in or ruling
out certain diagnoses (table 1A-B). Pathologic assessment of the proportion of anagen, catagen, and
telogen follicles; the proportion of terminal and vellus hairs; the follicular structure; and the degree of
inflammation can aid in distinguishing among the different types of nonscarring alopecia and can
provide important information for treatment selection and setting patient expectations. Scalp
biopsies are particularly useful for distinguishing among the diffuse presentations of alopecia
areata, telogen effluvium, and female pattern hair loss.
105
A single scalp biopsy processed with transverse sections usually is sufficient for the evaluation of
patients with clinical features suggestive of nonscarring alopecia [40].
Trichograms and phototrichograms — Trichograms and

phototrichograms are techniques for the evaluation of nonscarring hair loss that are primarily used
in research studies and specialized hair centers. Trichograms and phototrichograms can be used to
assist with diagnosis and following the response to treatment.
To perform a trichogram, approximately 25 to 50 hairs are grasped close to the scalp with a needle
holder. The hairs are then sharply plucked from the scalp. Following this, the proximal ends of the
hairs are microscopically examined to evaluate the proportion of hairs in each stage of the hair cycle
and to determine whether dystrophic hairs are present.
A phototrichogram is a less traumatic procedure in which hairs in a defined area are clipped to a
length of approximately 1 mm and photographed. This baseline photograph can be used to assess
hair density and the proportion of vellus, intermediate, and terminal hairs [55]. The same site is
photographed two to three days after the initial photograph to assess hair growth. Since only anagen
hairs grow substantially, catagen hairs elongate only slightly, and telogen hairs remain stable, the
proportion of anagen, catagen, and telogen (resting) hairs can be estimated by comparing the two
photographs [56].
Phototrichogram technology has evolved to include contrast-enhanced phototrichograms. Contrast-

enhanced phototrichograms involve the use of high-resolution photography and hair dye that
augments the contrast between hair color and skin color [56]. In addition, a software-based system
for performing phototrichograms (TrichoScan) has been developed [57].
Laboratory studies — Depending on the type of hair loss suspected, serologic

and microbiologic studies may also be useful for obtaining information to support the diagnosis and
to detect associated disorders. For patients with new-onset diffuse, nonscarring hair loss without a
clear cause, an initial laboratory evaluation focused on identifying potential causes can be
performed. Suggested initial laboratory tests for the primary care setting include thyroid stimulating
hormone to assess for thyroid disease as well as serum iron and ferritin to assess for iron
deficiency. In addition, a rapid plasma reagin test to rule out syphilitic alopecia is appropriate for
patients with patchy hair loss without visible inflammation or scarring.
Laboratory evaluation for hyperandrogenism can be beneficial for women presenting with both
pattern hair loss and other signs of hyperandrogenism, and testing for thyroid stimulating hormone
is typically performed for patients with alopecia areata, based upon an association of alopecia
areata with thyroid disease. The suggested laboratory work up for specific forms of alopecia is
discussed in detail in dedicated topic reviews in UpToDate. (See "Telogen effluvium", section on
'Laboratory tests' and "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis,
clinical features, and diagnosis", section on 'Laboratory tests' and "Alopecia areata: Clinical
manifestations and diagnosis", section on 'Additional evaluation'.)
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INDICATIONS FOR REFERRAL Patients with
signs of cicatricial alopecia (eg, hair loss with absent follicular ostia) should be referred to a
dermatologist for evaluation and management. Referral to a dermatologist is also indicated if the
cause of hair loss is unclear. Patients with extensive alopecia areata or chronic telogen effluvium
may also benefit from referral.
PATIENT SUPPORT Due to the cosmetic value placed upon hair in

many societies, hair loss can be a highly distressing condition. In addition to diagnosis and
treatment of the hair loss disorder, the clinician must also address the emotional and psychologic
well-being of the patient. Organizations such as the National Alopecia Areata Foundation
(www.naaf.org) and the Cicatricial Alopecia Research Foundation (www.carfintl.org) can provide
information and support for patients with hair loss. The North American Hair Research Society
(www.nahrs.org) is an additional source for information.

provided separately. (See "Society guideline links: Alopecia".)
SUMMARY AND
RECOMMENDATIONS
●Throughout life, hair follicles undergo cycling characterized by periods of growth (anagen),
involution (catagen), and rest (telogen). At any given time, 90 percent of hair follicles on the scalp are
in anagen. The duration of the anagen phase determines maximum length of hair growth. (See 'Hair
cycle' above.)
●Hair loss disorders can be divided into cicatricial (scarring) alopecias, nonscarring alopecias, and
structural hair disorders. When not treated early, cicatricial alopecias are characterized by
irreversible damage to the hair follicle that results in permanent hair loss. The primary cicatricial
alopecias are subdivided into lymphocytic, neutrophilic, and mixed inflammatory disorders (table
1A). (See 'Classification' above and 'Cicatricial alopecia' above.)
●Nonscarring alopecias are conditions in which the hair follicle is not destroyed; in many cases of
alopecia areata or telogen effluvium hair loss, spontaneous or treatment-induced hair regrowth can
occur. Recognition of the distribution of hair loss is useful for the diagnosis of nonscarring alopecias
(table 1B). (See 'Nonscarring alopecia' above.)
107
●Structural hair disorders result in fragile hair and may be inherited or acquired. Damaging hair care
techniques are a common cause of hair fragility. (See 'Inherited and acquired structural hair
disorders' above.)
●Assessment of the patient with hair loss begins with obtaining a description of hair loss from the
patient as well a medical history and family history. The physical examination incorporates
inspection of the scalp, hair, and other body sites. (See 'Patient interview' above and 'Physical
examination' above.)
●When the diagnosis remains uncertain after the patient history and clinical examination have been
performed, diagnostic techniques such as microscopic examination of cut or plucked hair fibers and
scalp biopsies may provide additional information that is helpful for diagnosis. Depending on the
differential diagnosis, additional laboratory studies may be performed. (See 'Diagnostic techniques'
above.)
ACKNOWLEDGMENT The editorial staff at UpToDate would like

to acknowledge Nina Otberg, MD, who contributed to an earlier version of this topic review.
108
Approach to the clinical dermatologic diagnosis
uptodate.com/contents/approach-to-the-clinical-dermatologic-diagnosis/print
Approach to the clinical dermatologic diagnosis
Author:
Cheryl A Armstrong, MD
Section Editors:
Robert P Dellavalle, MD, PhD, MSPH
Moise L Levy, MD
Deputy Editor:
Literature review current through: Apr 2020. | This topic last updated: Mar 11, 2019.
INTRODUCTION The initial approach to the patient presenting with a skin

problem requires a detailed history of the current skin complaint and a complete skin examination
(figure 1A-B) [1]. In many cases, the patient's general medical history may be relevant to the
diagnosis of skin disorders. Although the visual aspects are of primary importance in the recognition
of skin diseases, sometimes additional tests (eg, laboratory tests, skin biopsy) are required for
accurate diagnosis. (See "Office-based dermatologic diagnostic procedures" and "Skin biopsy
techniques".)
This topic will discuss the general approach to dermatologic diagnosis. The approach to the patient
with specific skin signs and symptoms is discussed separately. Skin biopsy techniques are
discussed separately. Laboratory tests used to refine or confirm a dermatologic diagnosis are
discussed in relevant topics. The approach to the patient with hair or nail abnormalities or oral
lesions is also discussed separately.
●(See "Approach to the patient with cutaneous blisters".)
●(See "Pruritus: Etiology and patient evaluation".)
●(See "Acquired hyperpigmentation disorders".)
●(See "Approach to the patient with pustular skin lesions".)
●(See "Skin biopsy techniques".)
●(See "Evaluation and diagnosis of hair loss".)
●(See "Overview of nail disorders".)
109
●(See "Oral lesions".)
●(See "Approach to the patient with retiform (angulated) purpura".)
HISTORY The most important initial questions to ask patients with a skin problem
include the following:
●How long has the eruption or lesion been present?
●How did it look when it first appeared, and how is it now different?
●Where did it first appear, and where is it now?
●What associated symptoms, such as itching, stinging, tenderness, or pain, are associated with the
lesion?
●Are any other family members affected or have a similar history?
●Has the patient ever had this rash or lesion before? If so, what treatment was used, and what was
the response?
●What does the patient think caused the rash or lesion?
●Is anything new or different (eg, medications, personal care products, occupational or recreational
exposures)?
●How does the skin problem impact the patient's life?
●What treatments have been used, and what was the response, this time and previously?
Additional questions that may be helpful include:
●Does the patient have any acute or chronic medical conditions?
●What medications does the patient take currently, what have they recently taken, including over-the-
counter and herbal therapies?
●Is there a family history of skin disorders or skin cancer?
●Has there been any increase in stress in their life?
●What is the social history, including occupation, hobbies, travel?
●Does the patient have any allergies?
●Does the patient have pets?
110
●Does the patient have risk factors for sexually transmitted diseases?

a patient with a skin complaint, which includes visual inspection and palpation of the skin and
sometimes additional examination aided by a Wood's lamp or a dermatoscope, is aimed at
assessing the following:
●Morphology of individual lesions (type of lesion)
●Distribution of lesions
●Color
●Consistency and feel
●Number of lesions present
●Arrangement of multiple lesions (eg, scattered, clustered, grouped, linear, zosteriform, or

coalescing)
Visual inspection — The patient should always be examined in a good light and
with a magnifying lens, if necessary. Ideally, the entire skin should be examined in every patient,
particularly if the diagnosis is in doubt, as this may reveal lesions that are more representative and
have not been modified by secondary changes [1]. Moreover, a full-body skin examination, including
nails, hair, and mucosal surfaces, may reveal a lesion or eruption of which the patient may be
unaware.
Patients may occasionally provide self-taken digital images of skin lesions or eruptions. They may
be useful in assessing changes over time or documenting evanescent eruptions, such as urticaria.
For the experienced clinician, visual inspection may sometimes provide an instant diagnosis.
However, such apparently effortless pattern recognition is actually an extremely complex
"nonanalytical reasoning" process where the individual components are analyzed separately [1-3].
Knowing which conditions are more frequently diagnosed can assist the clinician in arriving at the
most likely diagnosis for a given patient. In the United States, the top 10 most common dermatologic
conditions seen by dermatologists and nondermatologists between 2001 and 2010 were acne,
actinic keratosis, nonmelanoma skin cancer, benign tumors, contact dermatitis, seborrheic keratosis,
viral warts, psoriasis, rosacea, and epidermoid cyst [4].
Examination of highly pigmented skin — The

examination of patients with moderately to highly pigmented skin (Fitzpatrick skin types III to VI
(table 1)) requires a degree of clinical experience because the amount of pigmentation clearly
111
influences the characteristics of certain skin lesions. In patients with heavily pigmented skin, most
dermatoses induce darkening or lightening of the skin that affect our perception of the color of the
lesion and overwhelm other clinical manifestations [5]:
●Erythema may be particularly challenging to detect in dark-skinned individuals as it may appear

dark brown or violaceous instead of pink or red, as typically seen in patients with lighter
complexions. As an example, rosacea may be underdiagnosed in patients with darker skin tones
because erythema and telangiectasias are more difficult to appreciate in darker skin (picture 1) [6].
●The typical erythematous and scaly lesions of eczema may appear as scaly lesions with a grayish,
violaceous, or dark brown hue (picture 2A-B). Hyperpigmented areas may be mistaken for
postinflammatory hyperpigmentation, when in fact they are a marker of active inflammation.
●Wheals of urticaria appear skin-colored or paler because dermal edema lightens the skin (picture
3A-B). Papules may be pale or dark according to the degree of edema or the presence of acanthosis
or hyperkeratosis, which mask the natural pigmentation.
●Purpura may be difficult to detect, as it may be obscured by the skin color (picture 4).
●Dry skin may have a whitish or ashy color and a reduction in skin shininess (picture 5).
●Postinflammatory hypopigmentation (picture 6) and hyperpigmentation (picture 7A) are

exaggerated in darkly pigmented skin compared with lighter skin.
Moreover, some skin conditions are more frequently seen in patients of African descent and need to
be considered for accurate diagnosis, especially in their early manifestations [7]. They include:
●Acne keloidalis (picture 8) (see "Acne keloidalis nuchae")
●Pseudofolliculitis barbae (picture 9A-C) (see "Pseudofolliculitis barbae")
●Central centrifugal cicatricial alopecia (picture 10A-C) (see "Central centrifugal cicatricial alopecia")
●Dissecting cellulitis of the scalp (picture 11A-B) (see "Dissecting cellulitis of the scalp")
●Traction alopecia (picture 12A-B) (see "Traction alopecia")
●Dermatosis papulosis nigra (picture 13A-B) (see "Overview of benign lesions of the skin", section
on 'Dermatosis papulosa nigra')
●Keloids (picture 14A-D) (see "Keloids and hypertrophic scars")
Palpation of the skin — In addition to visual examination, palpation of skin

lesions has a central role in the diagnosis of skin diseases [8]. Intact skin can be palpated without
gloves after hands are sanitized or washed. Gloves should be worn when palpating nonintact skin
and for the examination of the mouth, genital, and perineal region.
112
Palpation provides information on the quality of scale or keratosis, texture changes, and skin
temperature, and detects consistency, induration, tenderness, depth, and fixation of a lesion.
Exerting pressure on the skin can demonstrate edema, blanching, or dermal defects. Examples of
the usefulness of skin palpation include:
●In morphea or scleroderma, dermal fibrosis can be felt as skin induration on palpation, where visual
inspection would detect only nonspecific hypo- or hyperpigmentation. (See "Pathogenesis, clinical
manifestations, and diagnosis of morphea (localized scleroderma) in adults".)
●Thin actinic keratoses are more easily "felt" than seen. (See "Epidemiology, natural history, and
diagnosis of actinic keratosis".)
●In a patient presenting with bullae, applying shearing forces to the skin can show skin detachment,
as in the Nikolsky sign in pemphigus. (See "Approach to the patient with cutaneous blisters", section
on 'Nikolsky sign'.)
●Stroking or rubbing with a tongue blade can demonstrate dermographism or urtication of mast cell
lesions (Darier's sign). (See "Physical (inducible) forms of urticaria", section on 'Dermographism' and
"Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations",
section on 'Darier's sign'.)
●Olfactory clues may help establish a diagnosis in rare cases. For instance, the epidermolytic
ichthyoses have a distinctive odor, as does pseudomonas infection.
ADDITIONAL EXAMINATION
Wood's light examination — A Wood's light is a hand-held source of
ultraviolet light from which virtually all visible rays have been excluded by a Wood's (nickel oxide)
filter. Under Wood's light, variations in epidermal pigmentation are more apparent than under visible
light, and some microorganisms may emit a fluorescence. As an example, the depigmented areas of
vitiligo are greatly enhanced under Wood's light, and erythrasma patches may appear as pink
fluorescent areas. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp
examination (black light)'.)
Dermoscopic examination — Dermoscopy, also known as

dermatoscopy or epiluminescence microscopy, is a skin examination technique performed with a
handheld instrument called a dermatoscope. The procedure allows the visualization of subsurface
skin structures in the epidermis, dermoepidermal junction, and upper dermis that are usually not
visible to the naked eye (picture 15A-B).
Dermoscopy is primarily used for the examination of pigmented skin lesions but can also assist
clinicians in assessing many nonpigmented skin lesions [9-11]. In general dermatology and in
primary care practices, the primary purpose of dermoscopy is the evaluation of pigmented and
113
nonpigmented skin lesions to decide whether or not a lesion should be biopsied or referred [12,13].
Dermoscopy requires some formal training to be effectively practiced [14,15]. Online tutorials on
dermoscopy can be found at www.dermnetnz.org/doctors/dermoscopy-course/introduction.html,
www.dermoscopy-ids.org/index.php/education/podcasts, or www.genomel.org/dermoscopy.
The principles of dermoscopy and dermoscopic examination of cutaneous lesions are discussed in
detail separately. (See "Overview of dermoscopy" and "Dermoscopic evaluation of skin lesions" and
"Dermoscopy of facial lesions" and "Dermoscopy of mucosal lesions" and "Dermoscopy of
pigmented lesions of the palms and soles" and "Overview of dermoscopy of the hair and scalp" and
"Dermoscopy of nail pigmentations" and "Dermoscopy of nonpigmented nail lesions".)
LESION MORPHOLOGY AND

DISTRIBUTION Two of the most useful characteristics that aid in forming a
differential diagnosis are the morphology of individual lesions (type of lesion) and distribution of
lesions. The arrangement of lesions in relationship to each other, the color of lesions, and the
consistency and feel of lesions also add important information.
Primary lesions — Primary lesions represent the initial pathologic change. The
terms used to describe primary skin lesions include the following:
●Macules are nonpalpable lesions <1 cm that vary in pigmentation from the surrounding skin
(picture 16A-C). Patches are nonpalpable lesions >1 cm. These lesions are flush with the
surrounding skin. The differential diagnosis of macules is shown in the table (table 2).
●Papules are palpable, discrete lesions measuring <1 cm in diameter (picture 13B). They may be
isolated or grouped. The differential diagnosis of papules is shown in the table (table 3).
●Plaques are elevated lesions that are >1 cm in diameter. Plaques may be formed by a confluence of
papules (picture 17A-B). The differential diagnosis of plaques is shown in the table (table 4).
●Nodules are palpable, solid or cystic, discrete lesions measuring between 1 and 2 cm in diameter.
Tumors are solid or cystic, discrete lesions measuring >2 cm in diameter. These lesions may be
isolated or grouped and may or may not have surface changes (picture 18A-B). The differential
diagnosis of tumors and nodules is shown in the table (table 5). (See "Overview of benign lesions of
the skin".)
●Telangiectasia is a dilated superficial blood vessel (picture 19).
●Purpura are red-purple lesions that do not blanch under pressure, resulting from the extravasation
of blood from cutaneous vessels into the skin. Purpuric lesions can be macular or raised (palpable
purpura) (picture 20).
114
●Pustules are small, circumscribed skin papules containing purulent material (picture 21A-B). The
differential diagnosis of pustules is shown in the table (table 6).
●Vesicles are small (<1 cm in diameter), circumscribed skin papules containing clear serous or
hemorrhagic fluid (picture 22). Bullae are large (>1 cm in diameter) vesicles. The differential
diagnosis of vesicles and bullae is shown in the table (table 7).
●Wheals are irregularly shaped, elevated, edematous skin areas that may be erythematous or paler
than surrounding skin (picture 3A-C). The borders of a wheal are well demarcated but not stable;
they may move to adjacent, uninvolved areas over periods of hours.
●Scale is flakes on the skin surface formed by desiccated, thin plates of cornified epidermal cells
(picture 23A-B).
●Atrophy is a depression from the surface of the skin caused by underlying loss of epidermal or
dermal substance (picture 24A-B).
●Hyperpigmentation is increased skin pigment (picture 7A-B); hypopigmentation is decreased skin

pigment (picture 25). Depigmentation is total loss of skin pigment (picture 26).
Secondary lesions — Secondary lesions of the skin represent evolved changes

from the skin disorder, due to secondary external forces, such as scratching, picking, infection, or
healing. Examples include:
●Excoriation describes superficial, often linear skin erosion caused by scratching (picture 27A-B).
●Lichenification is dry, leathery thickening of the skin with exaggerated skin markings secondary to
chronic inflammation caused by scratching or other irritation (picture 2B-E).
●Edema is swelling due to accumulation of water in tissue (picture 28).
●Scale describes superficial epidermal cells that are dead and cast off from the skin (picture 29).
●Crust is dried exudate of serum, blood, sebum, or purulent material on the surface of the skin, a
"scab" (picture 30).
●Fissure is a deep skin split extending into the dermis (picture 31).
●Erosion is a superficial, focal loss of part of the epidermis (picture 32A-B). Ulceration is focal loss
of the epidermis extending into the dermis. Lesions may heal with scarring (picture 33). The
differential diagnosis of erosions and ulcers is shown in the table (table 8).
●Scar is fibrous tissue that replaces normal dermal or subcutaneous tissue after skin injury (picture
34).
115
Lesion distribution — The location of one or multiple skin lesions and the
arrangement of multiple lesions in relation to each other can suggest a particular diagnosis. Initial
differential diagnoses based on typical distributions of common skin dermatoses are summarized in
the table (table 9) and shown graphically in the figures (figure 1A-B).
Common arrangements of lesions are:
●Clustered, as seen in herpes simplex infections (picture 22)
●Grouped, as seen in dermatitis herpetiformis (picture 35A-B) and granuloma annulare (picture 36)
●Linear, as seen in contact dermatitis (picture 37 and picture 38) and morphea (picture 39A-B)
●Zosteriform, as seen in herpes zoster infection (picture 40A-C) and metastatic breast carcinoma
●Coalescing or confluent, as seen in psoriasis and viral exanthems (picture 41)
Certain dermatologic conditions have a predilection for particular parts of the body and are seen in
distinct demographic groups. As an example, tinea capitis is a common scalp eruption in children
but is rare in adults. In contrast, tinea pedis is seen frequently in adults but rarely in children. Thus,
when a child presents with foot lesions, diagnoses in addition to tinea must be considered, including
atopic dermatitis, scabies, drug eruptions, and contact dermatitis. An adult with a scalp eruption is
likely to have seborrheic dermatitis, psoriasis, or allergic contact dermatitis. That said, it is important
to keep an open mind and broad differential diagnosis in all patients to avoid missing atypical
presentations.
SUMMARY
●The initial approach to the patient presenting with a skin problem requires a detailed history of the
current skin complaint and a full body skin examination (figure 1A-B). In some cases, the patient's
general medical history may be relevant to the diagnosis of skin disorders. (See 'Introduction'
above.)
●Key questions for the patient include the time of onset, duration, location, evolution, and symptoms
of the rash or lesion. Additional information on family history, occupational exposures,
comorbidities, medications, and social or psychologic factors may be helpful. (See 'History' above.)
●The physical examination of a patient with a skin complaint includes visual inspection and
palpation of the skin and sometimes additional examination aided by a Wood's lamp or a
dermatoscope. (See 'Physical examination' above.)
●The morphology, arrangement, and distribution of the lesions are cardinal features to be identified
by visual inspection and palpation. In many cases, the location of one or multiple skin lesions and
the arrangement of multiple lesions in relation to each other can suggest a particular diagnosis
116
(table 9 and figure 1A-B). (See 'Lesion morphology and distribution' above.)

to acknowledge Adam O Goldstein, MD, MPH, and Beth G Goldstein, MD, who contributed to an
earlier version of this topic review.

GRAPHICS
117
Common disorders encountered during the physical examination of skin, front view
Reproduced with permission from Fitzpatrick TB, Bernhard JD, Copley TG. In: Dermatology in
General Medicine, Freedberg IN, Eisin AZ, Wolff K, et al. (Eds), 5th ed, McGraw-Hill 1999. Copyright ©
1999 The McGraw-Hill Companies, Inc.
118
Common disorders encountered during the physical examination of skin, back view
Reproduced with permission from: Fitzpatrick TB, Bernhard JD, Copley TG. In: Dermatology in
General Medicine, Freeberg IN, Eisin AZ, Wolff K, et al. (Eds), 5th ed, McGraw-Hill 1999. Copyright ©
1999 The McGraw-Hill Companies, Inc.
119
Fitzpatrick skin phototypes
Skin type Unexposed skin color Reaction to sun exposure*
I White Always burns, never tans
II White Always burns, minimal tan
III White to olive Burns minimally, gradually tans
IV Light brown Burns minimally, tans well
V Brown Very rarely burns, tans profusely
VI Dark brown to black Never burns, tans deeply
Note: Slight variations on the definitions of the phototypes appear in the literature.
* After the first one hour of sun exposure on untanned skin on the first day of spring.
120
Papulopustular rosacea
Inflammatory papules are present on the nose.
121
Atopic dermatitis
Atopic dermatitis involving the sides of the neck. Note the scaling and characteristic reticular
pigmentation.
122
Atopic dermatitis
Hyperpigmented, slightly scaly patches and lichenified plaques are present in the popliteal fossae of
this patient with atopic dermatitis.
123
Urticaria
A well-circumscribed plaque, slightly lighter-than-normal skin is visible on the neck of this patient
with urticaria.
124
Urticaria
Large, well-circumscribed plaques on the chest of this patient with urticaria.
125
Henoch-Schönlein purpura
Purpuric lesions are clearly visible on the plantar surface but less obvious on the lower leg in this
patient with Henoch-Schönlein purpura.
126
Xerosis (dry skin)
Reduced skin shininess and ashy appearance in this patient with extreme skin dryness.
127
Postinflammatory hypopigmentation in a patient with psoriasis
Macular hypopigmented lesions are present on the back of this patient after resolution of plaque
psoriasis.
128
Postinflammatory hyperpigmentation and scarring in acne vulgaris
Multiple hyperpigmented macules and scars on the lower face of a woman with acne vulgaris.
129
Acne keloidalis nuchae
Mild acne keloidalis nuchae. Multiple small, follicular papules on the posterior scalp and posterior
upper neck.
130
Pseudofolliculitis barbae
Tight, curly hairs that have been sharpened by shaving penetrate the skin on the chin and neck.
Inflammatory papules and pustules that resemble acne are evident.
Reproduced with permission from: Goodheart HP, MD. Goodheart's Photoguide of Common Skin
Disorders, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 2003. Copyright ©2003 Lippincott
Williams & Wilkins.
131
Hyperpigmented papules and small pustules are present on the mandible and neck.
132
Numerous erythematous and hyperpigmented papules are present on the beard area in this patient
with pseudofolliculitis barbae.
133
Central centrifugal cicatricial alopecia
Inflammatory central centrifugal cicatricial alopecia demonstrating hair loss on the crown of the
scalp, inflamed papules, pustules, and scarring.
134
Severe central centrifugal cicatricial alopecia demonstrating hypopigmentation, hyperpigmentation,

and extensive scarring.
135
Reduced hair density on the crown of the scalp in a patient with early central centrifugal cicatricial
alopecia.
136
Dissecting cellulitis of the scalp
Fluctuant nodules and areas of scarring alopecia on the scalp.
137
Multiple alopecic nodules and plaques with crusting at sites of drainage.
138
Traction alopecia
Hair loss on the anterior scalp is evident

in this patient with traction alopecia.
Reproduced with permission from:

www.visualdx.com. Copyright VisualDx.
All rights reserved.
139
Traction alopecia
Loss of the frontal hairline is evident in this patient with traction alopecia. Traction alopecia may
result from tightly braided hairstyles.
140
Dermatosis papulosa nigra
Numerous hyperpigmented papules on the cheek and periocular region of this patient with
dermatosis papulosa nigra.
141
Dermatosis papulosa nigra
Multiple hyperpigmented papules are present on the face of this patient with dermatosis papulosa
nigra.
142
Keloids
Keloids presenting as firm, smooth nodules on the ear.
143
Multiple small, pigmented seborrheic keratoses of the face (dermatosis papulosa nigra)
144
Keloids from acne
Firm papules and nodules on the posterior shoulder.
Reproduced with permission from: Stedman's Medical Dictionary. Copyright © 2008 Lippincott
Williams & Wilkins.
145
Keloids
Patient with large, spontaneous keloids on the upper back.
146
Clinical and dermoscopic image of lichen planus-like keratosis
(A) Lichen planus-like keratosis, also called lichenoid keratosis, presenting as a solitary, gray to
brown papule or plaque on the face.
(B) On dermoscopy, coarse, large, and partially confluent gray dots are seen.
Clinical and dermoscopic images of Merkel cell carcinoma
(A) Merkel cell carcinoma presenting as a red nodule with scaling on the cheek of this patient. Note
the background sun-damaged skin.
(B) Dermoscopy shows a polymorphous, vascular pattern composed of linear vessels over a pink
background. White scales are also present.
147
Vitiligo
Depigmented macular lesions in a patient with vitiligo.
148
Viral exanthem
Multiple erythematous macules are present on the skin of this patient with a viral exanthem.
149
Solar lentigines presenting as brown macules on the dorsum of the hand
Multiple brown macules are present on the dorsal hand.
150
Differential diagnosis of macules
Erythematous macules Hyperpigmented macules
Drug eruption Nevi
Viral exanthem Fixed drug eruption
Secondary syphilis Postinflammatory
Rheumatic fever Ephelis (freckle)
Photodistributed macules Lentigo
Drugs Schamberg's purpura
Dermatomyositis Nevus
Lupus erythematosus Mongolian spot
Porphyria cutanea tarda Purpura
Polymorphous light eruption Stasis dermatitis
Hypopigmented macules Melasma
Postinflammatory Melanoma
Tinea versicolor Ochronosis
Vitiligo Mastocytosis
Halo nevus Café-au-lait spot
Sarcoidosis
Tuberous sclerosis
Cutaneous T cell lymphoma
Leprosy
Differential diagnosis of papules
Isolated papules Papular eruptions
h d
151
Acrochordon Acne rosacea
Actinic keratosis Acne vulgaris
Angiofibroma Appendageal tumors (usually benign)
Appendageal tumors (benign or malignant) Arthropod bite
Bacillary angiomatosis Bacillary angiomatosis
Basal cell carcinoma Dermatomyositis
Chondrodermatitis nodularis helicis Drug eruption
Dermatofibroma Eczematous dermatitis
Fungal infections (early) Flat warts
Hemangioma Folliculitis
Keratoacanthoma Granuloma annulare
Melanoma Keratosis pilaris
Milia Lichen nitidus
Molluscum contagiosum Lichen planus
Neurofibroma Lichen sclerosus
Nevus Lupus erythematosus
Pyogenic granuloma Lymphoma
Sebaceous hyperplasia Miliaria
Seborrheic keratosis Molluscum contagiosum
Squamous cell carcinoma Neurofibromatosis
Venous lake Pediculosis corporis
Wart Perioral dermatitis
Pityriasis rosea
Polymorphous light eruption
Psoriasis
Sarcoidosis
152
Sarcoma
Scabies
Syphilis
Urticaria
Vasculitis
Viral exanthem
Xanthoma
Plaque psoriasis
An erythematous plaque with coarse scale is present on the knee of this patient with psoriasis.
153
Chronic plaque psoriasis
Multiple large plaques with silver scale on the back.
154
Differential diagnosis of plaques
Acanthosis nigricans Lymphoma (cutaneous T cell)
Candidiasis Morphea
Cellulitis Myxedema
Deep fungal infections Necrobiosis lipoidica diabeticorum
Dermatomyositis Paget's disease
Diaper dermatitis Pityriasis rosea
Eczematous dermatitis Psoriasis
Erythrasma Sarcoidosis
Tinea infections Seborrheic dermatitis
Granuloma annulare Sweet's syndrome
Ichthyosis Syphilis
Lichen planus Tinea versicolor
Lichen sclerosus Vasculitis
Lupus erythematosus Xanthelasma
Lyme disease
155
Erythema nodosum
Multiple erythematous nodules on the lower leg.
156
Multiple lipomas
Nodules are present on the arm of this patient with multiple lipomas.
157
Differential diagnosis of nodules and tumors
Acrochordon Lymphoma (cutaneous)
Angioma Melanoma
Appendageal tumors Metastatic carcinoma
Basal cell carcinoma Neurofibroma
Callus/clavus Nevus
Chondrodermatitis nodularis helicis Prurigo nodularis
Dermatofibroma Pyogenic granuloma
Dermatofibrosarcoma Seborrheic keratosis
Erythema nodosum Squamous cell carcinoma
Hidradenitis suppurativa Syphilis
Histiocytosis Tuberous sclerosis
Inclusion cyst Venous lake
Kaposi's sarcoma Wart
Keloid Xanthoma
Lipoma
158
Telangiectasias
Multiple telangiectasias are present on the nose.
159
Henoch-Schönlein purpura
Palpable, purpuric lesions on the legs of a child with Henoch-Schönlein purpura.
Courtesy of Moise L Levy, MD.
160
Inflammatory acne
Erythematous papules and pustules.
161
Folliculitis
Small, inflammatory papules and pustules are present in this patient with folliculitis. Erythema is
difficult to appreciate due to dark skin pigmentation. Postinflammatory hyperpigmentation is also
present.
162
Differential diagnosis of pustules
Acne vulgaris
Arthropod bite (fire ants)
Drug eruption
Eosinophilic folliculitis
Erythema toxicum neonatorum
Folliculitis
Fungal or yeast infections (especially tinea capitis and Majocchi's granuloma)
Furunculosis
Gonorrhea (disseminated)
Herpes simplex/zoster
Impetigo
Keratosis pilaris
Neonatal pustulosis
Pustular psoriasis
Pyoderma gangrenosum
Rosacea/perioral dermatitis
Syphilis
Varicella
163
Herpes simplex infection
Grouped vesicles on erythematous background are characteristic of recurrent herpes simplex

infection.
164
Differential diagnosis of vesicles and bullae
Bullous disease in diabetes Herpes zoster
Bullous pemphigoid Id reaction
Burn Impetigo
Cellulitis Insect bite reaction
Congenital syphilis Lichen planus
Contact dermatitis Lupus erythematosus (bullous)
Dermatitis herpetiformis Pemphigus vulgaris/foliaceus
Eczema (especially hand/foot) Porphyria cutanea tarda
Epidermolysis bullosa Scabies
Erythema multiforme Staphylococcal scalded skin
Fixed drug eruption Streptococcal toxic shock
Fungal infections (especially tinea pedis) Toxic epidermal necrolysis
Hand, foot, and mouth disease Varicella
Herpes gestationis Vasculitis
Herpes simplex
165
Urticaria
Skin-colored wheals are present.
Reproduced with permission from: Goodheart

HP. Goodheart's Photoguide of Common Skin
Disorders, 2nd Edition. Philadelphia: Lippincott
Williams & Wilkins, 2003. Copyright © 2003
Lippincott Williams & Wilkins.
166
Annular psoriasis plaque.
167
Thick scale on the temporal scalp.
168
Extragenital lichen sclerosus
Multiple white, atrophic plaques are present on the chest.
169
Extragenital lichen sclerosus
Atrophic plaques with mottled hyperpigmentation are present on the shoulder and arm.
170
Lichenoid drug eruption (drug-induced lichen planus)
Hyperpigmentation following the resolution of lichenoid drug eruption.
171
Pityriasis alba
Hypopigmented macules are

present on the face of this young
girl with pityriasis alba.
Copyright © Nicole Sorensen, RN,

Dermatlas;
http://www.dermatlas.org.
Segmental vitiligo
Segmental vitiligo: patches of depigmentation

on the anterior trunk.
Reproduced with permission from: Stedman's

Medical Dictionary. Copyright ©2008 Lippincott
Williams & Wilkins.
172
Excoriations
Linear excoriations (secondary to scratching) are present.
173
Factitial dermatitis
Excoriated lesions and postinflammatory hyperpigmentation in a patient with factitial dermatitis.
174
Lichenification
Thickened skin with accentuated skin lines is present in this patient who chronically rubbed and
scratched this area.
175
Adult atopic dermatitis
Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings) of
the knee flexures in a 22-year-old woman.
Copyright © Monica Standish, RN, Dermatlas; http://www.dermatlas.org.
176
Adult chronic atopic dermatitis
Lichenified, hyperpigmented plaque in the elbow flexure of a 35-year-old woman with atopic
dermatitis.
Copyright © Yusoff Saifuzzaman, MD, Dermatlas; http://www.dermatlas.org.
177
Angioedema of the lips
Scale
Actinic keratosis. Scale overlies erythematous macules.
178
Impetigo
Crusted lesions in a patient with impetigo.
179
Hyperkeratotic hand eczema
Chronic, hyperkeratotic, and fissured hand eczema in a 69-year-old man.
Reproduced with permission from: Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Published
online at: www.dermis.net. Copyright © 1996-2015 DermIS. All rights reserved.
180
Erosions
Multiple shallow erosions are present in areas of sloughed skin in this patient with toxic epidermal
necrolysis.
181
Toxic epidermal necrolysis
Multiple bullae and areas of denuded epidermis are present.
Peristomal pyoderma gangrenosum is

caused by an inflammatory process that
produces severe and painful skin
ulcerations.
Courtesy of Dorothy B Doughty, MN, RN,

CWOCN, FAAN.
182
Differential diagnosis of erosions and ulcers
Mouth Genital Other
Aphthae Balanitis Basal cell carcinoma
Avitaminosis Candidiasis Bullous pemphigoid
Burn Chancroid Ecthyma
Candidiasis Diaper dermatitis Erythema multiforme
Epidermolysis bullosa Erythema multiforme Ischemia
Erythema multiforme Fixed drug eruption Necrobiosis lipoidica
Hand, foot, and mouth Fungal infections (tinea Pemphigus vulgaris

disease cruris)
Porphyria cutanea tarda
Herpangina Herpes simplex
Herpes simplex Intertrigo
Spider bite
Lichen planus Lichen planus
Squamous cell
Lupus erythematosus Lichen sclerosus carcinoma
Pemphigus vulgaris Lymphogranuloma venereum Stasis ulcer
Perlèche Squamous cell carcinoma Toxic epidermal necrosis
Toxic epidermal necrolysis Syphilis
183
Extensive scarring in a patient with dissecting cellulitis of the scalp.
Distribution of common skin dermatoses
Flexural distribution Mouth
Acanthosis nigricans Mucous cysts
Atopic dermatitis Leukoplakia
Bullous pemphigoid Fordyce spots
Extensor distribution Pyogenic granuloma
Psoriasis Skin cancers
Atopic dermatitis (infants) Kaposi's sarcoma
Dermatitis herpetiformis Axillae
Xanthomas Acanthosis nigricans
Feet/hands Hidradenitis suppurativa
184
Feet/hands Hidradenitis suppurativa
Eczema Impetigo
Tinea infections and "id" reactions Hailey-Hailey disease
Erythema multiforme Acrochordon
Wrists/ankles Folliculitis
Lichen planus Erythrasma
Scabies Contact dermatitis
Contact dermatitis Buttocks/anal
Eczema Folliculitis
Photodistributed Psoriasis
Lupus erythematosus Hidradenitis suppurativa
Photodrug eruption Lichen sclerosus et atrophicus
Dermatomyositis Streptococcal cellulitis
Pellagra Kawasaki disease
Porphyria cutanea tarda Scalp
Polymorphous light eruption Seborrhea
Contact dermatitis
Tinea capitis and kerion
Discoid lupus
Psoriasis
185
Dermatitis herpetiformis
Multiple
inflammatory
papules and
vesicles are present
near the elbow.
Courtesy of Scott
Florell, MD,
Department of
Dermatology,
University of Utah.
Graphic 86768
Version 3.0
186
Erythematous papules and vesicles are present on the knee.
187
Disseminated granuloma annulare
This 60-year-old patient with disseminated granuloma annulare presented with hundreds of
erythematous papules and plaques on the medial arms, medial thighs, and buttocks. None of the
lesions showed central clearing.
188
Acute irritant contact dermatitis
Paederus dermatitis. Acute contact dermatitis may occur after accidental exposure to an insect
belonging to the genus Paederus, common in the tropical regions. The insect does not sting or bite,
but accidental crushing may release its hemolymph that contains pederin, a potent vesicant.
(A) Well-defined, erythematous patches with central hyperpigmentation and vesicles in a kissing
lesion fashion.
(B) Well-defined, linear, erythematous patch with central vesicles and pustules.
(A) Courtesy of Kulthanan K Siriraj Hospital, Mahidol University, Bangkok, Thailand.

(B) Courtesy of Wanitphakdeedecha R Siriraj Hospital, Mahidol University, Bangkok, Thailand.
189
Berloque dermatitis
This adolescent developed hyperpigmented

streaks from a photosensitizer in his
sunscreen. After several days of erythema,
the red patches became dark brown.
Copyright © Kosman Sadek Zikry, MD,

Dermatlas; http://www.dermatlas.org.
190
Linear morphea
A shiny, sclerotic, hyperpigmented plaque is present in a linear distribution on the arm.
191
Linear morphea
Linear morphea in a child presenting as a midline band of skin atrophy and hyperpigmentation on
the forehead and scalp.
192
Herpes zoster
Courtesy of Vaibhav Parekh, MD, MBA.
193
Herpes zoster
Grouped vesicles and underlying erythema are present in a dermatomal distribution.
194
Herpes zoster
Courtesy of Vaibhav Parekh, MD, MBA.
195
Atypical hand, foot, and mouth disease caused by coxsackievirus A6 in adults
Dermatologic and mucosal manifestations of hand, foot, and mouth disease among military
personnel, demonstrating:
(A) Extensive and confluent purpuric and hemorrhagic crusted papules and plaques on the foot and
anterior shin.
(B) Erythematous papules and erosions on the palate.
(C) Grouped purpuric papules on the hand.
(D) Similar lesions with extensive involvement of the extensor aspects of the upper extremities —
September 18, 2015.
Reproduced from: Banta J, Lenz B, Pawlak M, et al. Notes from the Field: Outbreak of Hand, Foot,
and Mouth Disease Caused by Coxsackievirus A6 Among Basic Military Trainees - Texas, 2015.
MMWR Morb Mortal Wkly Rep 2016; 65:678.
Cheryl A Armstrong, MDNothing to discloseRobert P Dellavalle, MD, PhD, MSPHEquity
Ownership/Stock Options: Altus Labs [Itch, eczema]. Grant/Research/Clinical Trial Support: Pfizer
196
[Patient decision aids, inflammatory and immune-mediated skin disease]. Consultant/Advisory
Boards: Altus Labs [Itch, eczema]; ParaPRO [Scabies, lice]. Other Financial Interest: Journal of
Investigative Dermatology; Journal of the American Academy of Dermatology [Stipends]; Cochrane
Council meetings [Expense reimbursement].Moise L Levy, MDGrant/Research/Clinical Trial Support:
Galderma [Atopic dermatitis (Investigational drug)]; Janssen Pharmaceutica [Psoriasis
(Investigational drug)]; Pfizer [Atopic dermatitis (Investigational drug)]. Consultant/Advisory Boards:
Cassiopea [Pediatric and adolescent acne]; Regeneron Pharmaceuticals [Atopic dermatitis
(Dupilumab)]; UCB [Psoriasis (Certolizumab pegol)]. Patent Holder: Incontinentia pigmenti (NEMO
gene mutations). Other Financial Interest: Novan [Data safety monitoring board for molluscum
contagiosum trial (Investigational drug)].Rosamaria Corona, MD, DScNothing to disclose
197
Approach to the patient with a scalp disorder
uptodate.com/contents/approach-to-the-patient-with-a-scalp-disorder/print
INTRODUCTION Disorders of the scalp can result from a wide variety of

inflammatory, infectious, parasitic, neoplastic, and idiopathic dermatologic or systemic disorders.
Often, the patient history and physical examination significantly narrow the differential diagnosis.
This topic discusses the clinical assessment of patients with scalp disorders and reviews multiple
conditions that present with visible changes on the scalp. To aid with diagnosis, the disorders are
organized according to important clinical features. The evaluation of hair loss, a clinical finding that
occurs in some scalp disorders, is reviewed separately. (See "Evaluation and diagnosis of hair loss".)
PATIENT ASSESSMENT The patient history and physical

examination are often sufficient for identifying the most likely cause of a scalp eruption. In the
remainder of cases, this information helps to narrow the differential diagnosis.
Relevant information from the patient history may include:
●Age of onset (eg, birth, infancy, childhood, or adulthood)
198
●Duration
●Associated symptoms (eg, pruritus, pain, or systemic symptoms)
●Perceived inciting or exacerbating factors
●Personal history of skin disorders
●Hair and scalp care practices
●Occurrence of a similar condition in family members or cohabitants
The physical examination should include a thorough examination of the scalp. The clinician should
note the presence of characteristic physical features such as scale, erythema, papules, nodules,
pustules, blisters, erosions, and alopecia, as such features help to elucidate the most likely etiology.
Because some disorders affecting the scalp also affect other areas of the skin, performance of a full
skin examination is valuable.
Often, examination of the scalp is challenging because of hair covering the scalp area. Use of an
additional light source is helpful and hair should be physically parted to allow for examination as
much of the scalp area as possible.
In cases in which uncertainty about the diagnosis remains after the clinical evaluation, a scalp
biopsy may aid with diagnosis. Depending on the suspected disorder and the size and shape of the
involved area, a shave, punch, or excisional biopsy may be indicated. In particular, biopsies of some
hair loss disorders can be difficult to interpret. Examination of the specimen by a
dermatopathologist is often helpful in these cases. (See "Skin biopsy techniques" and "Evaluation
and diagnosis of hair loss", section on 'Scalp biopsies'.)
The text below organizes disorders that commonly affect the scalp according to key clinical findings.
Of note, some disorders may exhibit features from more than one of the listed categories.
SCALY PATCHES AND PLAQUES Scaly

patches or plaques on the scalp are typically an indicator of scalp inflammation. Concomitant
erythema is often present. In children, tinea capitis, seborrheic dermatitis, and atopic dermatitis are
common causes of scaly patches or plaques on the scalp. Seborrheic dermatitis, psoriasis, and
allergic contact dermatitis are common causes in adults. Focal areas of erythema with overlying
hyperkeratosis may represent actinic keratoses, particularly when found in middle-aged and older
adults.
Of note, inflammatory conditions of the scalp may result in hair loss. In most cases, the associated
hair loss is reversible. Permanent hair loss (cicatricial alopecia) can occur in inflammatory
conditions that lead to irreversible damage to hair follicles, such as discoid lupus erythematosus
and lichen planopilaris, forms of primary cicatricial alopecia (see 'Cicatricial alopecia' below).
Untreated tinea capitis may also eventually cause permanent alopecia [1].
199
Most of the conditions described below can be diagnosed based upon recognition of classic clinical
findings, with skin biopsy reserved for unclear or atypical presentations. The need for additional
testing is indicated for disorders in which this is often helpful or necessary.
Common disorders
Tinea capitis — Tinea capitis is a dermatophyte infection that is a common cause of
scaling scalp eruptions in children and an infrequent cause of scalp eruptions in adults. Trichophyton
and Microsporum species are the most frequent causative organisms [2].
Tinea capitis presents as scaly patches or plaques with or without inflammation (picture 1A-B).
Circular areas of scale and alopecia are common and hair breakage at follicular orifices can lead to
the appearance of numerous dark-colored dots within the affected area. Posterior cervical
adenopathy is common [2,3]. A potassium hydroxide (KOH) preparation or fungal culture from scale
or a hair shaft in an involved area is useful for confirming the diagnosis (picture 2). (See "Office-
based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)
Kerion is a manifestation of an acute, local inflammatory response to tinea capitis. Kerion presents
as a deep-seated boggy plaque with pustules (picture 3). (See 'Kerion' below.)
Seborrheic dermatitis — Seborrheic dermatitis is common in infants and adults.

In infants, seborrheic dermatitis most frequently presents as an accumulation of yellowish, greasy
scales on the scalp, a presentation often referred to as "cradle cap" (picture 4). Infants may also
develop facial involvement or retroauricular involvement manifesting as erythematous patches or
plaques with fine, greasy scale. Truncal, diaper-area, and intertriginous involvement are additional
presentations (picture 5A-B). (See "Cradle cap and seborrheic dermatitis in infants".)
Of note, infants with Langerhans cell histiocytosis may present with seborrheic dermatitis-like
eruptions with predilection for the scalp, trunk, or diaper areas (picture 6A-C). In Langerhans cell
histiocytosis petechiae are often present. (See 'Langerhans cell histiocytosis' below.)
Seborrheic dermatitis in adolescents and adults is typically found on the face (particularly eyebrows
and nasolabial folds), scalp, upper trunk, and postauricular areas (picture 7A-D) [4]. Patients develop
erythematous patches or plaques with overlying fine, greasy scale. In mild cases (ie, dandruff),
erythema may be minimal or absent. Pruritus may be present. (See "Seborrheic dermatitis in
adolescents and adults".)
Atopic dermatitis — Atopic dermatitis in infants often involves the face and scalp,
presenting with erythematous, scaly patches and crusts (picture 8). Extensor surfaces are an
additional common site of involvement (picture 9). The diaper-area is usually spared.
200
Scalp involvement is less common in older children and adults; a flexural distribution, particularly in
the antecubital and popliteal fossae, is common in this population (picture 10). Erythematous
patches, excoriated papules, lichenified plaques, and marked pruritus are common features.
However, scalp involvement may occur, particularly in severe cases. (See "Atopic dermatitis
(eczema): Pathogenesis, clinical manifestations, and diagnosis".)
Psoriasis — Psoriasis of the scalp tends to appear as erythematous plaques with overlying
silvery scale (picture 11). Pruritus may be nonexistent to severe. Other manifestations of psoriasis
may be present elsewhere, such as on extensor surfaces, elbows, knees, sacrum, or nails (eg, pitting,
onycholysis, oil spots) (picture 12A-E). A family history of psoriasis is often present. (See "Psoriasis:
Epidemiology, clinical manifestations, and diagnosis".)
Allergic contact dermatitis — Allergic contact dermatitis usually presents

with erythematous, scaly patches or plaques on the scalp (picture 13). Severe cases may exhibit
blistering, serous drainage, erosions, and crusting. Pruritus is usually significant. Use of hair care
products is a common culprit. Patch testing is used to evaluate for the inciting antigen. (See "Clinical
features and diagnosis of allergic contact dermatitis", section on 'Clinical features' and "Common
allergens in allergic contact dermatitis", section on 'Hair care products'.)
Actinic keratosis — Actinic keratoses may appear on the scalp as single or multiple
erythematous macules or small patches with overlying scale (picture 14). Adults with scalp hair loss,
light skin color, and a history of significant sun exposure are most susceptible. The diameter of
actinic keratoses usually ranges from a few millimeters to 2 cm. (See "Epidemiology, natural history,
and diagnosis of actinic keratosis", section on 'Clinical features'.)
A small proportion of actinic keratoses progress to cutaneous squamous cell carcinoma. Size
greater than 1 cm, induration, ulceration, tenderness, and rapid growth are among the signs that
suggest a biopsy may be indicated to rule out squamous cell carcinoma. (See "Epidemiology, natural
history, and diagnosis of actinic keratosis", section on 'Biopsy'.)
Less common disorders

Pityriasis amiantacea — Pityriasis amiantacea is an uncommon scalp condition
characterized by the accumulation of thick scale that adheres tightly to the scalp and hair (picture
15). Involvement may be localized or widespread. The etiology is uncertain; it has been proposed
that the disorder may be a reaction pattern observed in various scalp diseases (eg, psoriasis,
seborrheic dermatitis, tinea capitis, or atopic dermatitis) [5]. Secondary bacterial infection may
occur.
The diagnosis of pityriasis amiantacea is made based upon the classic clinical appearance. A full
skin examination aids in identifying an associated skin disorder. A KOH preparation or fungal culture
is indicated if the clinical findings suggest tinea capitis.
201
Pemphigus foliaceus — Pemphigus foliaceus is an autoimmune blistering
disorder in which superficial blistering results in erythematous patches or plaques with erosions,
crusts, and scale (picture 16A-B). The scalp, face, and trunk are common sites of involvement. Pain
or burning sensations may be present. The diagnosis of pemphigus foliaceus is confirmed based
upon clinical, histologic, and immunopathologic findings [6]. (See "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus' and "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus", section on 'Diagnosis'.)
Dermatomyositis — Dermatomyositis of the scalp usually presents as a pruritic

eruption characterized by diffuse erythema with scale and atrophy (picture 17) [7,8]. Other
cutaneous findings of dermatomyositis, such as a poikilodermatous eruption on the chest and
extremities, Gottron papules on the dorsal hands, or a violaceous heliotrope eruption on the face are
often present (picture 18A-E) [7]. Muscle involvement is also usually present. (See "Clinical
manifestations of dermatomyositis and polymyositis in adults".)
The diagnosis of dermatomyositis is usually based upon recognition of the characteristic skin
findings, muscle weakness, and laboratory evidence of myositis. Skin biopsy may be helpful for
ruling out other skin disorders, particularly when muscle involvement is absent. (See "Cutaneous
dermatomyositis in adults: Overview and initial management", section on 'Patient evaluation'.)
Langerhans cell histiocytosis — Langerhans cell histiocytosis (LCH) is a

rare disorder of histiocytes that can affect multiple organs. Both children and adults can develop
LCH.
Skin involvement in LCH is most likely to manifest on the scalp, groin, trunk, and face (picture 6A-C).
Patients may develop scaly or crusted erythematous to brown papules and thin plaques or other skin
manifestations. Petechiae are often present within involved areas. Hypopigmentation may occur in
patients with dark skin. A skin biopsy demonstrating Langerhans cells with kidney-shaped nuclei
and positive staining for CD1a and langerin confirms the diagnosis [9]. (See "Clinical manifestations,
pathologic features, and diagnosis of Langerhans cell histiocytosis".)
PLAQUES WITHOUT SCALE Nevus sebaceous,

syringocystadenoma papilliferum, alopecia mucinosa, and cutaneous B-cell lymphoma are
examples of skin conditions that can manifest as non-scaly plaques on the scalp. Nevus sebaceous
can often be diagnosed based upon clinical examination due to its characteristic yellow-orange
color. Skin biopsy is necessary to confirm a diagnosis of the other disorders.
Nevus sebaceous — Nevus sebaceous is a benign cutaneous hamartoma that

typically first presents at birth or in early childhood and commonly occurs on the scalp. Affected
patients exhibit a solitary, yellow-orange or tan, oval or linear hairless plaque (picture 19). In patients
202
with dark skin, nevus sebaceous may be a dark brown color (picture 20). (See "Nevus sebaceus and
nevus sebaceus syndrome".)
Nevus sebaceous typically becomes more prominent with age. As children enter early puberty,
nevus sebaceous tends to become thicker, verrucous, or nodular (picture 21).
Nevus sebaceous may also occur as a feature of nevus sebaceous syndrome (also known as
Schimmelpenning syndrome). In nevus sebaceous syndrome, nevus sebaceous is often extensive
and patients have associated cerebral, ocular, or skeletal defects [10]. (See "Nevus sebaceus and
nevus sebaceus syndrome".)
Syringocystadenoma papilliferum — Syringocystadenoma

papilliferum is an uncommon benign adnexal neoplasm with apocrine differentiation that has a
predilection for the scalp. Syringocystadenoma papilliferum usually first appears at birth or in
childhood and manifests as a single papule, multiple papules, or plaque (picture 22).
Syringocystadenoma papilliferum may arise independently or within a preexisting nevus sebaceous
[11].
The color of syringocystadenoma papilliferum is typically pink or red. At puberty the neoplasm
grows in size and may take on a verrucous appearance. (See "Cutaneous adnexal tumors", section
on 'Syringocystadenoma papilliferum'.)
Alopecia mucinosa — Alopecia mucinosa (also known as follicular

mucinosis) is usually characterized by an erythematous or skin-colored indurated plaque with
alopecia on the face or scalp (picture 23A-B). Follicular papules may be present. Alopecia mucinosa
may be idiopathic or associated with mycosis fungoides [12].
Cutaneous B-cell lymphoma — Cutaneous B-cell lymphoma can

present as solitary or multiple erythematous, red-brown, or violaceous papules, plaques, or nodules
(picture 24). The head is a common site for the primary cutaneous follicle center lymphoma subtype
of cutaneous B-cell lymphoma. A skin biopsy is necessary for diagnosis. (See "Primary cutaneous
follicle center lymphoma".)
PAPULES AND NODULES Nodular growths on the scalp

may be a manifestation of cysts, benign cellular proliferation, or malignancy. Of the diagnoses
reviewed below, pilar cyst, acne keloidalis nuchae, and juvenile xanthogranuloma can often be
diagnosed clinically. A skin biopsy is recommended for the diagnosis of the other disorders.
Pilar cyst — Pilar cysts (also known as trichilemmal cysts) present as smooth, mobile,
skin-colored nodules on the scalp (picture 25A-B). A punctum is usually absent. Spontaneous
rupture may result in prominent inflammation. (See "Overview of benign lesions of the skin", section
203
on 'Pilar (trichilemmal) cysts'.)
Acne keloidalis nuchae — Acne keloidalis nuchae is a common form of

cicatricial (scarring) alopecia that primarily affects the occipital scalp. Males of African origin with
Afro-textured hair are the population most commonly affected. Patients present with inflamed
papules, pustules, and smooth dome-shaped keloid-like papules on the posterior scalp (picture 26).
The condition may lead to the formation of large keloid-like plaques or nodules (picture 27A-B). (See
"Acne keloidalis nuchae".)
Dermoid cyst — Dermoid cysts are slow-growing, benign, subcutaneous nodules that
develop along embryonic fusion planes and result from an abnormality during fetal development.
The cysts are lined by stratified squamous epithelium and contain other cutaneous structures (eg,
hair follicles, sweat glands, and sebaceous glands) [13]. Dermoid cysts most frequently are found
periorbitally, but may also appear on the scalp and other areas [14]. Patients usually present in
infancy or childhood with a firm nodule (typically 0.5 to 5 cm) that is fixed to the underlying bone or
freely mobile (picture 28) [15]. Midline dermoid cysts may have intracranial extension. (See "Skin
nodules in newborns and infants", section on 'Dermoid cysts and sinuses'.)
Juvenile xanthogranuloma — Juvenile xanthogranuloma is a non-

Langerhans cell histiocytosis that becomes evident at birth or in early childhood [16]. Patients
usually have a 0.5 to 2 cm solitary reddish or yellowish papule or nodule on the head, neck, or upper
trunk (picture 29). Multiple lesions may also occur (picture 30). Spontaneous resolution usually
occurs within a few years. (See "Juvenile xanthogranuloma (JXG)".)
Cylindroma — Cylindromas are uncommon benign adnexal tumors that have a

predilection for the face and scalp of adults. Cylindromas usually occur as red-blue or blue, slow-
growing solitary papules or nodules that range from a few millimeters to a few centimeters in
diameter (picture 31). Multiple cylindromas are features of familial cylindromatosis or Brooke-
Spiegler syndrome (picture 32) [17]. (See "Cutaneous adnexal tumors", section on 'Cylindroma and
spiradenoma'.)
Angiolymphoid hyperplasia with

eosinophilia — Angiolymphoid hyperplasia with eosinophilia (ALHE, also known as
epithelioid hemangioma) is an uncommon benign vascular neoplasm that typically occurs in adults.
ALHE usually presents as a group of several red-brown or violaceous papules or small nodules in a
localized area on the skin (picture 33) [18]. ALHE usually occurs on the head or neck, and the ears
are a particularly common location. A skin biopsy is necessary for diagnosis.
204
Skin cancer — Various forms of skin cancer may present as papules or nodules on the
scalp. Non-healing or recurrent ulceration, skin induration, and progressive growth should raise
suspicion for malignancy. Patients may develop basal cell carcinoma and squamous cell carcinoma,
the most common forms of skin cancer, as well as a wide variety of less common cutaneous
malignancies that can occur on the head. Examples include Merkel cell carcinoma, which often
presents as a rapidly growing skin-colored or blue-red nodule (picture 34), and angiosarcoma, which
often presents as bluish to violaceous nodules, macules, or patches with or without ulceration
(picture 35) [19]. A biopsy is indicated to confirm the diagnosis of skin cancer. (See "Pathogenesis,
clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)
Metastatic carcinoma — The scalp is a common site for cutaneous

metastases of internal malignancy. Metastatic carcinoma often presents as a firm skin-colored, red,
violaceous, or hyperpigmented nodule; however, other presentations, such as patches or plaques,
also occur [20,21]. Ulceration may be present. A biopsy demonstrates features of the primary
malignancy.
PUSTULES Pustular eruptions on the scalp may occur as a result of infectious or

noninfectious inflammatory disorders. Recognition of the associated clinical features is important
for narrowing the differential diagnosis.
Folliculitis — Folliculitis is an inflammatory process of the hair follicles that most

frequently occurs as a result of the invasion of microorganisms into the follicle. Patients develop
inflamed follicular papules and pustules (picture 36A-B). Bacterial culture of pustules often reveals
Staphylococcus aureus infection. There are also fungal and viral forms of folliculitis. (See
"Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Dermatophyte (tinea)
infections", section on 'Majocchi's granuloma'.)
Kerion — Kerion is a complication of severe tinea capitis that results from an intense
inflammatory reaction to the infection (picture 3). Patients develop a boggy plaque that is often
studded by pustules. Purulent drainage may be present.
Dissecting cellulitis of the scalp — Dissecting cellulitis of the

scalp is an uncommon form of cicatricial alopecia that presents with follicular papules, pustules,
fluctuant nodules, and abscesses on the scalp (picture 37). Patients may develop permanent
alopecia, scarring, and sinus tract formation. Dissecting cellulitis of the scalp most frequently
occurs in young men of African descent, but is not exclusive to this population [22]. (See "Dissecting
cellulitis of the scalp".)
205
Folliculitis decalvans — Folliculitis decalvans is a form of cicatricial
alopecia that presents with inflamed papules and pustules on the scalp and scarring alopecia
(picture 38A-B). Pustules and papules are usually located at the periphery of areas of alopecia.
Tufting of hairs (multiple hairs emerging from a single follicular orifice) is an additional common
feature [23]. (See "Folliculitis decalvans".)
Acne keloidalis nuchae — Pustules are a common feature of acne

keloidalis, a form of scarring alopecia distinguished by the development of dome-shaped keloid-like
papules and keloid-like plaques on the posterior scalp. (See 'Acne keloidalis nuchae' above and
"Acne keloidalis nuchae".)
Erosive pustular dermatosis of the scalp — Erosive

pustular dermatosis of the scalp is a rare disorder characterized by the development of sterile
pustules, erosions, and crusted plaques on the scalp that lead to scarring (picture 39) [24]. Erosive
pustular dermatosis of the scalp may occur after scalp trauma or scalp surgery. The condition
primarily affects older adults.
BLISTERS AND EROSIONS Allergic contact dermatitis,

herpes zoster, and autoimmune blistering disease are examples of disorders that may cause
blistering eruptions on the scalp.
Allergic contact dermatitis — Severe allergic contact dermatitis may

present with erythematous patches or plaques with vesiculation or bulla formation (picture 40).
Pruritus is often intense. The diagnosis may be made clinically. Patch testing is used to identify a
causative allergen. (See 'Allergic contact dermatitis' above.)
Herpes zoster — Herpes zoster presents as a dermatomal eruption with localized

erythema and grouped vesicles that evolve to form erosions, pustules, and crusts (picture 41A-B).
Patients usually have unilateral symptoms of burning, aching, stinging, or throbbing. Symptoms can
be severe. The diagnosis is usually made clinically; however, laboratory tests are available to confirm
the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
Autoimmune blistering diseases — Autoimmune blistering

diseases, such as pemphigus foliaceus, dermatitis herpetiformis, and certain types of pemphigoid,
have a predilection for the scalp. Histopathologic examination and immunofluorescence studies are
used for diagnosis.
Key clinical features of these diagnoses include:
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●Pemphigus foliaceus – Multiple erythematous patches or plaques with superficial erosions, crusts,
or scale on the scalp, face, or upper trunk (picture 16A-B) (see "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus')
●Dermatitis herpetiformis – Intensely pruritic papules, vesicles, erosions, and excoriations with a
predilection for the elbows, forearms, knees, scalp, back, and buttocks (picture 42) (see "Dermatitis
herpetiformis")
●Mucous membrane pemphigoid with skin involvement – Mucous membrane blistering and
erosions; erythematous plaques with bullae on the scalp, face, or upper trunk that often heal with
scarring (see "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid", section on 'Mucous membrane pemphigoid')
●Brunsting-Perry pemphigoid –Bullae on the scalp, face, or upper trunk that heal with scarring
(picture 43) (see "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid", section on 'Brunsting-Perry pemphigoid')
THICKENED SCALP Thickening of the scalp is an uncommon

clinical finding that can occur in patients with cutis verticis gyrata and lipedematous scalp.
Cutis verticis gyrata — Cutis verticis gyrata is a rare disorder in which

extensive soft tissue proliferation results in an undulating appearance of the scalp that resembles
the surface of the cerebral cortex (picture 44). The scalp is soft to palpation.
Cutis verticis gyrata is classified as primary essential, primary nonessential, or secondary. Primary
essential cutis verticis gyrata occurs in isolation, whereas the primary nonessential form is
associated with neurologic or ophthalmologic abnormalities. The most common presentation of
cutis verticis gyrata is primary nonessential cutis verticis gyrata occurring in association with
mental retardation [25]. Secondary cutis verticis gyrata results from neoplastic or inflammatory
scalp conditions, genetic disorders, or systemic diseases (eg, acromegaly, myxedema, amyloidosis)
[25]. (See "Cutis verticis gyrata".)
Lipedematous scalp — Lipedematous scalp is a rare condition characterized

by thickening of the subcutaneous tissue of the scalp [26]. The condition results in a soft, spongy, or
doughy quality detected during palpation. Patients may have associated symptoms of pain,
paresthesias, headache, burning sensations, tenderness, or pruritus. The term lipedematous
alopecia has been used to refer to similar clinical findings accompanied by alopecia.
CICATRICIAL ALOPECIA Cicatricial (scarring) alopecia is a

permanent form of hair loss that occurs as a result of irreversible damage to hair follicles. Cicatricial
alopecia should be suspected when patients exhibit hair loss that is accompanied by a loss of
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visible follicular ostia.
There are multiple forms of cicatricial alopecia, each of which exhibits additional characteristic
clinical features. The major subtypes of cicatricial alopecia are listed below with their associated
clinical findings.
●Discoid lupus erythematosus – Well-demarcated inflammatory plaques with follicular plugging that
develop into atrophic, dyspigmented scars (picture 45A-D) (see "Overview of cutaneous lupus
erythematosus", section on 'Discoid lupus erythematosus')
●Lichen planopilaris – Perifollicular erythema and hyperkeratosis (picture 46) (see "Lichen
planopilaris")
●Central centrifugal cicatricial alopecia – Centrifugal progression of alopecia on the central scalp
(picture 47A-B); primarily affects women of African descent (see "Central centrifugal cicatricial
alopecia")
●Folliculitis decalvans – Papules, pustules, and tufted folliculitis (multiple hairs emerging from a
single inflamed follicle), particularly at the periphery of patches of alopecia (picture 38A-B) (see
"Folliculitis decalvans")
●Dissecting cellulitis of the scalp – Papules, pustules, fluctuant nodules, and abscesses (picture 37)
(see 'Dissecting cellulitis of the scalp' above and "Dissecting cellulitis of the scalp")
●Acne keloidalis nuchae – Papules pustules, dome-shaped keloid-like papules, and keloid-like
plaques on the occipital scalp (picture 26) (see 'Acne keloidalis nuchae' above and "Acne keloidalis
nuchae")
Performance of a scalp biopsy is usually recommended to confirm the diagnosis of cicatricial

alopecia. An exception is acne keloidalis nuchae, for which the distinctive clinical features (location
on posterior scalp and keloid-like papules) often negates the need for a biopsy diagnosis.
Additional subtypes of cicatricial alopecia and the evaluation and diagnosis of patients with
cicatricial alopecia are reviewed in detail separately. (See "Evaluation and diagnosis of hair loss".)
MARKED PRURITUS The presence of pruritus can be a useful

clue for diagnosis. Scalp pruritus may be the most prominent scalp manifestation of pediculosis
capitis and is a common feature of several other scalp diseases.
Pediculosis capitis — Pediculosis capitis (head lice) is a common cause of

scalp pruritus in children, but may also occur in adults. Affected patients often present with pruritus
of the scalp and excoriations without an identifiable eruption. Close examination will reveal nits (lice
eggs) firmly attached to hair shafts and lice (picture 48). Cervical adenopathy may be present. (See
"Pediculosis capitis".)
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Other disorders — Allergic contact dermatitis, atopic dermatitis, seborrheic
dermatitis, psoriasis, dermatomyositis, and dermatitis herpetiformis are examples of additional
scalp disorders that frequently present with pruritus. Scabies, another pruritic disorder, typically
spares the scalp but may involve the scalp in young infants and immunocompromised patients
(picture 49A-B). (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Clinical
manifestations'.)
CHILDREN Many of the disorders described above can develop in children.

Seborrheic dermatitis and atopic dermatitis are common scalp conditions in infants. In children, the
differential diagnosis for scalp eruptions often includes tinea capitis, pediculosis capitis, allergic
contact dermatitis, and psoriasis. Nevus sebaceous, juvenile xanthogranuloma,
syringocystadenoma papilliferum, and Langerhans cells histiocytosis are uncommon conditions that
often initially present in children.
Scalp disorders in the newborn infant are reviewed separately. (See "Skin lesions in the newborn and
infant".)
SUMMARY AND
RECOMMENDATIONS
●A wide variety of disorders may present with cutaneous changes on the scalp. The patient history
and physical examination are important tools for diagnosis. The recognition of certain clinical
features significantly narrows the differential diagnosis. (See 'Scaly patches and plaques' above and
'Plaques without scale' above and 'Papules and nodules' above and 'Pustules' above and 'Blisters
and erosions' above and 'Thickened scalp' above and 'Cicatricial alopecia' above and 'Marked
pruritus' above.)
●Many scalp conditions can be diagnosed based upon information obtained from the clinical
evaluation alone. If the diagnosis remains uncertain, a skin biopsy is often useful. Depending on the
clinical scenario, select laboratory studies may also be of value. (See 'Patient assessment' above.)
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Approach to the patient with an intertriginous skin disorder
uptodate.com/contents/approach-to-the-patient-with-an-intertriginous-skin-disorder/print
Literature review current through: Apr 2020. | This topic last updated: Oct 18, 2018.
INTRODUCTION Intertriginous skin disorders are a diverse group of

diseases that may occur as a manifestation of a variety of cutaneous and systemic diseases. The
differential diagnosis includes a broad list of inflammatory, infectious, genetic, and other disorders,
which often can be differentiated based upon clinical features. Diagnostic techniques, such as a
potassium hydroxide preparation, Wood's lamp examination, culture, or skin biopsy, may also be
useful.
The evaluation of intertriginous skin eruptions will be reviewed here. Intertrigo, one of the most
common intertriginous skin disorders, is reviewed in detail separately. (See "Intertrigo".)
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DEFINITION Intertriginous skin, also known as skin folds, are sites in which
opposing skin surfaces come into contact while at rest, resulting in chronic skin occlusion. The
primary intertriginous skin areas include the groin folds, axillae, and gluteal cleft. Body habitus may
contribute to additional intertriginous sites, such as inframammary skin and abdominal folds.
PATIENT ASSESSMENT The diagnosis of an intertriginous

skin disorder begins with review of the patient history and a physical examination.
Helpful historical information may include:
●Patient age
●Associated symptoms
●Duration
●Clinical course (eg, chronic, episodic)
●Family history
●Medication exposure
●Comorbidities
●Response to prior therapies
The physical examination provides the foundation for the differential diagnosis. A complete skin
examination should be performed, including careful examination of all intertriginous sites, the
remaining skin, and nails.
Important features to assess include:
●Distribution
●Lesion morphology (papules, pustules, plaques, erosions, scale, etc) (see 'Morphology' below)
●Concomitant abnormalities of nonintertriginous skin and nails that suggest specific diseases (see
'Associated physical findings' below)
Additional testing is indicated when the diagnosis remains uncertain based upon the history and
physical examination or testing is necessary to confirm a presumed diagnosis. Examples of
commonly performed tests include:
●Potassium hydroxide preparation of disorders with scale to detect superficial fungal infections (see
"Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation')
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●Wood's lamp examination of red to brown patches with fine or absent scale to detect erythrasma
(see "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black
light)')
●Bacterial culture of pustular or blistering eruptions to detect infections and determine the causative
organism
Skin biopsies are not usually necessary and are generally reserved for patients with an uncertain
diagnosis or for whom pathologic examination is required to confirm the suspected diagnosis. The
preferred type of biopsy to perform depends upon the differential diagnosis. A shave biopsy is
adequate for evaluation of disorders with pathology primarily involving the epidermis and the
superficial dermis; punch biopsies allow for examination of the epidermis and full thickness of the
dermis. Direct immunofluorescence is indicated if the differential diagnosis includes an autoimmune
blistering disorder, such as pemphigus vegetans. (See "Skin biopsy techniques", section on 'Biopsy
techniques' and "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)
MORPHOLOGY Careful evaluation of the morphology of intertriginous skin

disorders helps to narrow the differential diagnosis. Disorders characterized by erythematous
patches or plaques, hyperpigmentation, pustules, blisters, erosions, ulceration, papules, verrucous or
hyperkeratotic features, and nodules are reviewed below.
Erythematous patches or plaques — A wide variety of

disorders may result in inflamed patches or plaques on intertriginous skin. Of note, erythema may be
subtle in individuals with highly pigmented skin.
Common disorders — Careful examination for the presence of scale can facilitate
diagnosis. Erythrasma, pityriasis rosea, seborrheic dermatitis, and tinea cruris may have associated
scale, though scale generally is less prominent on intertriginous skin and may be absent. Scale is
typically absent in intertrigo and inverse psoriasis.
Scale sometimes present

●Erythrasma – Erythrasma is a superficial corynebacterial infection that can present with
erythematous to brown, well-defined patches or thin plaques in the skin folds (picture 1A-B). Fine
scale and wrinkling often gives the skin a "cigarette paper" appearance. Affected areas may be
asymptomatic or associated with mild pruritus. Examination with a Wood’s lamp demonstrating
coral red fluorescence or a Gram stain demonstrating gram-positive filaments and rods confirms the
diagnosis (picture 2). (See "Erythrasma" and "Office-based dermatologic diagnostic procedures",
section on 'Wood's lamp examination (black light)'.)
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●Pityriasis rosea – Occasionally, pityriasis rosea can present as well-defined, dull pink to brown
papules and plaques in the groin and axillae rather than the classic presentation (picture 3A-B).
Onset is sudden, often beginning with an initial, larger herald patch. The fine, peripheral scale seen in
classic pityriasis rosea plaques may be present or absent. Lesions are asymptomatic or minimally
pruritic. Spontaneous resolution usually occurs within several weeks [1]. (See "Pityriasis rosea".)
●Seborrheic dermatitis – Involvement of the groin, axillae, and inframammary creases may occur in
seborrheic dermatitis in infants and adults, manifesting as well-demarcated, moist, erythematous
patches or plaques, often with associated greasy scale (picture 4A-C). Involvement of the scalp,
facial creases, or postauricular creases usually accompanies intertriginous involvement, assisting
with diagnosis [2]. (See "Seborrheic dermatitis in adolescents and adults" and "Cradle cap and
seborrheic dermatitis in infants".)
●Tinea cruris – Tinea cruris is a superficial dermatophyte fungal infection of the groin skin folds and
may extend to the lower abdomen, proximal thighs, and buttocks. Erythematous patches or plaques
with peripheral scale are characteristic, but scale may also be minimal or absent (picture 5A-B). Tan
or reddish-brown hyperpigmentation may also be seen centrally. Mild pruritus is common, and there
is often concomitant tinea pedis or onychomycosis. The diagnosis can be confirmed with a
potassium hydroxide preparation of scale that reveals large, branching hyphae (picture 6). (See
"Dermatophyte (tinea) infections".)
Scale typically absent

●Intertrigo – Intertrigo is a common intertriginous dermatitis that usually results from friction and
moisture within skin folds. Intertrigo appears as moist, dull red to red-brown patches or thin plaques
(picture 7A-B). Pruritus is common and pain may occur if fissuring or erosion is present. Debilitation,
infancy, and obesity are risk factors for intertrigo [3]. The diagnosis is made based upon the
distribution limited to sites of friction and moisture and the exclusion of other disorders. (See
"Intertrigo".)
Candidal or bacterial infections may be inciting or exacerbating factors. Features suggestive of

candidal intertrigo are beefy red plaques with satellite papules and pustules (picture 8) (see
'Pustules' below). Often, satellite lesions demonstrate a collarette of scale. A potassium hydroxide
preparation from the scale or pustule can be used to confirm candidal infection. Streptococcal
intertrigo due to beta-hemolytic streptococcus usually presents with brightly erythematous patches
and intense itching or burning (picture 9A-B) [4,5]. A bacterial culture confirms the diagnosis. (See
'Pustules' below and "Intertrigo".)
●Psoriasis – Inverse psoriasis presents as well-demarcated, erythematous plaques in the groin, the
axillae, or inframammary creases (picture 10A-B). Unlike many other areas involved with psoriasis,
thick scaling in inverse psoriasis is uncommon. Often, the surface of intertriginous lesions of
psoriasis have a shiny appearance due to maceration. The presence of psoriatic involvement in
other skin areas, such elbows and knees, or psoriatic nail abnormalities (eg, nail pits, oil spots, and
distal onycholysis) can help distinguish inverse psoriasis. In addition, patients may have a family
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history of psoriasis. (See "Treatment of psoriasis in adults", section on 'Intertriginous psoriasis' and
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Inverse (intertriginous)
psoriasis' and "Nail psoriasis".)
Less common disorders — Examples of less common disorders that may

manifest with erythematous patches or plaques include extramammary Paget disease, Langerhans
cell histiocytosis, lichen planus, symmetric drug-related intertriginous and flexural exanthema, and
unilateral laterothoracic exanthem:
●Extramammary Paget disease – Extramammary Paget disease may present as well-demarcated,

erythematous plaques on genital or perianal skin or the perineum. The plaques may exhibit crusting,
erosions, lichenification, or a verrucous surface (picture 11A-B). Pruritus is common. The diagnosis
should be suspected when patients fail to respond to treatment for a presumed diagnosis as
expected. A biopsy is necessary to confirm the diagnosis. (See "Vulvar cancer: Epidemiology,
diagnosis, histopathology, and treatment", section on 'Paget disease of the vulva'.)
●Langerhans cell histiocytosis – Langerhans cell histiocytosis is a potentially life-threatening

disorder that can present in infancy or early childhood with red-orange or yellow-brown papules,
plaques, erosions, and petechiae on the scalp, groin, or intertriginous regions (picture 12). A skin
biopsy is necessary to confirm the diagnosis. (See "Clinical manifestations, pathologic features, and
diagnosis of Langerhans cell histiocytosis".)
●Lichen planus – Inverse lichen planus, also referred to as lichen planus pigmentosus inversus, is a
rare, pruritic dermatosis that affects the axillae and groin. Affected patients develop asymptomatic
or mildly pruritic, discrete, erythematous to violaceous patches and plaques that follow skin
cleavage lines (picture 13). Hyperpigmentation is a striking feature. Middle-aged adults are most
commonly affected. Classic lichen planus on areas such as the shins and wrists may also be
present. Mucosal involvement is generally absent [6]. A skin biopsy reveals a band-like infiltrate of
lymphocytes at the base of an atrophic epidermis. Pigment incontinence is a prominent histologic
feature. (See "Lichen planus".)
●Symmetric drug-related intertriginous and flexural exanthema –Symmetric drug-related

intertriginous and flexural exanthema is a medication reaction that presents as well-demarcated,
erythematous patches affecting at least one flexural area. The onset is acute, and there is history of
recent exposure to one of a wide variety of potential inciting medications. The diagnosis is made
based on history, clinical suspicion, and improvement upon stopping the offending medication. (See
"Drug eruptions", section on 'Symmetrical drug-related intertriginous and flexural exanthema'.)
●Unilateral laterothoracic exanthem – Unilateral laterothoracic exanthem is a viral exanthema that

typically occurs in young children. It generally begins as a unilateral, morbilliform exanthema in or
adjacent to one axilla and may also begin in the groin (picture 14). Mild pruritus is common.
Progression to the other side of the body often occurs. The diagnosis is made based upon the
clinical appearance. Complete resolution within five weeks is expected [7]. (See "Atypical exanthems
in children", section on 'Unilateral laterothoracic exanthem'.)
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Hyperpigmentation — Examples of disorders of intertriginous sites with
hyperpigmentation as a primary feature include acanthosis nigricans, confluent and reticulated
papillomatosis, and Dowling-Degos disease. Hyperpigmentation may also occur as a secondary
effect of any cutaneous inflammatory disorder (postinflammatory hyperpigmentation), particularly in
individuals with moderately to highly pigmented skin (see 'Erythematous patches or plaques' above):
●Acanthosis nigricans – Acanthosis nigricans is a common disorder that usually presents as

velvety, brownish, asymptomatic plaques on the neck and/or intertriginous skin (picture 15A-B). The
disorder is associated with obesity and insulin resistance [8]. Rarely, acanthosis nigricans is
associated with malignancy. The physical examination is usually sufficient for diagnosis. (See
"Acanthosis nigricans".)
●Confluent and reticulated papillomatosis – Confluent and reticulated papillomatosis (CARP)

presents as erythematous to dark brown, net-like patches involving the trunk, neck, and axillae
(picture 16A-B). CARP typically occurs in young adults and is asymptomatic in most patients. The
diagnosis usually can be made based upon the physical findings and the exclusion of tinea
versicolor with a potassium hydroxide preparation. (See "Confluent and reticulated papillomatosis".)
●Dowling-Degos disease – Dowling-Degos disease (reticulate pigmented anomaly of flexures) is a

rare autosomal dominant disease that typically presents in adulthood as reticular hyperpigmentation
involving the intertriginous skin, neck, and inner aspects of the arms and thighs (picture 17). Pruritus
is common. The diagnosis is made based upon the clinical appearance and a skin biopsy
demonstrating increased pigment in the basal layer of the epidermis and finger-like rete ridges with
thinning of the suprapapillary epithelium. Galli-Galli disease is an autosomal dominant disorder that
is considered an allelic variant of Dowling-Degos disease that has similar clinical and histologic
features but also exhibits suprabasal acantholysis. (See "Congenital and inherited
hyperpigmentation disorders", section on 'Dowling-Degos disease'.)
Pustules — Cutaneous disorders with intertriginous pustules as a common feature include

amicrobial pustulosis of the folds, folliculitis, candidal intertrigo, pemphigus vegetans, and
subcorneal pustular dermatosis:
●Amicrobial pustulosis of the folds – Amicrobial pustulosis of the folds is rare and occurs most
often in young women and in association with autoimmune diseases. Patients develop recurrent
eruptions of follicular and nonfollicular sterile pustules that exhibit a predilection for intertriginous
skin, scalp, and periorificial areas on the head (mouth, nostrils, ear canals). The diagnosis is based
upon the clinical findings as well as the exclusion of infection and other disorders. (See "Neutrophilic
dermatoses", section on 'Amicrobial pustulosis of the folds'.)
●Bacterial folliculitis – Bacterial folliculitis presents with multiple follicular pustules and
erythematous papules. Pruritus is common. Staphylococcus aureus is a frequent causative organism.
The diagnosis usually can be made based upon the physical examination. (See "Infectious
folliculitis", section on 'Bacterial folliculitis'.)
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●Candidal intertrigo – Candidal intertrigo is an intertriginous fungal skin infection caused primarily
by Candida albicans [9]. The typical manifestations consist of beefy red plaques with delicate,
peripheral pustules (picture 8). The pustules may present as superficial erosions due to their fragile
nature. Itching and burning are frequent symptoms. A potassium hydroxide preparation
demonstrating yeast, hyphae, and pseudohyphae confirms the diagnosis (picture 18). (See
"Intertrigo" and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide
preparation'.)
●Pemphigus vegetans – Pemphigus vegetans is a variant of pemphigus that may present with
vegetative plaques on intertriginous skin (picture 19). Pustules may precede the development of the
vegetative plaques (picture 20). Pemphigus vegetans is reviewed below. (See 'Verrucous or
hyperkeratotic papules or plaques' below.)
●Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is a rare disorder that presents
as an extensive eruption of fragile, sterile pustules favoring intertriginous areas, such as the groin
and axillae (picture 21). An annular or serpiginous distribution is common. There is significant
clinical overlap between subcorneal pustular dermatosis and variants of immunoglobulin A (IgA)
pemphigus [10]. IgA pemphigus is less likely to involve intertriginous skin, and a skin biopsy with
direct immunofluorescence helps to distinguish between these diagnoses. (See "Subcorneal
pustular dermatosis" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus",
section on 'IgA pemphigus'.)
Blisters, erosions, or ulcers — Intertriginous erosions can be

prominent in bullous impetigo and Hailey-Hailey disease and may also occur as secondary lesions in
other disorders, such as Langerhans cell histiocytosis and pustular diseases. Ulcers may occur in
the setting of metastatic Crohn disease or sexually transmitted diseases:
●Bullous impetigo –Bullous impetigo is a cutaneous infection caused by S. aureus strains that
produce an exfoliative toxin, resulting in superficial blisters. Intact blisters are rare, as they are often
denuded by friction. The more common findings are superficial erosions associated with
background erythema and golden or "honey" crusts (picture 22A-B). The face, extremities, groin,
axillae, and neck are common sites [11]. The diagnosis can be made based upon the clinical
appearance and confirmed with Gram stain and culture. (See "Impetigo".)
●Hailey-Hailey disease – Hailey-Hailey disease (benign familial pemphigus) is a rare autosomal

dominant, intraepidermal blistering disorder that presents as painful blisters, erosions, and
maceration in intertriginous areas (picture 23A-B) [12]. Onset usually occurs after puberty. Skin
biopsy confirms the diagnosis and demonstrates acantholysis of the epidermis. (See "Hailey-Hailey
disease (benign familial pemphigus)".)
●Metastatic Crohn disease – Metastatic Crohn disease may present as deep, jagged ulcerations in
the inguinal creases, often with associated genital swelling (picture 24) [13]. Skin lesions may occur
before or after development of gastrointestinal disease. A punch biopsy reveals noncaseating
granulomas in the dermis.
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Various sexually transmitted infectious diseases may cause ulcers in the genital region or groin.
This differential diagnosis is reviewed separately. (See "Approach to the patient with genital ulcers".)
Discrete papules — Discrete papules on intertriginous skin occur in patients with

acrochordons, Fox-Fordyce disease, and pseudoxanthoma elasticum:
●Acrochordons – Acrochordons, also known as skin tags, are benign skin growths that appear as
soft, pedunculated papules and most often occur on the axillae, neck, groin, and inframammary
regions (picture 25A-B). The diagnosis typically can be made based upon the clinical appearance.
(See "Overview of benign lesions of the skin", section on 'Acrochordon (skin tag)'.)
●Fox-Fordyce disease – Fox-Fordyce disease (apocrine miliaria) is an inflammatory disease that

predominantly occurs in young adult women. It typically presents as pruritic papules in the axillary
vaults, although it has been reported on other areas rich in apocrine glands, such as the areola and
the vulva. Occlusion of the apoeccrine sweat ducts is thought to cause the eruption (picture 26A-B)
[14]. The diagnosis can usually be made based upon the clinical appearance. (See "Fox-Fordyce
disease (apocrine miliaria)".)
●Pseudoxanthoma elasticum – Pseudoxanthoma elasticum is an autosomal recessive disease that

results in abnormal elastic tissue [15-17]. The classic cutaneous findings are collections of yellow
papules in flexural areas, such as the sides of the neck, antecubital fossae, axillae, and groin (picture
27) [18]. The papules are asymptomatic and may be detected incidentally. Skin biopsy confirms the
diagnosis. Patients with pseudoxanthoma elasticum are at risk for cardiovascular and ocular
complications. (See "The genodermatoses: An overview", section on 'Pseudoxanthoma elasticum'.)
Verrucous or hyperkeratotic papules or

plaques — Verrucous or hyperkeratotic papules or plaques on intertriginous skin may be
indicative of condylomata acuminata, condylomata lata, granular parakeratosis, or pemphigus
vegetans:
●Condylomata acuminata – Condylomata acuminata, caused by human papilloma virus infection,

may present as soft, verrucous plaques on the external genitalia, perianal skin, perineum, groin, or
lower abdomen (picture 28A-C). The physical examination is usually sufficient for diagnosis. A skin
biopsy can confirm the diagnosis when the diagnosis is uncertain. (See "Condylomata acuminata
(anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis".)
●Condylomata lata – Condylomata lata are a manifestation of secondary syphilis characterized by

the development of moist, warty plaques on perianal, perivaginal, or inguinal skin (picture 29).
Condylomata lata contain large numbers of spirochetes and are highly infectious. The diagnosis is
usually made through serologic testing for syphilis. A skin biopsy can be useful for differentiating
condylomata lata from other skin lesions. Dark field microscopy and polymerase chain reaction
diagnostic tests may be available in specialized centers. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in HIV-uninfected patients".)
217
●Granular parakeratosis –Granular parakeratosis presents as pink to brown, hyperkeratotic papules
that coalesce into plaques (picture 30A-B). The disorder most commonly affects the axillae of
women but may also occur in other intertriginous areas and in men or children [19,20]. Pruritus is
common. A biopsy can confirm the diagnosis. The name of this disorder reflects the histologic
pattern observed on skin biopsy [21]. (See "Granular parakeratosis".)
●Pemphigus vegetans – Pemphigus vegetans is an immunobullous disease and a variant of

pemphigus vulgaris. It can present as macerated, warty plaques involving intertriginous areas
(picture 19) [22]. Blisters and erosions may not be evident. A skin biopsy with direct
immunofluorescence can confirm the diagnosis. (See "Pathogenesis, clinical manifestations, and
diagnosis of pemphigus".)
●Seborrheic keratoses – Seborrheic keratoses are common, benign epidermal tumors that typically
arise during adulthood. Characteristic clinical features are well-demarcated, hyperpigmented, round
or oval papules or plaques with a verrucous surface and stuck-on appearance (picture 31A-B). In
addition, seborrheic keratoses have visible keratin plugs. Common intertriginous locations for
seborrheic keratoses are the inframammary skin and abdominal folds. (See "Overview of benign
lesions of the skin", section on 'Seborrheic keratosis'.)
Nodules — Cutaneous nodules on intertriginous skin may occur in patients with

furunculosis or hidradenitis suppurativa:
●Furunculosis – Furuncles, also known as boils, are perifollicular, cutaneous abscesses that occur
in sites of hair follicles. S. aureus infection is the most common cause. Furuncles appear as painful,
inflamed nodules that may be fluctuant and may drain purulent material. (See "Cellulitis and skin
abscess: Clinical manifestations and diagnosis", section on 'Skin abscess'.)
●Hidradenitis suppurativa –Hidradenitis suppurativa is a chronic inflammatory disorder that is

characterized by recurrent, inflamed nodules, abscesses, and comedones on intertriginous skin
(picture 32). The disease may progress to sinus tract formation and severe, rope-like scarring. The
axillae, groin, and inframammary areas are among the most common sites of involvement. The
patient history and physical findings support the diagnosis. (See "Hidradenitis suppurativa:
Pathogenesis, clinical features, and diagnosis".)
AGE Review of the typical age distribution of specific disorders may help to narrow the
differential diagnosis. The disorders often responsible for intertriginous eruptions in infants and
children are listed below. These disorders are not exclusive to children and may also occur in
adolescents and adults.
Infants — Intertriginous disorders often in the differential diagnosis for infants include:
●Bullous impetigo
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●Intertrigo
●Langerhans cell histiocytosis
●Psoriasis
Prepubertal children — Intertriginous disorders often in the differential

diagnosis for prepubertal children include:
●Acanthosis nigricans
●Bullous impetigo
●Condylomata acuminata
●Pityriasis rosea
●Psoriasis
●Unilateral thoracic exanthem
SYMPTOMS Associated symptoms, such as pruritus and pain, may help to

narrow the differential diagnosis.
Pruritus — Prominent pruritus may occur in association with:

●Bacterial folliculitis
●Dowling-Degos disease
●Extramammary Paget disease
●Fox-Fordyce disease
●Granular parakeratosis
●Intertrigo
●Tinea cruris
Pain — Pain is a common symptom in patients with:

●Metastatic Crohn disease
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●Furunculosis
●Hailey-Hailey disease
●Hidradenitis suppurativa
●Intertrigo with fissuring
●Pemphigus vegetans
FAMILY HISTORY Patients with psoriasis and autosomal dominant

disorders, such as Dowling-Degos disease and Hailey-Hailey disease, may report similar symptoms
in family members, assisting with diagnosis.
OTHER HISTORY Information regarding the clinical course, medication

exposure, and response to previous treatments may facilitate diagnosis. For example, an acute
onset is typical of bacterial folliculitis, bullous impetigo, furunculosis, and symmetric drug-related
intertriginous and flexural exanthemata, in contrast to the chronic and relapsing course that
characterizes hidradenitis suppurativa, subcorneal pustular dermatosis, amicrobial pustulosis of the
folds, and other disorders. The medication exposure history may indicate susceptibility to
intertriginous infections due to immunosuppression or exposure to drugs associated with
symmetric drug-related intertriginous and flexural exanthemata. Failure to respond to topical
corticosteroids or other therapies as expected may result in a shift in the presumed diagnosis, such
as from psoriasis to extramammary Paget disease.
ASSOCIATED PHYSICAL FINDINGS An

examination for additional physical findings can help to support a diagnosis.
Skin abnormalities — Knowledge of current or prior characteristic

nonintertriginous skin lesions may be helpful. Examples include:
●Lichen planus – Violaceous, polygonal, intensely pruritic papules or plaques on the extremities,
particularly wrists and ankles
●Pityriasis rosea – Numerous oval, erythematous plaques with peripheral collarettes of scale, often
following the initial appearance of a larger, similar "herald patch"
●Psoriasis – Erythematous plaques with thick, silvery scale on the scalp, trunk, or extremities
●Seborrheic dermatitis – Greasy scale involving the scalp, nasolabial folds, eyebrows, or
postauricular skin
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●Syphilis – History of painless chancre, diffuse macular or papular eruption including palms and
soles, or alopecia
Nail abnormalities — Nail abnormalities may occur in association with certain

intertriginous skin disorders. Examples include:
●Hailey-Hailey disease – Longitudinal white bands
●Lichen planus – Longitudinal ridging, nail plate thinning, longitudinal fissuring, trachyonychia,
erythema of the lunula, hyperpigmentation, onycholysis (see "Overview of nail disorders", section on
'Lichen planus')
●Psoriasis – Pitting, oil drop discoloration, onycholysis, subungual hyperkeratosis, nail plate
crumbling, other findings (see "Nail psoriasis")
SUMMARY AND
RECOMMENDATIONS
●Intertriginous skin areas are sites in which opposing skin areas come into contact while at rest
leading to chronic skin occlusion. Examples include the axillae, groin folds, and gluteal cleft. The
presence of additional intertriginous areas, such as inframammary skin and abdominal folds, is
dependent on body habitus. (See 'Definition' above.)
●Intertriginous skin disorders are a diverse group of inflammatory, infectious, genetic, and other
disorders and exhibit a wide variety of clinical features. Many intertriginous disorders can be
diagnosed based upon the patient history and physical examination. When this is insufficient, tests
such as potassium hydroxide preparation, Wood’s lamp examination, culture, and skin biopsy may
help with diagnosis. (See 'Patient assessment' above.)
●Important diagnostic information may include the patient age, associated symptoms, and family
history. The physical examination should include an assessment of the distribution and morphology
of the intertriginous skin disorder. In addition, examination of the entire skin surface and nails
should be performed to identify other findings suggestive of specific diseases. (See 'Morphology'
above and 'Age' above and 'Symptoms' above and 'Family history' above and 'Associated physical
findings' above.)
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Approach to the patient with annular skin lesions
uptodate.com/contents/approach-to-the-patient-with-annular-skin-lesions/print
Literature review current through: Apr 2020. | This topic last updated: Dec 13, 2019.
INTRODUCTION A wide variety of cutaneous and systemic disorders

present with annular (ring-like) skin lesions (table 1). The careful assessment of lesion
characteristics and accompanying clinical features is valuable for narrowing the differential
diagnosis.
Diagnostic clues for the identification of disorders that present with annular lesions will be reviewed
here. Greater detail on many of the disorders discussed below is available elsewhere in UpToDate.
DEFINITION Annular skin lesions are figurate lesions characterized by a ring-like

morphology. Although plaques represent the most common presentation of annular lesions, lesions
may also be macular, nodular, or composed of grouped papules, vesicles, or pustules.
Additional terms that are frequently used to describe the characteristics of annular lesions include:
●Arcuate – Consists of arc-shaped lesions that represent incompletely formed annular lesions
(picture 1).
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●Polycyclic – Exhibits multiple coalescing arcuate or annular lesions (picture 2A-B).
●Target/targetoid – Demonstrates a dusky red center surrounded by a zone of pallor, which in turn
is surrounded by a peripheral erythematous ring (a characteristic feature of erythema multiforme)
(picture 3A-B).
●Atypical target – Lacks full criteria for target lesions; only two zones of color change are present
(picture 4).
PATIENT ASSESSMENT The identification of the underlying

diagnosis in patients with annular lesions begins with the assessment of several factors. The
clinician should consider the following points during the skin examination:
●What are additional physical characteristics of the lesions?
●Are the lesions stationary, expanding, or migratory?
●Where are the lesions located?
●Are there associated systemic or cutaneous signs or symptoms?
If the diagnosis is not apparent after these questions have been answered, additional studies may be
considered (see 'Diagnostic tests' below). A table of disorders that may present with annular
features and their clinical and pathologic features is provided (table 1).
In some disorders, such as tinea corporis and erythema annulare centrifugum, annular lesions
represent the most common clinical presentation. In contrast, other disorders may demonstrate
annular lesions only as an occasional or incidental feature. For example, annular lesions are not a
classic feature of psoriasis, nummular dermatitis, seborrheic dermatitis, secondary syphilis,
sarcoidosis, mycosis fungoides, or malignant skin tumors, but occasionally occur in the context of
these diseases. A distinct annular variant of lichen planus has been reported [1].
The concomitant detection of features that are more typical of a particular skin disease can be of
value in the diagnosis of annular lesions in conditions in which this morphology is not common. As
an example, the identification of classic psoriatic plaques on the scalp or signs of psoriatic nail
disease may lead to the inclusion of psoriasis into the differential diagnosis for a scaly and
erythematous annular lesion.
Lesion characteristics
Color — Lesion color can be useful for narrowing the differential diagnosis. The vast majority of
annular lesions represent inflammatory processes, and thus, manifest with blanchable cutaneous
erythema. Of note, in patients with dark skin pigmentation, this erythema may be difficult to
appreciate.
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Acute inflammatory lesions often present with bright erythema (picture 5A-C). In contrast, erythema
tends to be muted in lesions of granuloma annulare, a disorder characterized by annular plaques
that persist for months to years (picture 6A-C).
Lesion color may also be influenced by disorder-specific characteristics. Lesions of acute or chronic
urticaria characteristically have a pink color that results from the combination of dermal edema and
vascular dilation (picture 7A-B). Moreover, a dusky red to violaceous color, which is often seen in the
setting of epidermal necrosis, is a common feature in lesions of erythema multiforme (picture 3B).
(See "Granuloma annulare", section on 'Clinical features' and "New-onset urticaria", section on
'Clinical manifestations' and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis",
The color of lesions may shift with lesion age. As acute inflammatory lesions resolve, erythema may
become less prominent. Postinflammatory hyperpigmentation, when present, may be the only
remnant of resolved lesions.
Scale — The presence, absence, and quality of scale are key diagnostic features for several
annular dermatoses. When a rim of fine scale is present, the clinician should take note of whether it
is "leading" (present at the advancing edge), or "trailing" (present more centrally):
●Leading scale – The prototypical annular inflammatory skin lesion with leading scale is the
dermatophyte infection tinea corporis (picture 5A, 5D). Single or multiple lesions may be present.
●Trailing scale – Trailing scale is most commonly seen in pityriasis rosea and superficial erythema
annulare centrifugum.
•Pityriasis rosea – Patients with pityriasis rosea typically present with numerous oval erythematous
thin plaques on the trunk and proximal extremities. The long axis of the oval is arranged along lines
of skin tension. On the back, this classically results in a "Christmas tree-like" distribution. The scale
is typically described as a collarette (picture 8). A larger, oval, erythematous plaque (herald patch)
occurs as the initial sign of disease in 50 percent or more of patients. (See "Pityriasis rosea".)
•Superficial erythema annulare centrifugum – Erythema annulare centrifugum is an inflammatory

reactive disorder that occurs in both superficial and deep forms. Patients present with single or
multiple annular or arcuate erythematous plaques on the face, neck, trunk, or extremities. Trailing
scale is a characteristic feature of the superficial form (picture 5B, 5E). In contrast, scale is typically
absent in the deep variant of the disease. The cause of the disorder is often unknown; infections and
medications are among the possible triggers [2]. (See "Erythema annulare centrifugum".)
In addition, a very thin, palpable rim of ribbon-like scale known as a cornoid lamella is a
pathognomonic feature of lesions of porokeratosis (picture 9A-B). These lesions also have a distinct
histopathologic appearance (picture 10). The absence of scale is a relevant feature for granuloma
annulare, distinguishing these lesions from the more prevalent diagnosis of tinea corporis.
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Granuloma annulare presents as single or multiple papules or plaques that exhibit a dull,
erythematous color and tend to be slightly firm and smooth to palpation (picture 6A-C). (See
"Porokeratosis" and "Granuloma annulare".)
Vesicles or pustules — Linear IgA dermatosis is an autoimmune subepidermal

blistering disorder that may be triggered by medications (particularly vancomycin) [3]. It classically
presents with annular clusters of tense vesicles and bullae in a "string of jewels" pattern (picture 11).
In the early stages of the condition, the vesicles may be tiny, few in number, and located on an
annular erythematous, edematous base. Linear IgA dermatosis may be idiopathic or drug-induced.
When it occurs in children, the term chronic bullous dermatosis of childhood is also used to describe
this condition. (See "Linear IgA bullous dermatosis".)
Flaccid pustules coalescing into annular, polycyclic, or serpiginous configurations are typical of
subcorneal pustular dermatosis (also known as Sneddon-Wilkinson disease) (picture 12A-B).
Intertriginous areas, skin flexures, and the abdomen are preferred sites of involvement. (See
"Subcorneal pustular dermatosis".)
Neutrophilic figurate erythema typically begins with a target-like, erythematous papule that expands
to an annular, erythematous patch with vesicles or purpura. It has histologic features similar to other
neutrophilic dermatoses with a lesser degree of inflammation [4].
Purpura — Purpura results from the extravasation of erythrocytes from cutaneous vessels.
Examples of disorders that characteristically present with purpuric annular lesions include:
●Purpura annularis telangiectodes of Majocchi – Purpura annularis telangiectodes of Majocchi is a

subtype of pigmented purpuric dermatosis [5]. Patients present with symmetric, asymptomatic
eruptions of pinpoint nonblanchable red to red-brown macules that coalesce to form annular
patches (picture 13). The most common site of involvement is the lower extremity. Mycosis
fungoides (a form of cutaneous T cell lymphoma) can present with lesions with similar features and
should be considered in the differential diagnosis in patients with extensive or chronic involvement.
(See "Pigmented purpuric dermatoses (capillaritis)", section on 'Purpura annularis telangiectodes
(Majocchi's disease)'.)
●Acute hemorrhagic edema of infancy –Acute hemorrhagic edema of infancy is a benign small
vessel vasculitis that is characterized by edematous urticarial plaques that progress to purpuric
plaques that often have a targetoid appearance (picture 14) [6]. Lesions are primarily distributed on
the head, genitals, and distal extremities. Fever may be present, but patients typically do not appear
toxic. Children under the age of two represent the population that is usually affected. (See "IgA
vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on
'Differential diagnosis'.)
●Immunoglobulin A vasculitis (Henoch-Schönlein purpura) – Immunoglobulin A vasculitis (Henoch-

Schönlein purpura) is an IgA-mediated small vessel vasculitis that occurs in children and adults.
Cutaneous features include symmetric palpable purpura that are predominantly distributed in
225
dependent regions (picture 15). Some lesions may have an annular appearance. Systemic
involvement can occur, including renal failure. (See "IgA vasculitis (Henoch-Schönlein purpura):
Clinical manifestations and diagnosis".)
●Traumatic purpura – Trauma may lead to annular purpuric or ecchymotic lesions on the skin. Skin
injury sustained during participation in paintball, a sport that involves shooting nonlethal capsules at
other players, is a classic example. Teenagers are common participants in this activity. The impact
of the paintball capsule on the skin typically results in an annular purpuric lesion that persists for
one to two weeks (picture 16). Suction purpura from the Chinese practice of "cupping" or romantic
liaisons may be annular. In general, the diagnosis of traumatic purpura is facilitated by the patient
history.
●Urticarial vasculitis – Urticarial vasculitis is another disorder in which purpura may occur in the
setting of annular lesions. (See 'Symptoms' below.)
●Dependent purpura in annular inflammatory disorders – Purpura on the lower legs or other
dependent areas are common secondary occurrences in nonpurpuric inflammatory disorders. The
purpura develop as a result of vascular leakage. This is particularly common in serum sickness-like
eruptions in children (picture 5G) (see 'Expanding lesions' below). The most prominent purpura are
usually located in areas with the highest hydrostatic forces (eg, lower legs), as blood extravasation is
most likely to occur in those sites.
Symptoms — Most annular eruptions are either asymptomatic or mildly to moderately

pruritic, and knowledge of associated symptoms may be useful for supporting the diagnosis of
specific diseases. A less commonly observed feature that occurs fairly frequently in urticarial
vasculitis is the presence of burning or painful sensations in addition to pruritus. Lesions of
urticarial vasculitis often look identical to classic urticaria (edematous pink wheals), but frequently
persist beyond 24 hours and may be associated with residual bruising or hyperpigmentation (picture
17A-B) [7]. Such features should prompt consideration for urticarial vasculitis in patients who
present with urticarial lesions. Urticarial vasculitis may occur in association with autoimmune
diseases, medications, injections, and malignancy. (See "Urticarial vasculitis".)
Lesion progression — Several disorders are characterized by transient or

migratory features, and asking patients about lesion expansion, lesion migration, and lesion time
course can be useful for diagnosis.
Expanding lesions — Outward spread of individual annular lesions is commonly

noted in tinea corporis, granuloma annulare, erythema chronicum migrans, and erythema annulare
centrifugum. Lesions progressively advance into areas of previously uninvolved tissue, resulting in a
progressive increase in size.
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●Tinea corporis – Lesions of tinea corporis expand slowly over the course of weeks as the fungal
infection spreads outward, often leaving central clearing (picture 5A, 5D). (See "Dermatophyte (tinea)
infections", section on 'Tinea corporis'.)
●Erythema migrans – The hallmark feature of early localized Lyme disease is erythema migrans. A
set of concentric erythematous rings appears 7 to 14 days after tick detachment and progressively
enlarges to form a lesion that is usually at least 5 cm in diameter (picture 18A-B). Lesions may
demonstrate a "bulls-eye" appearance, and last approximately four weeks if untreated [8]. In patients
with early disseminated Lyme disease, multiple annular lesions may be present (picture 19). (See
"Clinical manifestations of Lyme disease in adults".)
The clinical appearance of erythema migrans is indistinguishable from that of the skin findings of
southern tick-associated rash illness (STARI); however, the different endemic areas of the vectors
assist with diagnosis. (See "Southern tick-associated rash illness (STARI)".)
●Granuloma annulare – In contrast to the fairly rapid outward spread of erythema migrans, lesions
of granuloma annulare expand slowly over the course of weeks to months. Solitary or multiple
annular plaques with a firm border are seen (picture 6A-C). Lesions are commonly found on distal
extremities. (See "Granuloma annulare".)
●Erythema annulare centrifugum – The annular erythematous scaly or nonscaly plaques of

erythema annulare centrifugum tend to expand over the course of days to weeks (picture 5B, 5E).
(See 'Scale' above.)
●Serum sickness-like reactions – Serum sickness-like reactions occur due to a variety of

medications (most commonly antibiotics [6]) and are most frequently seen in children. Symptoms
begin one to three weeks after initiation of the offending agent. (See "Serum sickness and serum
sickness-like reactions".)
Patients with serum sickness-like reactions usually present with urticarial lesions that start in the
flexures and then become generalized (picture 5C, 5F-G). These eruptions are frequently initially
mistaken for acute urticaria, but in contrast to acute urticaria, individual lesions remain for greater
than 24 hours. The skin lesions typically gradually expand, leaving central clearing or central faint
purpura, which are usually most evident on the abdomen or lower legs. Affected patients commonly
also develop fever, arthralgias, and erythematous and edematous hands and feet.
●Erythema gyratum repens – Erythema gyratum repens is a rare, often paraneoplastic eruption
characterized by concentric polycyclic, annular, and circinate red plaques that give a characteristic
"wood grain" appearance (picture 20A-C). (See "Cutaneous manifestations of internal malignancy",
section on 'Erythema gyratum repens'.)
●Erythema papulatum centrifugum (EPC) – EPC, also known as erythema papulosa semicircularis
recidivans, is an annular, eczematous eruption that primarily has been described in Japanese and
Chinese males. Patients present with tiny, grouped papules on the trunk that spontaneously resolve
but frequently relapse. EPC is characterized by histologic evidence of perieccrine inflammation [9].
227
Migratory lesions — Transient lesions are characteristic of urticaria and erythema
marginatum.
●Urticaria – Although an outbreak of urticaria may last days to weeks or more, a hallmark feature of
urticaria is that the individual erythematous, edematous plaques last less than 24 hours (picture 7A-
C). Marking a few lesions with a pen can be useful for confirming the transient nature in patients
with numerous lesions. (See "New-onset urticaria" and "Chronic spontaneous urticaria: Clinical
manifestations, diagnosis, pathogenesis, and natural history".)
●Urticaria multiforme (acute annular urticaria) – Urticaria multiforme, also known as acute annular
urticaria, is a self-limited urticarial hypersensitivity eruption that primarily occurs in infants and very
young children [10,11]. Lesions appear on the face, trunk, and extremities as annular erythematous
plaques with central clearing or dusky blue centers. Unlike serum sickness-like reactions and
erythema multiforme, the duration of individual lesions does not exceed 24 hours. Myalgias and
arthralgias are absent. Pruritus is typically present. Other associated findings may include
angioedema of the face or acral areas, dermatographism, and low-grade fever. Viral or bacterial
infections, antibiotics, and vaccinations have been proposed as potential triggers. The disorder is
treated with antihistamines and discontinuation of a triggering medication, if present.
●Erythema marginatum – The migratory, polycyclic, and nonpruritic erythematous plaques of

erythema marginatum typically migrate within minutes to hours(picture 2A, 2C). These annular
lesions tend to have a thin border and often display arciform, polycyclic, and other incompletely
formed annular lesions. Erythema marginatum occurs in association with rheumatic fever due to
group A streptococcal infection. (See "Acute rheumatic fever: Clinical manifestations and
diagnosis".)
●Eosinophilic annular erythema – Eosinophilic annular erythema is a rare disorder that presents
with recurrent, annular or gyrate, often asymptomatic erythematous plaques on the trunk and
extremities [12-14]. Both children and adults may be affected. A hypersensitivity reaction to an
unknown antigen has been proposed as an inciting factor for eosinophilic annular erythema;
however, the cause of the condition remains unknown [12]. Histopathologic examination of lesional
tissue typically reveals a dense perivascular and interstitial lymphocytic infiltrate with many
eosinophils. Although some authors have proposed that eosinophilic annular erythema may be a
subtype of eosinophilic cellulitis (Wells syndrome) [13,15], the relationship between these disorders
remains unclear. Responses to antimalarials or systemic glucocorticoids have been reported;
however, the condition also may spontaneously resolve over months to years [12]. (See "Eosinophil
biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific
organs'.)
Lesion location — The location of annular skin lesions can offer clues for
diagnosis. Disorders that frequently present with photodistributed, acral, or genital lesions are
reviewed below.
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Photodistributed — Photoexacerbated dermatoses tend to occur on sites that are not
typically covered by clothing or other adornments such as the balding scalp, forehead, dorsal nose,
zygomatic cheeks, posterolateral neck, upper chest, extensor upper extremities, and shins. On the
face, the shadow areas of the orbital rim, chin, and nasolabial folds are often spared.
●Lupus erythematosus – Lupus erythematosus is the most common cause of annular lesions in a
photodistributed arrangement. Subacute cutaneous lupus erythematosus, tumid lupus
erythematosus, and neonatal lupus erythematosus may present with such features.
•Subacute cutaneous lupus erythematosus – Subacute cutaneous lupus erythematosus often

presents with annular erythematous scaly plaques (picture 21) [16]. Scaling at the borders of lesions
is common. The neck, upper trunk, and arms are typical sites of involvement. (See "Overview of
cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)
•Lupus erythematosus tumidus – Lupus erythematosus tumidus features smooth, raised, fixed
erythematous plaques (picture 22). Lesions may be annular with central clearing or solid plaques.
Scale is uncommon.
•Neonatal lupus erythematosus – Neonatal lupus erythematosus is a self-limited condition that

results from transplacental transmission of maternal SSA/Ro, SSB/La, or U1RNP antibodies. These
infants present with annular, scaly red plaques on the face, arms, or trunk that are triggered by
ultraviolet light (picture 23). Diagnosis should prompt evaluation for cardiac manifestations. (See
"Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
●Actinic lichen planus –Photodistributed annular lesions are also a common manifestation of
actinic lichen planus (lichen planus actinicus), an idiopathic condition that most commonly occurs
in dark-skinned young adults in subtropical climates [1]. Individuals of Middle-Eastern descent
appear to be most susceptible. Patients present with annular hyperpigmented plaques (picture 24A-
B).
●Annular elastolytic giant cell granuloma – Annular elastolytic giant cell granuloma is characterized
by annular red plaques with raised borders and an atrophic center and is typically found on sun-
exposed skin (picture 25A-B). It closely resembles granuloma annulare and can be differentiated
histopathologically. (See "Granuloma annulare", section on 'Differential diagnosis'.)
Acral — The palms and soles are often spared in generalized eruptions such as urticaria. In
contrast, the target or atypical target lesions of erythema multiforme have a predilection for these
and other acral sites. Target lesions of erythema multiforme classically demonstrate a dusky red
center, surrounded by a zone of pallor, which is in turn surrounded by a peripheral erythematous ring
(picture 3A-C). Patients often have a history of oral or genital herpes simplex virus infection. (See
"Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
The dorsal hands and feet are common sites for the nonscaly, erythematous plaques of granuloma
annulare (picture 6A-C). (See "Granuloma annulare".)
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Genital
●Erythema multiforme – Erythema multiforme may involve the genitals with either typical target
lesions or atypical target lesions that do not include all three color zones (picture 26) (see 'Definition'
above). Approximately 20 percent of patients with recurrent erythema multiforme have genital
involvement [17]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
●Circinate balanitis – Circinate balanitis associated with reactive arthritis is characterized by

serpiginous lesions on the glans penis that may take on an arcuate or annular appearance (picture
27A-B). Conjunctivitis, urethritis, and palmoplantar hyperkeratosis (keratoderma blennorrhagicum)
are additional features of reactive arthritis. (See "Reactive arthritis".)
●Annular lichen planus – Annular lichen planus may involve the male genitalia or other body sites
(picture 28A-B) [18].
Intertriginous — Intertriginous eruptions localize to the flexures (neck, axilla, inguinal

folds, inframammary folds, and gluteal cleft).
●Annular lichenoid dermatitis of youth – Annular lichenoid dermatitis of youth typically features
smooth, annular, red plaques on the groin or flanks in young people. The histopathology reveals a
lichenoid infiltrate with apoptotic cells in the tips of the rete ridges with a polyclonal infiltrate [19].
●Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is characterized by

asymptomatic, chronic, recurrent crops of small pustules in annular, arcuate, or serpiginous
configurations in intertriginous regions. (See "Subcorneal pustular dermatosis".)
●Interstitial granulomatous dermatitis – Interstitial granulomatous dermatitis (IGD) is a granuloma

annulare-like disorder associated with systemic disease, such as autoimmune diseases, infections,
and malignancy. Classically, IGD is characterized by linear, "cord-like" eruptions on the trunk. Other
variants are recognized, including an annular form that may occur on the proximal limbs or
intertriginous areas [20].
FEBRILE PATIENTS Several diagnoses should be considered in

febrile patients with annular skin lesions.
●Acute febrile neutrophilic dermatosis (Sweet syndrome) – Patients with acute febrile neutrophilic
dermatosis present with an abrupt onset of red, well-demarcated, tender, and often annular plaques
accompanied by fever and leukocytosis (picture 29A-B). The cutaneous lesions often demonstrate
an edematous, almost vesicular (pseudovesicular) appearance, and are typically located on the
upper body. Associated factors include inflammatory bowel disease, malignancy, infections, and
medications [21]. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis,
clinical manifestations, and diagnosis".)
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●Serum sickness-like reaction –Patients with serum sickness-like reactions frequently present with
fever. (See 'Expanding lesions' above.)
The possibility of the following disorders also should be considered in febrile children:
●Acute hemorrhagic edema of infancy – This disorder presents as annular purpuric edematous
plaques in young children (picture 14). (See 'Purpura' above.)
●Kawasaki disease – Kawasaki disease is a self-limited vasculitis of childhood that presents with
fever, conjunctivitis, mucositis, acral edema, lymphadenopathy, and an exanthematous skin eruption.
Occasionally, the cutaneous eruption of Kawasaki disease manifests as an annular or targetoid
eruption (picture 30) [22]. (See "Kawasaki disease: Clinical features and diagnosis".)
●CANDLE syndrome – Chronic atypical neutrophilic disorder with lipodystrophy and elevated
temperature (CANDLE) syndrome is an autoinflammatory disorder due to mutations in PSMB8.
Patients typically present with early-onset fever and generalized, annular violaceous plaques as well
as other systemic findings associated with chronic inflammation [23]. (See "Periodic fever
syndromes and other autoinflammatory diseases: An overview", section on 'Chronic atypical
neutrophilic dermatitis with lipodystrophy and elevated temperature'.)
DIAGNOSTIC TESTS If after a careful history (including a

thorough chronologic drug history) and physical examination, the diagnosis of an annular skin
eruption remains unclear, select diagnostic studies may be helpful (table 1). As noted above, circling
lesions with a pen or marker can be useful for identifying the migratory nature of certain disorders.
(See 'Migratory lesions' above.)
Examples of scenarios in which additional studies can be of value are below:
●Scaly annular eruption – Potassium hydroxide preparation (KOH) is instrumental in diagnosing or

ruling out tinea corporis (picture 31). (See "Office-based dermatologic diagnostic procedures",
section on 'Potassium hydroxide preparation'.)
●Photodistributed annular eruption – Antinuclear antibody (ANA) testing and skin biopsy can be
useful for confirming a diagnosis of cutaneous lupus erythematosus. (See "Overview of cutaneous
lupus erythematosus".)
●Target or atypical target lesions – Herpes simplex virus (HSV) is a common trigger of erythema
multiforme. If lesions suspicious for active HSV infection are present in a patient with erythema
multiforme, the performance of Tzanck smears, direct fluorescent antibody preparations, viral
cultures, or PCR studies on specimens taken from the site of suspected HSV infection may be used
to confirm the presence of the virus. (See "Erythema multiforme: Pathogenesis, clinical features, and
diagnosis", section on 'Diagnosis'.)
231
●Migratory, serpiginous eruption – In patients with symptoms or signs suggestive for rheumatic
fever, throat cultures, rapid streptococcal antigen tests, and antistreptolysin O antibody titers are
confirmatory tests for streptococcal pharyngitis, the most common inciting factor for acute
rheumatic fever. (See "Acute rheumatic fever: Clinical manifestations and diagnosis", section on
'Diagnosis'.)
Other laboratory tests may be performed based upon suspicion of the underlying disorder.
Skin biopsy — Skin biopsy is always an option when the diagnosis is uncertain. It is
most useful when the disorders being considered have different histopathologic findings (table 1). A
4 mm punch biopsy from the active edge of an annular lesion is generally preferred over a shave
biopsy, as it allows for evaluation of the full thickness of the epidermis and dermis. (See "Skin biopsy
techniques", section on 'Punch biopsy'.)
EMPIRICAL DIAGNOSIS OF TINEA

CORPORIS If performing a KOH is not feasible prior to treatment in a patient who
presents with lesions suspicious for tinea corporis, empirical therapy with a topical antifungal agent
with activity against dermatophytes (eg, azole antifungals, ciclopirox, or terbinafine) is reasonable,
due to the relatively high prevalence of tinea corporis and the low risk for adverse effects of topical
agents. Combination products containing antifungal agents and potent corticosteroids (eg,
betamethasone dipropionate with clotrimazole, Lotrisone) should be avoided, as the corticosteroid
component may exacerbate tinea and cause cutaneous atrophy. A recurrence or a failure of
presumed tinea corporis to resolve after treatment may indicate inadequate treatment, reinfection
(from autoinoculation or an external source), or an incorrect diagnosis. (See "Dermatophyte (tinea)
infections", section on 'Tinea corporis'.)
INDICATIONS FOR REFERRAL Urgent

dermatologic consultation should be performed if the underlying diagnosis is uncertain in
systemically ill patients with inflammatory annular lesions. The acute illness or an underlying
systemic disorder may be associated with significant morbidity (eg, immunoglobulin A vasculitis
[Henoch-Schönlein purpura], acute rheumatic fever, systemic lupus erythematosus, etc).
Infants with annular eruptions should have prompt dermatology referral because of the potential for
morbidity even in the absence of obvious signs of systemic illness. As examples, untreated neonatal
lupus and immunoglobulin A vasculitis (Henoch-Schönlein purpura) may have serious long-term
sequelae.
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●Basics topic (see "Patient education: Granuloma annulare (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Annular skin lesions are characterized by a ring-like morphology. Annular lesions are common in
skin disease, and occur in the setting of a variety of disorders (table 1). (See 'Definition' above.)
●The identification of associated clinical features is often useful for the diagnosis of annular lesions.
Physical characteristics such as lesion color and the presence or absence of scale, vesicles, or
pustules can be quickly assessed. Other factors to consider include the course of lesion
progression, lesion location, and associated cutaneous or systemic symptoms. (See 'Patient
assessment' above.)
●If the diagnosis remains uncertain after the patient history and physical examination, diagnostic
studies such as potassium hydroxide (KOH) preparations to evaluate for tinea corporis, skin
biopsies, and select laboratory studies based upon clinical suspicion of the underlying diagnosis
can be useful. (See 'Diagnostic tests' above.)
●Whenever feasible the diagnosis of tinea corporis should be confirmed with a KOH preparation
prior to treatment. If it is not possible to perform a KOH preparation, empirical treatment with a
topical antifungal agent may be prescribed. Combined antifungal and potent corticosteroid agents
should not be used. (See 'Empirical diagnosis of tinea corporis' above.)
●Serious systemic disorders may present with inflammatory annular lesions. Urgent dermatologic
consultation should be obtained if the diagnosis remains uncertain in patients who are systemically
ill. (See 'Indications for referral' above.)
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234
Approach to the patient with cutaneous blisters
uptodate.com/contents/approach-to-the-patient-with-cutaneous-blisters/print
Approach to the patient with cutaneous blisters
Authors:
Christopher Hull, MD
John J Zone, MD
Section Editor:
Erik Stratman, MD
Deputy Editor:
Abena O Ofori, MD
Literature review current through: Apr 2020. | This topic last updated: Jul 30, 2019.
INTRODUCTION Cutaneous blisters occur in a wide variety of clinical

settings, including autoimmune disorders, drug reactions, infections, genetic disorders, and physical
injury. The ability to narrow the differential diagnosis for patients with blistering skin lesions is
essential for the prompt recognition of life-threatening disorders and the appropriate management of
other blistering diseases (algorithm 1).
The clinical approach to the diagnosis of disorders that present with cutaneous blisters and a
summary of common investigative tests used to assist with diagnosis is discussed here. Blistering
disorders in the newborn infant and specific blistering disorders are discussed in greater detail
separately. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)
DEFINITION Blistering skin disorders are characterized by the presence of fluid-

filled lesions on the skin that occur as a result of a loss of adhesion between cells within the
epidermis (acantholysis), edema between epidermal cells (spongiosis), or disassociation of the
epidermis and dermis. Pathologic events that may lead to the formation of blisters include the
following:
●Disruption of cellular or extracellular adhesion molecules (eg, autoimmune blistering disorders,

congenital epidermolysis bullosa)
●Epidermal cell injury or death (eg, toxic epidermal necrolysis, erythema multiforme)
●Accumulation of excessive edema (spongiosis) within the epidermis (eg, contact dermatitis, acute
and chronic vesicular palmoplantar dermatitis)
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●Traumatic injury (eg, friction or coma blisters)
Specific terms are used to describe cutaneous blisters based upon lesion size. Vesicles are usually
designated as lesions that are less than 1 cm in diameter (picture 1A). In contrast, bullae are
classified as lesions that are greater than 1 cm in size (picture 2).
The watery clear fluid content of vesicles and bullae distinguishes these lesions from pustules,
which contain thicker, yellow-white purulent material (see "Approach to the patient with pustular skin
lesions"). Although the clear fluid contents of vesicles and bullae may develop a more turbid quality
over time, the watery quality is retained and such lesions are still easily distinguished from pustules.
In cases in which blister formation is associated with damage to the blood vessels in the dermis, red
blood cells may enter the blister cavity, resulting in red-colored blister fluid. The term "hemorrhagic
blister" is used to refer to such lesions.
Blisters may occur at a variety of histologic locations within the skin. The location in which blisters
form is often useful for diagnosis and can be determined via histopathologic examination (table 1).
The general categories used to describe the location of blister formation include [1]:
●Intracorneal or subcorneal – Cleavage plane within the stratum corneum or immediately beneath
the stratum corneum (eg, pemphigus foliaceus, staphylococcal scalded skin syndrome) (picture 3)
●Intraepidermal – Cleavage plane within the malpighian layer of the epidermis, excluding
subcorneal and suprabasilar disorders (eg, contact dermatitis, viral infections) (picture 4A-B)
●Suprabasilar – Cleavage plane within the epidermis with only an intact basal layer (picture 5A) (eg,
pemphigus vulgaris, paraneoplastic pemphigus)
●Subepidermal – Cleavage plane within or below the basement membrane zone (picture 5B) (eg,
bullous pemphigoid, porphyria cutanea tarda)
The clinical features of a blistering disorder often correlate with the histopathologic subtype.
Whereas subcorneal blistering disorders tend to present with extremely fragile blisters that quickly
evolve to scale, erosions, and desquamation, slightly less fragile flaccid vesicles or bullae are
characteristic of intraepidermal or suprabasilar blisters. Lastly, tense bullae are typically seen in
subepidermal blistering disorders due to the relatively greater proportion of epidermis overlying the
blister cavity.
LIFE-THREATENING
EMERGENCIES Several blistering disorders represent potentially life-
threatening emergencies, warranting the need for early diagnosis and therapy. These include:
236
●Toxic epidermal necrolysis – Widespread sloughing of skin and severe mucositis in this disorder
are associated with risk for sepsis (picture 6A-C). (See 'Generalized blisters with systemic illness'
below.)
●Staphylococcal scalded skin syndrome – A high mortality rate occurs in adults with this disorder
(picture 7A-B). (See 'Generalized blisters with systemic illness' below.)
●Disseminated herpes simplex or herpes zoster infection in immunocompromised patients – May

result in life-threatening internal complications (picture 8). (See 'Generalized blisters with systemic
illness' below.)
●Purpura fulminans – Although retiform purpura are the primary feature of purpura fulminans,
associated necrotic bullae may also be present (picture 9). (See "Approach to the patient with
retiform (angulated) purpura", section on 'Recognition of life-threatening emergencies'.)
PATIENT ASSESSMENT Blistering skin lesions can present

a diagnostic challenge since the differential diagnosis is vast. The recognition of the distribution of
the lesions is a useful clinical tool to begin to narrow the differential diagnosis (algorithm 1). A
thorough patient history, the identification of additional clinical features, and pathologic and
laboratory studies are often of additional value.
Examples of questions that may be useful during the assessment of the patient with cutaneous
blisters include:
●Where are the lesions located (generalized, localized, specific sites)?
●Are mucous membranes involved?
●What is the size and configuration of blisters?
●If bullae are present, are they flaccid or tense?
●What is the patient's age?
●Does the patient have a history of exposure to a new medication?
Lesion distribution — The identification of cutaneous blisters as generalized,

localized, or associated with mucous membrane involvement can offer valuable clues for diagnosis
(table 2A-C).
Generalized distribution
237
Generalized blisters with systemic illness — Acute or chronic signs or
symptoms of systemic illness are frequent features of several disorders that present with
generalized blisters.
●Stevens-Johnson syndrome and toxic epidermal necrolysis – Stevens-Johnson syndrome and

toxic epidermal necrolysis (TEN) are acute, severe disorders characterized by epidermal sloughing
of the skin and mucous membranes. These conditions most commonly occur as a result of
exposure to an inciting medication [2]. Following a brief prodromal period of fever and flu-like
symptoms, patients develop painful erythematous and purpuric macules or areas of diffuse macular
erythema that progress to vesicles, bullae, and skin sloughing (picture 6A-D). The extent of body
surface area involvement differentiates Stevens-Johnson syndrome (<10 percent) from TEN (>30
percent). Skin biopsies of fully developed lesions demonstrate epidermal-dermal separation and full-
thickness epidermal necrosis. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Pathogenesis, clinical manifestations, and diagnosis".)
●Staphylococcal scalded skin syndrome – Staphylococcal scalded syndrome occurs as a reaction

to toxin released by Staphylococcus aureus, and most commonly occurs in infants, young children,
and adults with renal failure [3]. Fever, malaise, and skin tenderness typically precede the eruption.
The fragile subcorneal bullae often demonstrate the appearance of wrinkled skin with subsequent
desquamation (picture 7A-C). Examination of a frozen tissue specimen of sloughed epidermis can
be used to rapidly distinguish staphylococcal scalded skin from the epidermal sloughing of toxic
epidermal necrolysis. Frozen sections taken from staphylococcal scalded skin syndrome
demonstrate cleavage at the granular layer, whereas full-thickness epidermal necrosis and cleavage
at the dermal-epidermal junction characterize toxic epidermal necrolysis. The site of the primary
staphylococcal infection also should be identified. (See "Staphylococcal scalded skin syndrome".)
●Varicella zoster virus infection – Varicella (chicken pox) is a disorder that most frequently occurs
in children who are not vaccinated against the disease. Patients experience a prodrome of fever and
malaise followed by the development of a generalized eruption of 1 to 3 mm intraepidermal or
subepidermal vesicles surrounded by erythema. These lesions are often described as "dew drops on
a rose petal," and subsequently evolve to form pustules and crusts (picture 1A-B). (See "Clinical
features of varicella-zoster virus infection: Chickenpox".)
●Disseminated herpes zoster – Disseminated herpes zoster can occur in immunocompromised

patients. Unlike classic herpes zoster, the vesicular lesions are not restricted to a dermatome
(picture 8). Disseminated herpes zoster may also result in life-threatening infection including
pneumonia, hepatitis, encephalitis, or other organ involvement. (See "Epidemiology, clinical
manifestations, and diagnosis of herpes zoster", section on 'Special considerations in
immunocompromised hosts'.)
●Disseminated herpes simplex virus –Immunocompromised patients and patients with a

compromised skin barrier (eg, atopic dermatitis, Darier disease) may develop widespread vesicles,
pustules, and crusts due to herpes simplex virus infection. The term eczema herpeticum is used to
238
describe this occurrence in patients with atopic dermatitis (picture 10A-B). (See "Epidemiology,
clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)
●Sweet syndrome (acute febrile neutrophilic dermatosis) –Although edematous, erythematous

plaques with a pseudovesicular quality are most characteristic of Sweet syndrome, the plaques
occasionally exhibit frank vesicle or bulla formation (picture 11A-B). The plaques are most frequently
found on the upper body; fever and leukocytosis are also typically present. Sweet syndrome may
occur in the setting of malignancy, infection, drug exposure, autoimmune disease, or inflammatory
bowel disease. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical
manifestations, and diagnosis".)
●Bullous systemic lupus erythematosus – Bullous systemic lupus erythematosus presents as

widespread, tense, subepidermal bullae in patients with systemic lupus erythematosus. The skin
lesions may resemble bullous pemphigoid or dermatitis herpetiformis (picture 12) [4]. Antibodies
against type VII collagen have been associated with this disease. (See "Bullous systemic lupus
erythematosus".)
●Paraneoplastic pemphigus – Paraneoplastic pemphigus is an uncommon mucocutaneous

suprabasilar or subepidermal blistering disorder that occurs in the setting of malignancy. Stomatitis
is characteristically severe (picture 13), but the morphology of skin lesions is variable [5]. In some
cases, the skin lesions may resemble blisters of pemphigus vulgaris or erythema multiforme (picture
14A-B). Non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman's disease are the
conditions most commonly associated with this disorder [5]. Serologic testing reveals reactivity with
multiple antigens, including desmoplakins, desmogleins, and bullous pemphigoid antigen 1 (BPAg1,
BP230) [6,7]. (See "Paraneoplastic pemphigus".)
Other generalized blistering disorders — Examples of generalized blistering

disorders that are not necessarily associated with systemic illness are listed below.
●Miliaria crystallina –Miliaria crystallina results from the obstruction of the ducts of eccrine sweat
glands and usually occurs in the setting of excessive warmth. The fragile intracorneal or subcorneal
1 mm vesicles typically occur on the face and trunk (picture 15). (See "Miliaria".)
●Bullous impetigo –Subcorneal vesicles and bullae containing clear or yellow fluid on the face,
trunk, perineum, or extremities characterize bullous impetigo, a disorder that most frequently occurs
in neonates and children (picture 16). The bullae rupture easily, leaving erosions with a collarette of
scale. (See "Impetigo", section on 'Bullous impetigo'.)
●Pemphigus – The formation of flaccid bullae that quickly evolve to erosions are typical of
pemphigus vulgaris (picture 17) [8]. Mucous membrane vesicles and erosions are a frequent
associated finding (picture 18A-B). The level of blister formation in pemphigus vulgaris is
suprabasilar. By contrast, the most prominent feature of pemphigus foliaceus, a subcorneal
blistering disorder, is erythematous plaques with overlying scale or crust (picture 19A-B). These
patients do not develop mucosal blisters. (See "Pathogenesis, clinical manifestations, and diagnosis
of pemphigus".)
239
●Bullous pemphigoid – Bullous pemphigoid is a subepidermal blistering disorder that most
commonly occurs in older adults (picture 20A-B) [9]. The classic skin lesions are urticarial plaques
and tense bullae on the trunk and extremities. Intense pruritus is common, and lesions typically do
not scar. Localized forms of bullous pemphigoid may also occur [10]. Bullous pemphigoid patients
may also develop mucosal involvement. (See "Clinical features and diagnosis of bullous pemphigoid
and mucous membrane pemphigoid".)
●Pemphigoid gestationis – Pemphigoid gestationis is a subepidermal blistering disorder that occurs

during pregnancy or in the immediate postpartum period. Urticarial plaques and vesicles typically
begin around the umbilicus prior to spreading elsewhere with large bulla formation (picture 21A-C).
(See "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)
●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is a subepidermal blistering
disorder associated with the deposition of IgA at the basement membrane zone of skin and mucosal
tissues [11]. This disorder may occur as a primary autoimmune disease or as a drug reaction. The
cutaneous bullae often have a distinctive grouped appearance that resembles a cluster of jewels
(picture 22). The term chronic bullous disease of childhood is used to refer to this disorder in
children. (See "Linear IgA bullous dermatosis".)
●Dermatitis herpetiformis – Dermatitis herpetiformis is a cutaneous manifestation of gluten

sensitivity that presents with grouped vesicles and excoriated papules with a predilection for the
extensor extremities, scalp, and buttocks (picture 23) [12,13]. The lesions of this subepidermal
blistering disorder are intensely pruritic. (See "Dermatitis herpetiformis".)
●Epidermolysis bullosa – Congenital epidermolysis bullosa is a rare genetic disorder that consists
of multiple variants. Depending on the type of epidermolysis bullosa, lesions may be intraepidermal
or subepidermal, localized or generalized, and detected as early as birth or not until adulthood
(picture 24). (See "Epidemiology, pathogenesis, classification, and clinical features of epidermolysis
bullosa".)
●Epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare, acquired subepidermal

blistering disorder that may affect both skin and mucous membranes (picture 25). Tense bullae,
scarring, and milia formation are common associated features. Antibodies against type VII collagen
are pathogenic in this disease and can be measured in serum [14]. (See "Epidermolysis bullosa
acquisita".)
Localized distribution — The recognition that blisters are primarily located in

certain body locations, such as dependent areas, acral areas, or sun-exposed skin may assist with
diagnosis (table 2B and algorithm 1). In addition, a linear distribution of skin lesions suggests the
possibility of an external insult as the cause of blistering.
Dependent areas
240
●Coma blisters – Coma blisters are tense, subepidermal bullae that have been reported to occur in
sites of pressure in comatose patients. These lesions have been associated with exposure to drugs
(eg, opiates, tricyclic antidepressants, antipsychotics) and a variety of medical conditions, such as
chronic renal failure, diabetic ketoacidosis, hyperparathyroidism, and neurologic disease [15].
Erythematous or ecchymotic patches or plaques may precede the development of bullous lesions.
The blisters spontaneously resolve within two to four weeks [15].
●Bullous disease of diabetes (bullosis diabeticorum) – Bullous disease of diabetes is a term used to
describe the abrupt development of noninflammatory, tense, subepidermal bullae in patients with
diabetes in sites of otherwise normal-appearing skin (picture 2) [16]. Lesions most commonly occur
on the feet or lower legs and may be up to several centimeters in diameter. The bullae spontaneously
resolve over the course of a few weeks. The term bullous diabeticorum has also been used to refer
to this disorder.
●Bullous leukocytoclastic vasculitis –Hemorrhagic vesicles or bullae may occur among the purpuric
macules, papules, or plaques of cutaneous leukocytoclastic vasculitis (picture 26). Necrosis of the
skin overlying areas of small vessel vasculitis leads to the development of these subepidermal
bullous lesions. (See "Evaluation of adults with cutaneous lesions of vasculitis".)
●Edema (stasis) blisters – Bullae may form in areas of edema. These asymptomatic lesions often
occur on the lower legs and resolve upon resolution of the cause of edema (picture 27) [15]. There is
little published information on edema blisters, and it is not definitively known whether the majority of
these blisters are subepidermal or intraepidermal. (See "Stasis dermatitis", section on 'Clinical
presentation'.)
Hands or feet
●Acute palmoplantar (dyshidrotic) eczema – Intensely pruritic vesicles or bullae on the hands or
feet are consistent with this disorder (picture 28A-B). The palms, soles, and sides of the digits are
typical sites for involvement. Spongiotic intraepidermal vesicles are present on histopathologic
examination. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
●Dermatophytosis –Blistering tinea pedis is most often associated with Trichophyton

mentagrophytes or Epidermophyton floccosum infection [17]. The associated intraepidermal
spongiotic vesicles and bullae are often present on the soles or between the toes (picture 29). In
addition, dermatophytid reactions (autoeczematization or id reactions that occur in the setting of
dermatophyte infection) may result in vesicular eruptions on the hands (picture 30). (See
"Dermatophyte (tinea) infections", section on 'Tinea pedis' and "Dermatophyte (tinea) infections",
section on 'Dermatophytid (id) reactions'.)
●Friction blister –Friction blisters are intraepidermal blisters that result from trauma-induced
separation within the epidermis. They most frequently occur on the heels and soles of the feet due to
friction from shoes during walking or running. The possibility of epidermolysis bullosa simplex
should be considered in patients with frequent and excessive blistering. (See "Friction blisters".)
241
●Sucking blisters – Blisters on the hands or feet due to intrauterine sucking may be detected in
neonates (picture 31A-B).
●Erythema multiforme – The acral extremities are a site of predilection for lesions of erythema
multiforme, a disorder that most commonly occurs in association with herpes simplex virus
infection. The classic dusky erythematous target lesions of erythema multiforme may exhibit a
central subepidermal blister (picture 32). Mucosal involvement is also frequently present (picture
33A-B). (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on
'Clinical manifestations'.)
●Localized epidermolysis bullosa simplex – Localized epidermolysis bullosa simplex (formerly

known as the Weber-Cockayne variant of epidermolysis bullosa simplex) is a rare autosomal
dominant genetic disorder in which intraepidermal blisters form in sites of friction or trauma. The
hands and feet are frequently affected (picture 34A-B). (See "Epidemiology, pathogenesis,
classification, and clinical features of epidermolysis bullosa", section on 'EBS, localized'.)
Photodistributed
●Polymorphous light eruption – Polymorphous light eruption is a fairly common disorder that
usually develops within hours of sun exposure. Although the most common manifestations are
pruritic erythematous papules or plaques, vesicles or bullae may also occur as a manifestation of
extensive dermal edema (picture 35). (See "Polymorphous light eruption".)
●Porphyria cutanea tarda – Photosensitivity is a key feature of porphyria cutanea tarda, an inherited
or acquired metabolic disorder that may present with the formation of predominantly
noninflammatory vesicles and bullae (picture 36A-B). Sun-exposed areas are typically affected. The
dorsal hands and forearms are common sites of involvement, and crusts, scars, and milia are often
present. Other cutaneous features of porphyria cutanea tarda include hyperpigmentation,
hypertrichosis, and localized sclerodermoid plaques [18]. (See "Porphyria cutanea tarda and
hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on
'Clinical features'.)
●Pseudoporphyria – Although pseudoporphyria presents with clinical and histopathologic features

that resemble porphyria cutanea tarda, abnormalities of porphyrin metabolism are absent. Like
porphyria cutanea tarda, subepidermal bullae, crusts, and scarring on the dorsal hands are common
clinical findings (picture 37). A number of medications have been associated with this condition [19].
(See "Pseudoporphyria".)
●Sunburn and phototoxic reactions –Severe sunburns can result in blister formation on the skin
(picture 38). Phototoxic eruptions, which usually occur due to sun exposure after ingestion of a
photosensitizing drug, resemble sunburns and can also present with blistering. (See "Sunburn" and
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment",
section on 'Phototoxicity'.)
Dermatomal
242
●Herpes zoster – Herpes zoster (shingles) presents with a grouped eruption of painful
intraepidermal vesicles in a dermatomal distribution (picture 39A-B). In immunocompromised
patients, disseminated lesions may occur. (See "Epidemiology, clinical manifestations, and diagnosis
of herpes zoster".)
Linear distribution
●Contact dermatitis – Intensely pruritic dermatitis and intraepidermal spongiotic bullae often
develop in patients with severe contact dermatitis, such as can occur after exposure to poison ivy
(picture 40). Lesions develop in sites of contact of the inciting substance with the skin. A linear
distribution is common. (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Phytophotodermatitis –Erythema, edema, and vesiculation occurring in a linear or odd

configuration may develop after topical exposure to certain of plant-derived substances (eg, lemons,
limes, celery, wild parsnip, or parsley) followed by sun exposure (picture 41A-B) [20]. The term
"berloque dermatitis" has been used to refer to lesions secondary to natural oil of bergamot in
products used on the skin. Significant postinflammatory hyperpigmentation after resolution of the
acute process is common. (See "Photosensitivity disorders (photodermatoses): Clinical
manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)
Other localized blistering disorders

●Herpes simplex virus – A localized eruption composed of grouped, small, often umbilicated
vesicles or vesicopustules is characteristic of herpes simplex virus infection (picture 42A-B). The
lips, genitals, and buttocks are common sites of involvement. Primary infections tend to be most
severe and can be accompanied by lymphadenopathy and flu-like symptoms. Extensive lesions may
occur in patients with atopic dermatitis, a condition referred to as eczema herpeticum (also referred
to as Kaposi's varicelliform eruption). (See "Epidemiology, clinical manifestations, and diagnosis of
herpes simplex virus type 1 infection" and "Epidemiology, clinical manifestations, and diagnosis of
genital herpes simplex virus infection".)
●Bullous arthropod bite – Occasionally, vesicles and bullae occur at sites of arthropod bites (picture
43A-B). (See "Insect and other arthropod bites".)
●Fixed drug eruption –Central bullae may appear in lesions of fixed drug eruptions, which present as
single or multiple dusky erythematous to violaceous round plaques (picture 44). The lips, genitalia,
face, and acral areas are common sites of involvement. The lesions tend to heal with significant
postinflammatory hyperpigmentation and typically recur in the same sites with subsequent drug
exposure. (See "Fixed drug eruption".)
●Transient acantholytic dermatosis (Grover's disease) –Transient acantholytic dermatosis is a

disorder that is most commonly detected in middle-aged Caucasian men. Pruritic, erythematous
papules and papulovesicles are typically localized to the trunk (picture 45). Acantholysis and
dyskeratosis are evident on histopathologic examination of papulovesicular lesions. (See "Grover's
disease (transient and persistent acantholytic dermatosis)".)
243
●Hailey-Hailey disease – Hailey-Hailey disease is an uncommon genetic disorder that presents with
fragile acantholytic blisters that quickly evolve to erosions that are primarily localized to the neck
and intertriginous areas (picture 46A-C). Erythematous vegetative plaques develop in involved areas
as the disease progresses. (See "Hailey-Hailey disease (benign familial pemphigus)".)
●Bullous pyoderma gangrenosum –Atypical variants of pyoderma gangrenosum may present with
subepidermal bullae in conjunction with superficial ulcers (picture 47). (See "Pyoderma
gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)
Mucous membrane involvement — Many blistering eruptions may also

have mucosal involvement. When blistering disorders involve the mucous membranes, frank
vesicles and bullae often are not seen. Rather, mucosal inflammation or erosions tend to be the
predominant clinical finding.
The following disorders are examples of blistering diseases that may present with both cutaneous
and mucosal findings (table 2C):
●Mucous membrane pemphigoid –Mucous membrane pemphigoid (MMP) is defined as a diverse

group of blistering disorders characterized by mucous membranes as the primary site of
involvement. Inflamed, eroded, or scarred mucosa may be present (picture 48A-E). Cutaneous
blisters accompany the mucosal lesions in some patients. (See "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid".)
●Pemphigus vulgaris (see 'Other generalized blistering disorders' above)
●Paraneoplastic pemphigus (see 'Generalized blisters with systemic illness' above)
●Bullous pemphigoid (see 'Other generalized blistering disorders' above)
●Linear IgA bullous dermatosis (see 'Other generalized blistering disorders' above)
●Epidermolysis bullosa acquisita (see 'Other generalized blistering disorders' above)
●Erythema multiforme (see 'Hands or feet' above)
●Stevens-Johnson syndrome and toxic epidermolytic necrolysis (see 'Generalized blisters with
systemic illness' above)
●Herpes simplex virus infection (see 'Other localized blistering disorders' above)
Additional clinical features — In addition to the recognition of the

distribution of cutaneous blisters, knowledge of the patient's age, blister characteristics, and the
patient's drug history may help to narrow the differential diagnosis.
244
Patient age — Although patient age cannot be used to definitively exclude most blistering
disorders, this information may provide additional clues for diagnosis.
●Neonates – In neonates, blistering lesions can occur due to intrauterine or postpartum exposure to
infections or trauma, congenital disorders, miliaria crystallina, or other disorders. The differential
diagnosis for neonates with cutaneous blisters is reviewed separately. (See "Vesicular, pustular, and
bullous lesions in the newborn and infant".)
●Young children – Disorders such as bullous impetigo and staphylococcal scalded skin occur with
greater frequency in infants and young children than in other age populations.
●Older adults – Pemphigus and pemphigoid occur with greater frequency in older adults than in
younger individuals.
Blister configuration — Grouped blisters are characteristic of herpes simplex virus

infection (picture 39A), herpes zoster (picture 39B), dermatitis herpetiformis (picture 23), and linear
IgA bullous dermatosis. An annular configuration is often present in linear IgA bullous dermatosis
(picture 22) and a linear arrangement of bullous lesions suggests the possibility of contact
dermatitis or phytophotodermatitis.
Blister size — Small vesicles are the primary lesions in miliaria crystallina, acute
palmoplantar eczema, herpes simplex virus or varicella zoster virus infection, and dermatitis
herpetiformis.
Blister quality — Tense blisters are a characteristic feature of subepidermal blistering

disorders, such as bullous pemphigoid, pemphigoid gestationis, linear IgA bullous dermatosis,
epidermolysis bullosa acquisita, and porphyria cutanea tarda. More flaccid blisters are typically seen
in conditions in which the level of bulla formation is more superficial.
History of drug exposure — Drug exposure is frequently associated with fixed

drug eruptions, pseudoporphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, and linear
IgA dermatosis (table 3). Occasionally, erythema multiforme, pemphigus vulgaris, pemphigus
foliaceus, bullous pemphigoid, and mucous membrane pemphigoid are linked to an inciting
pharmacologic agent.
Nikolsky sign — The Nikolsky (or Nikolskiy) sign is a clinical finding that describes
the elicitation of skin blistering as a result of gentle mechanical pressure on the skin. Depending on
the clinical scenario, a positive Nikolsky sign may be observed at the edge of an existing lesion, in an
area of normal-appearing skin, or in both locations [21].
245
The Nikolsky sign is often cited as a feature of the acantholytic, suprabasilar blistering disorder
pemphigus vulgaris; however, the absence of this finding does not rule out this diagnosis. In
addition, the Nikolsky sign has been detected in multiple blistering diseases with divergent modes of
blister formation and levels of blister cleavage, including among them toxic epidermal necrolysis,
staphylococcal scalded skin syndrome, and a subset of patients with bullous pemphigoid [21]. (See
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Clinical features'.)
DIAGNOSTIC TESTS Many blistering disorders share clinical

features, and diagnostic tests are essential in differentiating these conditions and making an
accurate diagnosis. The principle tests utilized in the evaluation of blistering diseases include light
microscopy, direct immunofluorescence, indirect immunofluorescence, antigen-specific serologic
testing, and microbiologic studies. The selection of the most appropriate studies to order is patient-
specific and based upon the suspected diagnoses.
Skin biopsy — A skin biopsy with or without direct immunofluorescence studies is

often the first step in the evaluation of patients with an unknown skin blistering disorder.
Light microscopy — Examination of a skin biopsy with light microscopy is useful for
identifying the histopathologic features that characterize specific disorders. Light microscopy can
detect the level of blister formation, the type of inflammatory cell infiltrate, the presence of
dyskeratotic cells, and histopathologic features suggestive of infection (picture 5A-B).
Specimens for light microscopic examination are usually obtained from lesional tissue. If small
vesicles are present, removal of an entire lesion is preferred. For larger lesions, the specimen should
be obtained from the edge of a blister; the specimen should contain both portions of the blister and
intact skin.
Punch biopsies are most frequently utilized for the evaluation of blistering lesions, as they allow for
evaluation of the full thickness of the epidermis and dermis, which can be useful in cases in which
dermal findings may offer additional clues for diagnosis. A deep shave biopsy that extends into the
reticular dermis can also be utilized, but may result in a larger, scoop-like scar. Specimens for light
microscopy can be placed in formalin for preservation. (See "Skin biopsy techniques", section on
'Punch biopsy' and "Skin biopsy techniques", section on 'Shave biopsy'.)
Direct immunofluorescence — Direct immunofluorescence is a technique

that allows for the detection of antibody or complement deposition within the skin. Direct
immunofluorescence studies are typically utilized when an autoimmune blistering disorder is
suspected. The recognition of the pattern and location of antibody binding can offer valuable insight
for diagnosis. For example, intercellular antibody deposition in the epidermis characterizes
pemphigus vulgaris and pemphigus foliaceus, whereas linear antibody deposition along the
basement membrane zone is detected in bullous pemphigoid (picture 49A-C).
246
The specimen should be taken from normal-appearing skin adjacent to the blister, which is referred
to as a perilesional biopsy. A biopsy of lesional skin is more likely to result in false negative results
because of destruction of the immunoreactants by the inflammatory process. Tissue obtained for
direct immunofluorescence should not be placed in formalin; rather, Michel's medium or Zeus
medium can be used for preservation. Fresh specimens also may be sent to the laboratory, provided
they are kept moist with saline, and processing within 24 hours is feasible.
The basic procedure for direct immunofluorescence is as follows [22]:
●Cut sections from the specimen are placed on microscope slides
●A solution containing antisera against IgG, IgA, IgM, complement factor C3, and fibrinogen
conjugated to fluorescent dye is incubated with the sections
●The sections are subsequently washed and mounted for examination utilizing an epifluorescence
microscope
Serologic tests — Indirect immunofluorescence studies and antigen-specific

serologic testing may be useful for the evaluation of autoimmune blistering disorders.
Indirect immunofluorescence — Indirect immunofluorescence can be

used to detect antibodies within the circulation. In this technique, the presence of antibodies in the
patient's serum that are capable of binding to components of an epithelial specimen that is not from
the patient is assessed (picture 50). Similar to direct immunofluorescence, this test is typically
utilized to aid in the diagnosis of autoimmune blistering disease.
The basic procedure for indirect immunofluorescence is as follows [22]:
●Blood is drawn from the patients and centrifuged to separate serum
●The selected substrate (eg, monkey esophagus, guinea pig esophagus, rat bladder, or human skin
depending upon the suspected diagnosis) is incubated with progressive dilutions of patient serum
●The tissue is incubated with antibodies conjugated to a fluorescent dye that are directed against
the antibodies bound to the substrate
●The slides are washed, mounted, and examined utilizing an epifluorescent microscope
●Results are reported as the limiting dilution in which specific fluorescence is detected
Antigen-specific serologic testing — If the target of circulating

antibodies associated with specific autoimmune blistering diseases is known, antigen-specific
testing can be used to detect the presence of antibodies in serum. Enzyme-linked immunosorbent
assay (ELISA) is the most common test utilized and is frequently employed in disorders such as
bullous pemphigoid, pemphigoid gestationis, and pemphigus vulgaris. Other antigen-specific
247
serologic tests, such as immunoblotting and immunohistochemistry, have also been utilized for the
diagnosis of autoimmune blistering diseases. These tests are more labor-intensive than ELISA, but
may be the only way to definitively identify epidermolysis bullosa acquisita and laminin-332
pemphigoid. These disorders may be associated with inflammatory bowel disease or malignancy,
respectively.
Basement membrane zone-split skin

technique — Tissue specimens with an artificially induced cleavage zone between the
epidermis and dermis (known as basement membrane zone-split skin or salt-split skin) are utilized
to obtain more precise information on the localization of antibody binding within the basement
membrane zone in direct and indirect immunofluorescence studies [22]. Incubation of the skin
substrate in a 1 M sodium chloride (NaCl) or ethylenediaminetetraacetic acid (EDTA) solution
induces separation at the level of the lamina lucida. The location of antibody binding to the
epidermal (roof) or dermal (floor) side of the split can be used to further narrow the differential
diagnosis (picture 51). (See "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Laboratory tests'.)
Microbiologic studies — If infection is suspected, microbiologic tests can

be useful for diagnosis. A potassium hydroxide (KOH) preparation is a quick diagnostic test for
bullous tinea pedis (picture 52). In addition, bacterial cultures of the blister site may aid in the
diagnosis of bullous impetigo, and in staphylococcal scalded skin syndrome, culture of the potential
sites of the primary staphylococcal infection can be of value. In patients with suspected herpes
simplex virus or varicella zoster virus infection, studies such as Tzanck smear (picture 53), viral
culture, polymerase chain reaction, and direct fluorescent antibody testing may be used to confirm a
diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide
preparation' and "Office-based dermatologic diagnostic procedures", section on 'Tzanck smear'.)
INDICATIONS FOR REFERRAL Referral to a

dermatologist is indicated if an autoimmune blistering disease is suspected, if the cause of
blistering is unknown, or if the disease continues to progress despite appropriate treatment. Patients
with suspected toxic epidermal necrolysis require immediate transfer to an experienced burn unit.
Patients with staphylococcal scalded skin syndrome require hospital admission for intravenous
antibiotic therapy. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management,
prognosis, and long-term sequelae" and "Vesicular, pustular, and bullous lesions in the newborn and
infant", section on 'Staphylococcal scalded skin syndrome'.)

248
●Basics topics (see "Patient education: Blisters (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●A wide variety of disorders can result in the formation of blisters on the skin. Autoimmune
disorders, drug reactions, infections, genetic disorders, and traumatic injury are among the potential
causes of cutaneous blistering. (See 'Introduction' above and 'Definition' above.)
●Cutaneous blisters may occur at various sites within the skin (table 1). Blisters that form within the
epidermis tend to be more fragile and flaccid than the tense blisters that are typically associated
with subepidermal blistering diseases. (See 'Definition' above.)
●Life-threatening cutaneous blistering disorders include toxic epidermal necrolysis, staphylococcal

scalded skin syndrome, disseminated herpes simplex virus infection, disseminated herpes zoster,
and purpura fulminans. Identification of these disorders should be prompt to reduce the risk of fatal
complications. (See 'Life-threatening emergencies' above.)
●The distribution of cutaneous blisters is often useful for narrowing the differential diagnosis (table
2A-C and algorithm 1). Blistering conditions may be divided in to generalized or localized disorders,
and additional features such as the patient's age, blister characteristics, and the patient's drug
history may also offer clues for diagnosis (table 3). (See 'Patient assessment' above.)
●Diagnostic tests commonly utilized in the evaluation of blistering skin disorders include light
microscopy, direct and indirect immunofluorescence studies, antigen-specific serologic studies, and
microbiologic tests. The specific disorders considered in the differential diagnosis determine the
selection of the most appropriate test(s). (See 'Diagnostic tests' above.)

GRAPHICS
249
Approach to the differential diagnosis of cutaneous blisters
HSV: herpes simplex virus; LCV: leukocytoclastic vasculitis; IgA: immunoglobulin A; VZV: varicella
zoster virus.
250
Varicella
A vesicle on an erythematous base is present. Varicella lesions are often described as resembling a
"dew drop on a rose petal."
251
Bullous disease of diabetes (bullosis diabeticorum)
A noninflammatory bulla is present on the lower leg in this patient with bullosis diabeticorum.
Histopathologic sites of blister formation in blistering disorders
Intracorneal/subcorneal Intraepidermal Suprabasilar Subepidermal
Staphylococcal scalded Varicella zoster Paraneoplastic Stevens-

skin syndrome virus infection* pemphigus* Johnson
syndrome
Miliaria crystallina Herpes simplex Pemphigus vulgaris
virus infection* Sweet's
Bullous impetigo Transient acantholytic syndrome
Epidermolysis dermatosis (Grover's
IgG/IgA pemphigus bullosa simplex disease) Bullous
foliaceus systemic lupus
Acute palmoplantar Hailey-Hailey disease erythematosus
Subcorneal pustular (dyshidrotic)
dermatosis eczema Darier's disease Bullous
pemphigoid
Autoeczematization
(id) reaction Pemphigus
gestationis
Friction blister
Linear IgA
252
Linear IgA
Polymorphous light bullous
eruption dermatosis
Contact dermatitis Dermatitis

herpetiformis
Junctional
epidermolysis
bullosa
Dystrophic
epidermolysis
bullosa
Epidermolysis
bullosa
acquisita
Coma blister
Bullous disease
of diabetes
Bullous
leukocytoclastic
vasculitis
Erythema
multiforme
Porphyria
cutanea tarda
Phototoxic
reaction
Arthropod bite¶
Fixed drug
eruption
Bullous
pyoderma
gangrenosum
Mucous
membrane
pemphigoid
IgG: immunoglobulin G; IgA: immunoglobulin A.
253
* May also be subepidermal.
¶ May also be intraepidermal.
Pemphigus foliaceus
Blister formation within the superficial granular layer in pemphigus foliaceus.
254
Allergic contact dermatitis
Epidermal spongiosis and spongiotic vesicles are present in this biopsy taken from a patient with
poison ivy. Infiltrating lymphocytes are apparent in the epidermis.
Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd Edition. Philadelphia:
Lippincott Williams & Wilkins, 1999. Copyright © 1999 Lippincott Williams & Wilkins.
255
Varicella
This photomicrograph of the skin from a patient with varicella shows an intraepidermal vesicle.
Multinucleated giant cells and nuclear inclusions are present.
Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd Edition. Philadelphia:
256
Pemphigus vulgaris
Histology-stained section of a skin biopsy specimen from a blister in a patient with pemphigus
vulgaris demonstrates characteristic loss of cohesion between epidermal keratinocytes
(acantholysis) above an intact basement membrane zone.
Courtesy of Beth G Goldstein, MD, and Adam O Goldstein, MD.
257
Bullous pemphigoid
This hematoxylin and eosin stain of a skin tissue biopsy specimen from the edge of an established
lesion of bullous pemphigoid demonstrates a subepidermal blister with an edematous papillary
dermis as its base. The roof of the blister consists of the intact epidermis, including the stratum
basalis. Eosinophil-rich inflammatory cells, fibrin, and tissue fluid fill the blister.
Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd ed, Lippincott Williams &
Wilkins, Philadelphia 1999. Copyright ©1999 Lippincott Williams & Wilkins.
258
Cutaneous changes of Stevens-Johnson syndrome (SJS)
Generalized eruption of lesions that initially had a target-like appearance but then became confluent,
brightly erythematous, and bullous. The patient had extensive mucous membrane involvement and
tracheobronchitis.
Reproduced with permission from: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. In:
Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd edition,
Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds), McGraw-Hill, New York 1997. Copyright © 1997
McGraw-Hill.
259
Diffuse erythema and large areas of denuded epidermis are present.
260
Multiple bullae and areas of denuded epidermis are present.
261
Staphylococcal scalded skin syndrome
A wrinkled appearance to the skin, bullae, and desquamation are present in this patient with
staphylococcal scalded skin syndrome.
262
Diffuse erythema and desquamation are present in this child with staphylococcal scalded skin
syndrome.
263
Disseminated herpes zoster
The multiple vesicles and crusts of herpes zoster are not limited to a dermatome.
Reproduced with permission from: Herbert A Hochman, MD. Originally published in Goodheart HP.
Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia: Lippincott Williams &
Wilkins, 2003.
264
Purpura fulminans
A large, retiform, purpuric lesion is present on the leg. Purpura fulminans is characterized by the
presence of extensive purpura.
Examples of generalized cutaneous blistering disorders
Disorder Clinical features Pathology Laboratory

findings
Bullous Tense bullae, H&E: subepidermal blister IIF: IgG anti-BP

pemphigoid urticarial papules with eosinophils; DIF: linear antigen 180 and
and plaques; basement membrane zone 230
mucous membrane deposition of IgG and C3
involvement in up
to 30 percent of
cases
Pemphigus Flaccid vesicles H&E: intraepidermal blister IIF: intercellular

vulgaris and erosions on formation, acantholysis; DIF: IgG staining of
skin and mucous intercellular epidermal IgG skin substrate,
membranes, deposition involving lower anti-desmoglein
desquamative epidermis 3 IgG
gingivitis; scalp
involvement
265
involvement
common
Pemphigus Flaccid vesicles H&E: intraepidermal vesicle IIF: intercellular

foliaceus and erosions; no and acantholysis (blister is IgG staining of
mucous membrane subcorneal); DIF: intercellular skin substrate;
involvement IgG deposition in upper anti-desmoglein
epidermis 1 IgG
Stevens- Exudative erosions H&E: vacuolar interface None

Johnson of lips, oral dermatitis or epidermal
syndrome and mucosa, eyes, necrosis
toxic epidermal genital mucosa;
necrolysis targetoid
papulovesicles of
skin, skin
sloughing, and skin
pain
Paraneoplastic Targetoid H&E: mixed histology with IIF: antibodies to

pemphigus papulovesicles, overlapping features of multiple antigens
erythema pemphigus vulgaris, erythema (desmoplakins,
multiforme-like multiforme, and lichen planus; desmogleins,
cutaneous lesions; DIF: staining of transitional bullous
exudative erosions epithelium (rodent bladder) pemphigoid
of lips, oral antigen 1, etc)
mucosal, eyes,
genital mucosa
Dermatitis Grouped H&E: subepidermal blister Elevation of

herpetiformis papulovesicles on with neutrophils in dermal serum IgA anti-
elbows, knees, papillae; DIF: IgA in dermal epidermal
buttocks, scalp; papillae transglutaminase
intense pruritus antibodies
Disseminated Fever, hepatitis, Intraepidermal blister; Viral culture,

HSV/VZV CNS involvement; ballooning of keratinocyte Tzanck smear,
grouped and cytoplasm and margination of DFA, PCR
scattered chromatin to form
monomorphic intranuclear inclusion bodies;
vesicles mixed inflammatory infiltrate
Linear IgA Annular or arcuate H&E: subepidermal blister IIF: circulating

bullous vesicles and bullae; with predominance of IgA
dermatosis can have mucous neutrophils; DIF: linear IgA antibasement
membrane along basement membrane membrane
involvement zone antibodies
Epidermolysis Tense blisters and H&E: subepidermal blisters

bullosa erosions with with mixed inflammatory
i i i d ili i fil f hil
266
acquisita scarring and milia infiltrate of neutrophils,
eosinophils, lymphocytes;
DIF: broad, linear IgG along
the basement membrane
zone; in salt-split skin, IgG
stains dermal side
Staphylococcal Widespread H&E: subcorneal blister (split Toxin-mediated

scalded skin erythema, flaccid within the granular cell layer) condition; culture
syndrome bullae, erosions, often negative at
desquamation of sites of blistering
skin
Bullous Other skin findings H&E: similar to dermatitis Antinuclear

systemic lupus of SLE: nail fold herpetiformis; DIF: mixed antibody test
erythematosus telangiectasias, features similar to bullous
malar erythema, pemphigoid and lupus
discoid or subacute
cutaneous lupus
H&E: hematoxylin and eosin pathology stain; DIF: direct immunofluorescence; IIF: indirect
immunofluorescence; IgG: immunoglobulin G; IgA: immunoglobulin A; HSV: herpes simplex virus;
VZV: varicella zoster virus; CNS: central nervous system; DFA: direct fluorescent antibody test; PCR:
polymerase chain reaction; SLE: systemic lupus erythematosus.
Select examples of localized cutaneous blistering disorders
Disorder Clinical features Diagnostic tests
Dermatitis Linear configuration if contact dermatitis. H&E: spongiosis
Bullous tinea Vesicles on soles of feet or between the KOH examination

pedis toes. demonstrating hyphae or
positive fungal culture
Fixed drug Dusky violaceous patch, hemorrhagic bulla; History

eruption may recur at same location with future drug
exposures. H&E: lichenoid or
interface dermatitis
Erythema Targetoid papules on extremities and acral H&E: vacuolar interface

multiforme locations; hemorrhagic vesicles/bullae; dermatitis; positive
intermittent recurrences usually associated confirmation of
with HSV infection. concurrent HSV outbreak
Friction Most commonly seen on soles of feet or History
267
blisters palms of hands at sites of friction.
H&E: intraepidermal
blister
Coma blisters Tense blisters at sites of pressure in History

comatose patients.
H&E: subepidermal
blister and eccrine gland
necrosis
Bullous insect Intense pruritus and erythematous papules. History

bites
Bullous Tense blisters found predominately on lower H&E: pauci-inflammatory

disease of extremities. Lack of erythema or subepidermal blister
diabetes inflammation. Rare manifestation of
(bullous diabetes. DIF: negative
diabeticorum)
Grover's Keratotic eroded papules and vesicles on the H&E: dyskeratosis and
(transient abdomen, chest, back. Male predominance. acantholysis
acantholytic Often worsens with heat, exercise,
dermatosis) hospitalization. DIF: negative
H&E: hematoxylin and eosin pathology stain; DIF: direct immunofluorescence; KOH: potassium
hydroxide; HSV: herpes simplex virus.
Blistering disorders with mucous membrane involvement
Disorder Associated Clinical features Pathology Laboratory

conditions findings
Herpes None Recurrent, H&E: Viral culture,

simplex virus grouped intraepidermal Tzanck smear,
(HSV) vesicles; most blister; ballooning HSV DFA, PCR
commonly of keratinocyte
found on lips or cytoplasm and
genitalia margination of
chromatin to form
intranuclear
inclusion bodies;
mixed
inflammatory
infiltrate
268
Erythema HSV or Mucosal H&E: vacuolar HSV testing on
multiforme Mycoplasma erythema and interface active lesions,
pneumoniae erosions, most dermatitis, serology, or
infection, frequently necrotic biopsy
occasionally involving oral keratinocytes, specimen;
drug exposure cavity; target subepidermal testing for M.
lesions on skin clefts and pneumoniae
vesiculation infection
Pemphigus None Vesicles, H&E: IIF: intercellular

vulgaris erosions and intraepidermal IgG staining of
desquamative vesicle, skin substrate,
gingivitis acantholysis IgG
antidesmoglein
DIF: intercellular 3
epidermal IgG
deposition
Mucous Reflects a Vesicles and H&E: IIF: varies with

membrane diverse group erosions, subepidermal subtype
pemphigoid* of desquamative blisters;
subepidermal gingivitis; can inflammatory
blistering have ocular infiltrate and DIF
disorders with involvement and findings vary with
mucous symblepharon subtype
membranes
as the primary
site of
involvement
Stevens- Medication, Exudative H&E: vacuolar None

Johnson Mycoplasma erosions of lips, interface
syndrome and infection oral mucosa, dermatitis or
toxic eyes, genital epidermal
epidermal mucosa; necrosis
necrolysis targetoid
papulovesicles
of skin, skin
sloughing, skin
pain
Paraneoplastic Underlying Targetoid H&E: mixed IIF: intercellular

pemphigus malignancy papulovesicles; histology; IgG deposition
erythema overlapping on transitional
multiforme-like features of epithelium
cutaneous pemphigus (rodent
lesions; vulgaris, erythema bladder)
exudative multiforme, and
269
erosions of lips, lichen planus
oral mucosal,
eyes, genital DIF: intercellular
mucosa IgG deposition;
basement
membrane zone
IgG deposition
also may be
present
HSV: herpes simplex virus; H&E: hematoxylin and eosin pathology stain; DFA: direct fluorescent
antibody; PCR: polymerase chain reaction; DIF: direct immunofluorescence; IgG: immunoglobulin G;
IIF: indirect immunofluorescence.
* Skin-predominant forms of bullous pemphigoid, linear IgA bullous dermatosis, and epidermolysis
bullosa acquisita may also present with mucosal involvement.
Stevens-Johnson syndrome (SJS)
Multiple erosions and crusts are present on the lips of this patient with SJS.
270
Perioral crusting is present in this child with staphylococcal scalded skin syndrome.
271
Chickenpox (varicella-zoster infection)
Numerous vesicles, some of which are hemorrhagic, on the face of a child with chickenpox.
272
Eczema herpeticum

273
Eczema herpeticum
Hemorrhagic crusts and vesicles due to herpes simplex virus infection are present on the hand of
this infant with underlying atopic dermatitis.
Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency
Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams &
Wilkins.
274
Sweet syndrome
Vesicles and inflammatory papules and plaques are present in this patient with Sweet syndrome.
275
Sweet syndrome
Vesiculation is present in this inflammatory plaque of Sweet syndrome.
276
Bullous lupus
Multiple blisters in a young woman with bullous systemic lupus erythematosus.
Courtesy of Samuel L Moschella, MD.
Paraneoplastic pemphigus
An erosive mucositis in a patient with

paraneoplastic pemphigus associated with
Castleman's tumor; mucous membrane and
cutaneous lesions cleared with tumor
removal.
Copyright © Chris Ha, MD, Dermatlas;

277
Vesicles and flaccid bullae are present on the skin.
278
Bullae, erosions, and crusts are present on the skin.
279
Miliaria crystallina
Multiple small vesicles on the skin.
280
Bullous impetigo
Vesicles and pustules that easily rupture and evolve to erosions and crusts are characteristic of
bullous impetigo.
281
Pemphigus vulgaris
Flaccid bullae and erosions on the skin of a patient with pemphigus vulgaris.
282
Pemphigus vulgaris - oral lesions
Multiple erosions on the palate in a patient with pemphigus vulgaris.
283
Pemphigus vulgaris
Erosions on the tongue and lips are present in this patient with pemphigus vulgaris.
284
Pemphigus foliaceus
Pemphigus foliaceus lesions exhibit

erythema, scaling, and crusting. The face
and scalp are often the initial sites of
involvement.

Stedman's Medical Dictionary. Copyright ©
2008 Lippincott Williams & Wilkins.
285
Pemphigus foliaceus
Pemphigus foliaceus is characterized by erythema, scaling, and crusting that first appears on the
face and scalp, and later involves the chest and back.
Reproduced with permission from: Bystryn J, Ruldolph J. Pemphigus. Lancet 2005; 266:61.
Copyright © 2005 Nicholas Soter, MD. Reproduced in Lancet with permission from: the New York
University Department of Dermatology.
286
Bullous pemphigoid
Multiple tense bullae arising on erythematous plaques, ruptured bullae, and erosions in and around
skin of the axilla.
287
Bullous pemphigoid
Multiple erythematous plaques, bullae, erosions, and crusts on the trunk and extremity skin.
288
Pemphigoid gestationis
Periumbilical erythematous papules, vesicles, erosions, and crusts are present in this patient with
pemphigoid gestationis.
289
Widespread erythematous plaques, bullae, and erosions are present on this patient with extensive
disease.
290
Multiple tense bullae on skin.
291
Linear IgA bullous dermatosis
Tense bullae, erosions, and crusts, often in a pattern described as "clusters of jewels" or "strings of
pearls," on skin of a patient with linear IgA bullous dermatosis.
IgA: immunoglobulin A.
292
Vesicles, bullae, erosions, and crusts on elbow skin.
293
Dystrophic epidermolysis bullosa
Multiple bullae and erosions are present in this infant with dystrophic epidermolysis bullosa.
294
Epidermolysis bullosa acquisita
Tense bullae, erosions, and crusts on skin of a patient with epidermolysis bullosa acquisita.
295
Bullous cutaneous small vessel vasculitis
Vesicles overlying purpuric macules are present on the lower leg.
296
Stasis dermatitis
A bulla is present within an area of stasis dermatitis on the lower leg.
297
Dyshidrotic eczema
Small vesicles (arrows) are visible on the lateral fingers.
Reproduced with permission from: Goodheart HP. Goodheart's photoguide to common skin
disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
298
Dyshidrotic eczema with large bullae
Large bullae resulting from coalescence of vesicles on the palms of a patient with severe dyshidrotic
eczema.
299
Acute tinea pedis
The medial aspect of the left great toe demonstrates erythematous, papulovesicular lesions caused
by Trichophyton mentagrophytes.
Courtesy of John T Crissey, MD.
300
Autoeczematization (id reaction)
Numerous pinpoint vesicles are present on the hand.
301
Sucking blister
A blister is present on the thumb of this neonate.
302
Intrauterine sucking lesions
Intrauterine sucking lesions can be seen in the

dorsum of the fingers, hand, or radial aspect of
the wrist of newborn infants. The lesions may
appear as ruptured (pictured above) or intact
vesicles. They can be multiple, unilateral, or
bilateral. Rarely, they may have a hemorrhagic
component.
Courtesy of Gerardo A Cabrera-Meza, MD.
303
Target lesions of erythema multiforme
Target lesions with central bullae are present on the hand.
304
Erythema multiforme
Erosions are present on the penis of this patient with erythema multiforme. A target-like lesion is
present on the distal glans.
305
Erythema multiforme
Hemorrhagic crusting and mucosal erosions

involving the lips and tongue in a patient with
erythema multiforme.

www.visualdx.com. Copyright VisualDx. All
rights reserved.
306
Epidermolysis bullosa simplex
Bullae are present on the hands of this infant with epidermolysis bullosa simplex.
307
Epidermolysis bullosa simplex
Multiple erosions and bullae are present on the foot of this child with epidermolysis bullosa simplex.
308
This photo shows a 35-year-old woman with a symmetrical papulovesicular eruption on the
forearms. Lesions were also present on the neck and lower legs.
Copyright © Eric Ehrsam, MD, Dermatlas; http://www.dermatlas.org.
309
Vesicles and erosions are visible on the dorsum of the hand in a patient with porphyria cutanea tarda
related to underlying hepatitis C virus infection.
Courtesy of Jean-François Dufour, MD.
310
Macular erythema, erosions, crusts, and scars are present on the hands of this patient with
porphyria cutanea tarda.
Williams & Wilkins.
311
Pseudoporphyria
Vesiculation and crusting are present on the dorsal hand.
312
Sunburn
Erythema, edema, and bullae are present on this child with a severe sunburn.
Wilkins.
313
Vesicles of herpes zoster
Multiple vesicles are present in this patient with herpes zoster.
314
Herpes zoster
Grouped vesicles and underlying erythema are present in a dermatomal distribution.
315
Poison ivy allergic contact dermatitis
Large bullae on the hand of a child with acute allergic contact dermatitis from poison ivy.
316
Phytophotodermatitis
After making lemonade during an outdoor excursion trip, this 38-year-old female presented with
erythematous linear and angulated patches and crusts on the face.
Copyright © Shahbaz A Janjua, MD, Dermatlas; http://www.dermatlas.org.
317
Berloque dermatitis
This adolescent developed hyperpigmented

streaks from a photosensitizer in his
sunscreen. After several days of erythema,
the red patches became dark brown.
Copyright © Kosman Sadek Zikry, MD,

Dermatlas; http://www.dermatlas.org.
318
Female genital herpes simplex virus

319
Herpes simplex labialis
Grouped vesicles are evident on the lower vermilion border.
Reproduced with permission from: Bickley LS, Szilagyi P. Bates' Guide to Physical Examination and
History Taking, Eighth Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003
320
Bullous arthropod bite
Multiple erythematous papules consistent with arthropod bites are present on the foot. An intact,
fluid-filled bulla is present at the site of one lesion.
321
Bullous arthropod (insect) bite
A bulla is present in the site of an insect bite.
322
Fixed drug eruption
Multiple violaceous, round plaques are present on the skin. A central bulla is present in one lesion.
323
Grover's disease
Typical appearance of scattered pruritic, erythematous papules and papulovesicles on the trunk.
Courtesy of Whitney High, MD.
324
Vulvar Hailey-Hailey disease
A large, erythematous plaque with multiple superficial erosions involving the vulvar and groin area in
a patient with Hailey-Hailey disease.
Courtesy of Lynne J Margesson, MD.
325
Hailey-Hailey disease
Typical axillary plaque of

Hailey-Hailey disease,
showing superficial erosions
and crusts.
326
Perianal Hailey-Hailey disease
Large, erythematous, and crusty

perianal plaque in a patient with
Hailey-Hailey disease.
327
Bullous pyoderma gangrenosum
Three large hemorrhagic bullae on the dorsum of the hand and fingers. The bulla on the index finger
has ruptured, resulting in a large erosion with an irregular, raised, pustular border and a purulent
hemorrhagic exudate.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al. Color atlas and
synopsis of clinical dermatology, 3rd ed, McGraw-Hill, New York 1997. Copyright © 1997 McGraw-
Hill.
328
Mucous membrane pemphigoid
Irregular erosions and a blister on the mucosal surface of the lip.
329
Mucosal erosions on the gingiva and palate.
330
Erosions are present on the genital mucosa.
331
Stage 3 ocular cicatricial pemphigoid
Note the symblepharon bridging between the eyeball and the eyelid.
332
Cicatricial pemphigoid
Erosions are present on the gingiva in this patient with cicatricial pemphigoid.
333
Bullous drug eruptions
Drug eruption Clinical features Common

medications
Linear IgA Annular erythema and blisters ("crown of Vancomycin,

bullous jewels"). penicillin,
dermatosis cephalosporins,
ACE inhibitors,
NSAIDs
Pseudoporphyria Photodistributed blisters on dorsal hands, NSAIDs,

forearms, face. Similar clinical presentation as tetracyclines,
porphyria cutanea tarda (with negative furosemide
porphyrin studies).
Fixed drug Dusky, violaceous patch. Hemorrhagic vesicle Sulfonamides,

eruption or bulla. History of recurrences at same location NSAIDs,
with medication usage. tetracyclines
Stevens- Widespread, dusky erythema with epidermal Antibiotics,

Johnson detachment and flaccid blisters. Prominent anticonvulsants,
syndrome, toxic mucosal involvement. allopurinol,
epidermal dapsone, NSAIDs
necrolysis
IgA: immunoglobulin A; ACE: angiotensin-converting enzyme; NSAID: nonsteroidal anti-inflammatory

drug.
334
Pemphigus vulgaris direct immunofluorescence
An intercellular pattern of IgG antibody binding is evident on direct immunofluorescence in this

specimen from a patient with pemphigus vulgaris.
Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology,

University of Utah, Salt Lake City, Utah.
335
Pemphigus foliaceus direct immunofluorescence
Intercellular antibody binding is evident within the upper epidermis in this direct
immunofluorescence specimen from a patient with pemphigus foliaceus.

336
Direct immunofluorescence of bullous pemphigoid
Direct immunofluorescence discloses linear deposits of IgG and C3 along the dermoepidermal
junction. Ultrastructurally, these antibodies and complement are present in the lamina lucida.
Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd ed, Lippincott Williams &
Wilkins, Philadelphia 1999. Copyright ©1999 Lippincott Williams & Wilkins.
337
Pemphigus vulgaris indirect immunofluorescence
Pemphigus vulgaris. Indirect immunofluorescence performed on monkey esophagus demonstrates

intercellular IgG antibody deposition.

338
Serum IgG basement membrane zone antibodies localizing to the epidermal side of split skin
substrate in bullous pemphigoid by indirect immunofluorescence microscopy
Linear IgG antibody staining on the epidermal side of basement membrane zone-split skin substrate
characteristic of bullous pemphigoid. This pattern also is referred to as staining the roof of the
blister.

339
Dermatophyte potassium hydroxide preparation
Septate hyphae are visible on a background of squamous cells in this potassium hydroxide
preparation taken from a lesion of tinea corporis. Potassium hydroxide preparations from tinea pedis
and tinea cruris have a similar appearance.
Tzanck preparation
This Tzanck preparation of a specimen

from a patient with herpes simplex virus
infection demonstrates a multinucleated
giant cell.
340
Christopher Hull, MDNothing to discloseJohn J Zone, MDNothing to discloseErik Stratman,
MDNothing to discloseAbena O Ofori, MDNothing to disclose
341
Approach to the patient with facial erythema
uptodate.com/contents/approach-to-the-patient-with-facial-erythema/print
Approach to the patient with facial erythema
Author:
Mark V Dahl, MD
Section Editor:
Erik Stratman, MD
Deputy Editor:
Abena O Ofori, MD
INTRODUCTION Facial erythema (facial redness), a clinical finding most

noticeable in fair-skinned individuals, occurs as a result of cutaneous blood vessel dilation and
increased blood flow to the skin. Although transient facial erythema is often observed as a normal,
neurologically mediated response to strong emotion, exercise, or heat exposure, inflammation and a
variety of medical conditions can lead to longer-lasting and symptomatic or cosmetically distressing
facial erythema.
Examples of disorders that may present with diffuse or localized facial erythema and the evaluation
of patients with this clinical finding will be reviewed here. More detailed information on flushing and
many of the other disorders associated with facial erythema is available separately. (See "Approach
to flushing in adults" and 'Etiology' below.)
ETIOLOGY A variety of factors, including primary skin diseases, external insults,

and systemic illness may cause facial redness. Knowledge of the distinctive characteristics of these
disorders is helpful for diagnosis.
Primary inflammatory skin diseases

●Rosacea –The erythematotelangiectatic subtype of rosacea is characterized by centrofacial
erythema and telangiectasias (picture 1A-B) [1-3]. Affected patients also often exhibit flushing and
sensitivity of facial skin. The patient history and physical findings are usually sufficient for the
diagnosis of this disorder. Other rosacea subtypes may also demonstrate these clinical features.
(See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
342
●Perioral dermatitis – Perioral dermatitis (also known as periorificial dermatitis) presents with
multiple small, erythematous, inflammatory papules clustered around the mouth, nose, or eyes
(picture 2). Fine scale is also often present, but the rash is characteristically more red and bumpy
than red and scaly. In patients with perioral lesions, the skin immediately adjacent to the vermillion
border of the lip is classically spared. Perioral dermatitis most frequently affects young women;
occasionally, the disorder occurs in children. (See "Perioral (periorificial) dermatitis".)
●Seborrheic dermatitis – Erythema accompanied by greasy, yellow-white scale is a characteristic

feature of seborrheic dermatitis in adults. In patients with dark skin, the scale may have a gray or
brown hue. Involvement of the face typically manifests in the nasolabial folds, eyebrows, glabella,
and lateral nasal areas (picture 3A-B). Other potential sites of involvement include the scalp, ears,
chest, axillae, and groin. The diagnosis of seborrheic dermatitis is usually made based upon the
clinical findings [4,5]. (See "Seborrheic dermatitis in adolescents and adults".)
●Atopic dermatitis – Facial involvement of atopic dermatitis is common in infants (picture 4A-C) but
may also occur in older children and adults (picture 5A-B). Intensely pruritic, erythematous patches
or plaques with accompanying scale, exudate, excoriations, or lichenification are often seen. The
presence of a chronic, very pruritic, dermatitic skin disorder with lichenification in a typical
distribution (eg, flexures in adults, cheeks in infants) suggests the possibility of atopic dermatitis [6].
Patients may also exhibit an extra skin fold beneath the bilateral lower eyelids that is known as a
Dennie-Morgan fold (picture 6). An uncommon variant is photosensitive atopic dermatitis, which
occurs predominantly in atopic skin exposed to ultraviolet light [7]. (See "Atopic dermatitis (eczema):
●Psoriasis – The clinical findings in facial psoriasis may be more subtle than the classic thick
plaques with silver scale that are typical of lesions in other body areas (picture 7A-B). In some
patients, lesions closely resemble the erythematous patches and finer scale of seborrheic
dermatitis. The detection of lesions consistent with the classic presentation of psoriasis elsewhere
on the body is helpful for diagnosis. (See "Psoriasis: Epidemiology, clinical manifestations, and
diagnosis".)
Disorders due to external insults

●Irritant contact dermatitis – Contact with skin care products, cosmetics, or other substances that
contain irritants may result in facial eruptions with features of eczematous dermatitis. The
dermatitis may be diffuse or localized depending on the sites of contact. The facial folds and the
delicate skin of the eyelids are particularly susceptible to more severe involvement.
Unlike allergic contact dermatitis, which is typically associated with intense pruritus, patients with
irritant contact dermatitis tend to complain of burning or prickling sensations [8]. The patient history
is critical for identifying this diagnosis. (See "Irritant contact dermatitis in adults".)
343
●Allergic contact dermatitis – Delayed hypersensitivity reactions to external substances that
contact the skin can cause acute, intense inflammatory reactions characterized by bright erythema,
scale, and exudate (picture 8A-B) [8]. Other times, the dermatitis is only mildly inflamed and chronic.
Patch testing can be useful for identifying the causative antigenic substance. (See "Clinical features
and diagnosis of allergic contact dermatitis" and "Patch testing".)
Photosensitive disorders
●Sunburn – The appearance of confluent, erythematous patches following sun exposure is a classic
feature of sunburn. Pruritus or pain may also be present. In severe cases, edema and blistering can
occur. Desquamation commonly occurs during healing. (See "Sunburn".)
●Polymorphous light eruption (PMLE) – Often colloquially referred to as sun poisoning or sun
allergy, PMLE may present with a wide variety of clinical manifestations [9,10]. Erythematous
patches, papules, vesicles, or plaques may occur within hours to days after sun exposure (picture 9).
PMLE is particularly likely to occur in early spring, as patient tolerance to sunlight tends to rise with
increasing exposure. (See "Polymorphous light eruption".)
●Phototoxic and photoallergic eruptions – Phototoxic eruptions are sunburn-like reactions induced
by the ingestion or application of photosensitizing substances (picture 10) [11-14]. The
photosensitizing agent decreases the amount of ultraviolet light exposure required to elicit this
reaction. Severe eruptions with blistering and edema may occur. (See "Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
Photoallergic reactions are characterized by pruritic, eczematous eruptions in sun-exposed areas

(picture 11) [11-13]. Topical, rather than ingested, agents are the most frequent causes of
photoallergic reactions [15]. (See "Photosensitivity disorders (photodermatoses): Clinical
manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
●Photodamage – The formation of numerous telangiectasias and a ruddy complexion secondary to

chronic sun exposure is a common cause of facial redness [16]. Sun-protected areas of the face are
relatively spared. Patients may have accompanying poikiloderma of Civatte, a disorder characterized
by mottled pigmentation and telangiectasias on the lateral neck (picture 12). (See "Photoaging",
section on 'Clinical features'.)
●Acute cutaneous lupus erythematosus, dermatomyositis, and lupus tumidus erythematosus [17].
(See 'Systemic disorders' below and 'Localized inflammatory infiltrates' below.)
Systemic disorders
●Lupus erythematosus – Patients with systemic lupus erythematosus may develop acute
cutaneous lupus erythematosus, which often manifests as persistent, violaceous erythema on the
malar area of the face (picture 13) [18,19]. This clinical finding is often referred to as a "butterfly
rash." The prominent telangiectasias of rosacea are not a feature of acute cutaneous lupus
344
erythematosus. The presence of signs or symptoms of systemic lupus erythematosus suggests this
diagnosis. (See "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus
erythematosus' and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations
and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in
adults", section on 'Clinical manifestations'.)
Patients with subacute cutaneous lupus erythematosus have a photosensitive form of lupus
erythematosus. Erythematous, annular or nummular, scaling, psoriasiform plaques usually appear
on the trunk, but the face may be involved. The inner edge of annular plaques often shows fine white,
trailing scales. Patients are otherwise usually healthy but some may have arthritis or other findings
of systemic lupus erythematosus. (See "Overview of cutaneous lupus erythematosus", section on
'Subacute cutaneous lupus erythematosus'.)
●Dermatomyositis – A classic sign of dermatomyositis is the "heliotrope eruption," a violaceous and

often edematous eruption that occurs on the eyelids and periorbital skin (picture 14A-B). Patients
may or may not have accompanying proximal muscle weakness. The detection of other cutaneous
signs of dermatomyositis, such as Gottron papules and periungual telangiectasias, raises suspicion
for this diagnosis. In addition, the possibility of an underlying malignancy must be considered in
adults with dermatomyositis. (See "Clinical manifestations of dermatomyositis and polymyositis in
adults" and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical
manifestations".)
Infectious disorders
●Viral infections – Erythema infectiosum is a viral disease caused by parvovirus B19 that most
commonly occurs in children [20]. A common feature of this disorder is the appearance of red
patches on the cheeks that resemble facial skin after a slap on the face (picture 15). Nonspecific
constitutional symptoms, such as fever, coryza, headache, or gastrointestinal distress, usually
precede the cutaneous findings. A reticulated eruption on the trunk and extremities frequently
appears one to two days after the facial lesions. (See "Clinical manifestations and diagnosis of
parvovirus B19 infection", section on 'Erythema infectiosum'.)
Morbilliform or confluent facial redness may also occur as early features of other viral infections,
such as measles or rubella; other body sites are typically also involved (picture 16A-B). (See
"Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Rubella".)
●Erysipelas – Erysipelas is a superficial form of cellulitis that usually results from infection with
beta-hemolytic streptococci [21]. Patients typically present with the acute development of an
erythematous, warm, edematous, and well-defined plaque (picture 17). Fever and lymphadenopathy
often accompany the cutaneous symptoms. (See "Cellulitis and skin abscess: Clinical
manifestations and diagnosis".)
Localized inflammatory infiltrates
345
●Lupus tumidus erythematosus – Also known as tumid lupus erythematosus, lupus tumidus
erythematosus is an uncommon disorder that presents with erythematous plaques in sun-exposed
areas, such as the face, neck, upper trunk, and upper extremities, and scale is typically absent
(picture 18) [22,23]. The vast majority of patients do not have associated systemic lupus. The
performance of a biopsy assists with diagnosis. (See "Overview of cutaneous lupus erythematosus",
section on 'Lupus erythematosus tumidus'.)
●Jessner's lymphocytic infiltrate – This idiopathic disorder most commonly manifests as

erythematous, asymptomatic, often annular plaques on the face, neck, or upper trunk (picture 19A-B)
[24,25]. A skin biopsy is useful for diagnosis. Jessner's lymphocytic infiltrate shares clinical and
histopathologic features with lupus tumidus erythematous. The relationship between these
disorders remains unclear [25].
●Granuloma faciale –Granuloma faciale usually presents as a solitary, red-brown, asymptomatic,

round plaque with follicular prominence on the face (picture 20) [26]. The histopathologic finding of
a normal-appearing thin zone in the papillary dermis (Grenz zone) above a dense inflammatory
dermal infiltrate containing eosinophils, lymphocytes, neutrophils, and plasma cells is characteristic
of this diagnosis. The disorder is most common in Caucasian men [26]. (See "Granuloma faciale".)
●Cutaneous lymphoid hyperplasia (lymphocytoma cutis) – Cutaneous lymphoid hyperplasia occurs

as a result of antigenic stimulation in the skin leading to lymphocyte proliferation. The specific
cause of the disorder is often unknown, but insect bites and infections, including Lyme disease, have
been linked to some cases [27,28]. Patients typically present with a red-brown to violaceous nodule
or plaque. A skin biopsy is necessary for diagnosis. (See "Clinical manifestations of Lyme disease in
adults", section on 'Borrelial lymphocytoma'.)
●Tinea faciei –Infections with dermatophytic fungi can mimic other acute and chronic facial skin
diseases depending upon the nature of the infecting organism and the intensity of the host's defense
reaction. In general, facial fungal infections tend to be unilateral; sharply marginated; occasionally
annular, scaling, or weeping; and slowly enlarging plaques (picture 21) [29]. Potassium hydroxide
examination of scale or culture confirms the clinical diagnosis. If lesions have been treated with a
topical corticosteroid, they typically seem to improve as inflammation is reduced (tinea incognito)
but recur when treatments are stopped. (See "Dermatophyte (tinea) infections", section on 'Tinea
faciei'.)
Other
●Flushing –Flushing is characterized by the sudden and transient appearance of facial erythema.
The etiology and clinical manifestations of flushing are discussed separately [30]. (See "Approach to
flushing in adults".)
●Ruddy complexion – Generalized redness of the skin may occur as a normal feature in some
individuals with fair skin (eg, Fitzpatrick skin phototype I or II (table 1)). Unlike
erythematotelangiectatic rosacea, redness is not limited to the central face.
346
●Keratosis pilaris rubra – Keratosis pilaris rubra faciei is most common in children, adolescents,
and young adults with fair complexions. Triangular, erythematous patches are present on the
bilateral cheeks (picture 22). Follicular keratotic papules are located within the areas of redness,
giving the skin a rough texture [31]. Clinical examination is usually sufficient for diagnosis.
●Topical corticosteroid withdrawal –Some patients develop a red face from prolonged use of
moderate- to high-potency topical corticosteroids on the face. Symptoms of burning or stinging
develop within several days after applications are stopped or reduced. Diagnostic difficulties arise
from the inability to clearly distinguish the redness from topical corticosteroid withdrawal from the
redness due to exacerbation of the underlying dermatosis. Features suggesting topical
corticosteroid withdrawal include the appearance of generalized redness of the face within four days
of withdrawal and symptoms of pain, especially burning sensations [32].
●Burning face syndrome (facial erythrodysesthesia) – Painful or burning sensations are associated
with facial erythema due to mild dilation of blood vessels. Some patients have rosacea, while others
seem to have a neuropathic pain syndrome [33].
PATIENT ASSESSMENT The first step for narrowing the

differential diagnosis of facial erythema is the performance of a thorough patient history and skin
examination. The recognition of associated symptoms, exacerbating factors, lesion time course, and
subtle clinical features of the affected area are often valuable for diagnosis. In addition, the
performance of a full skin examination may yield additional skin findings that suggest an underlying
cutaneous or systemic disorder.
The clinician should consider the following points during the patient evaluation:
●What are the physical characteristics of the eruption?
•Diffuse and symmetrical without scale – ruddy complexion, flushing
•Diffuse and symmetrical with scale – irritant contact dermatitis, airborne allergic contact dermatitis,
atopic dermatitis in infants
•Symmetrical, central face or cheeks without scale – rosacea, erythema infectiosum, keratosis
pilaris rubra faciei
•Symmetrical, central face with scale – seborrheic dermatitis, atopic dermatitis, psoriasis
•Photodistributed – sunburn; polymorphous light eruption; phototoxic reaction; photoallergic

reaction; photodamage; acute, subacute, and discoid cutaneous lupus erythematosus;
dermatomyositis; lupus erythematosus tumidus
•Localized plaques or patches – erysipelas, lupus tumidus erythematosus, cutaneous lymphoid

hyperplasia, Jessner's lymphocytic infiltrate, granuloma faciale
347
•Presence of telangiectasias – photodamage, rosacea
●Are there associated symptoms?
•Prominent pruritus – allergic contact dermatitis, atopic dermatitis, photoallergic reaction
•Painful or burning sensations – sunburn, irritant contact dermatitis, phototoxicity, erysipelas,

rosacea
•Sick patient – lupus erythematosus, systemic infection, drug eruption
●How long has the eruption been present; how long do symptoms last?
•Acute – allergic contact dermatitis, atopic dermatitis flare, erythema infectiosum and other viral
infections, sunburn, phototoxic reaction, photoallergic reaction
•Transient – flushing
●Has the patient applied any products to the skin that could cause an irritant or allergic reaction?
•Allergic contact dermatitis, irritant contact dermatitis, photoallergic reaction
●Is the eruption exacerbated by sun exposure?
•Sunburn, phototoxic reaction, photoallergic reaction, cutaneous lupus erythematosus,

dermatomyositis, lupus tumidus erythematosus
●Is the patient ingesting any photosensitizing medications or supplements?
•Phototoxic reaction, occasionally photoallergic reactions
●Are other body sites involved, and in what distribution?
•Psoriasis, atopic dermatitis, seborrheic dermatitis, viral exanthems, drug eruptions,

photodermatoses, erythroderma, other disorders
DIAGNOSTIC TESTS The workup of patients with facial redness is

dependent upon the disorders suspected as a result of the clinical assessment. Diagnostic tests that
can be useful for the evaluation of select patients include:
●Patch testing
●Skin biopsy
●Directed serologic studies (eg, investigative tests for autoimmune disease)
348
Patch testing — Patch testing can be useful for identifying the causative allergen in
patients with contact dermatitis. The procedure is most appropriate for patients in whom an allergic
contact dermatitis is strongly suspected (eg, history of contact with a potential allergen, paroxysmal
nature of eruptions, or severe pruritus) or in patients with persistent, pruritic, eczematous facial
eruptions without another identifiable cause. (See "Patch testing".)
The results of patch testing must be interpreted carefully since a positive patch test result does not
definitively indicate that a specific allergen is the cause of dermatitis. A thorough patient interview
prior to patch testing and reevaluation following the elimination of the identified allergen are
essential for confirming the relevance of patch test results.
Biopsy — Skin biopsies are not necessary in most patients with facial erythema, as a
thorough clinical history and skin examination often yields the diagnosis. However, in cases in which
the diagnosis remains uncertain and the disorders being considered have distinctive histopathologic
findings, skin biopsies can be of value.
Punch biopsies are typically performed for the evaluation of facial dermatoses as they allow for the
evaluation of the full thickness of the epidermis and dermis through the removal of a relatively small
skin sample. We most commonly perform 3 mm punch biopsies when evaluating inflammatory
facial dermatoses. Larger punch biopsies are typically avoided to minimize scarring, and smaller
biopsies may increase the risk for inconclusive histopathologic results. (See "Skin biopsy
If multiple sites are acceptable for biopsy, a site that minimizes cosmetic disfigurement should be
selected.
Serology and other tests — Serologic studies and other investigative

tests may be useful in the diagnostic workup of patients with facial redness related to systemic
disorders such as acute cutaneous lupus erythematosus, dermatomyositis, or certain infections.
The selection of studies is based upon the clinical suspicion for specific underlying disorders. (See
"Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Childhood-
onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on
'Diagnosis' and "Juvenile dermatomyositis and polymyositis: Diagnosis" and "Clinical manifestations
of dermatomyositis and polymyositis in adults".)
TOPICAL CORTICOSTEROID USE The

treatment of facial erythema should be selected based upon the measures appropriate for the
specific underlying disorder. For corticosteroid-responsive inflammatory dermatoses, low-potency
agents (eg, hydrocortisone 1% or 2.5%) are most frequently employed to minimize risk for the
induction of acneiform eruptions and cutaneous atrophy that may lead to telangiectasias and a red
hue to the skin (table 2).
349
With the exception of specific disorders in which higher-potency topical corticosteroids are required
(eg, discoid lupus erythematosus), the use of medium- or high-potency topical corticosteroids for
inflammatory facial dermatoses generally is not recommended. Facial dermatoses requiring
treatment with medium- or high-potency topical corticosteroids are best managed by a
dermatologist. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
INDICATIONS FOR REFERRAL Evaluation by a

dermatologist is appropriate for patients with facial redness of unknown cause or that fails to
respond as expected to therapy. Facial biopsies and patch testing are best performed by clinicians
trained in these procedures. (See 'Patch testing' above and 'Biopsy' above.)
SUMMARY AND
RECOMMENDATIONS
●Facial redness is a common cutaneous finding that may occur as a normal feature or as a
consequence of cutaneous or systemic disorders. Examples of conditions that may lead to facial
redness include inflammatory skin disease, photosensitive disorders, autoimmune disorders,
vascular reactions, and infections. (See 'Etiology' above.)
●The evaluation of the patient with facial redness begins with a thorough patient history and whole
body skin examination. Details such as the features of cutaneous lesions, symptoms, duration of the
eruption, and exacerbating factors should be assessed. (See 'Patient assessment' above.)
●Although the diagnosis of disorders of facial erythema can commonly be made based upon the
patient history and clinical examination, patch testing, skin biopsy, or laboratory studies may be
beneficial in select patients. Antinuclear antibody testing is not indicated in all patients with facial
redness. (See 'Diagnostic tests' above.)

GRAPHICS
350
Rosacea
Centrofacial redness with telangiectasias in rosacea.
351
Rosacea
Erythema and telangiectasias on the

cheek.

352
Perioral dermatitis
Small, acne-like papules and scale are typically present in perioral dermatitis. The skin nearest to the
mouth is characteristically spared.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin
Disorders, 2nd ed. Lippincott Williams & Wilkins, Philadelphia 2003. Copyright ©2003 Lippincott
Williams & Wilkins.
Seborrheic dermatitis
Facial redness and scale involving the

nasolabial folds and central face.

Goodheart HP. Goodheart's photoguide of
common skin disorders, 2nd ed, Lippincott
Williams & Wilkins, Philadelphia 2003.
Copyright © 2003 Lippincott Williams &
Wilkins.
353
Facial seborrheic dermatitis
Intense erythema and scaling involving the central face and nasolabial folds.
Atopic dermatitis - infantile
Hyperpigmented, lichenified patches are

present on the face of this infant with
atopic dermatitis.

rights reserved.
354
Atopic dermatitis: Infantile
Confluent erythema, microvesiculation,

scaling, and crusting on the face, with similar
involvement (to a lesser degree) on the trunk
and arms.
Reproduced with permission from: Fitzpatrick

TB, Johnson RA, Wolff K, et al (Eds). Color
Atlas and Synopsis of Clinical Dermatology,
3rd ed, McGraw-Hill, New York, 1997. Copyright
© McGraw-Hill.
355

papules, crust, and scale on the face of an
infant.

TB, Johnson RA, Wolff K, et al (Eds), Color
3rd ed, McGraw-Hill, New York 1997. Copyright
© McGraw-Hill.
356
Atopic dermatitis
Erythema and scale on the periocular skin in atopic dermatitis. The pruritus associated with eyelid
involvement can be severe.
357
Atopic dermatitis
Slightly lichenified dermatitic plaques are present on the face. Erythema is subtle in this dark-
skinned patient.
358
Dennie-Morgan fold in atopic dermatitis
An extra skin fold is present under the eyes in this patient with facial atopic dermatitis.
Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed, Lippincott Williams &
Wilkins, Philadelphia 2003.
359
Psoriasis
On the face, the appearance of psoriasis is often more eczematous than papulosquamous. Most
patients with facial psoriasis also have extensive generalized psoriasis.
360
Psoriasis
Erythematous, scaly plaques are present on the face.
361
An intense, inflammatory eruption is present on the face.
362
Acute allergic contact dermatitis is severely pruritic. Skin often weeps.
363
This 12-year-old girl developed a pruritic eruption that consisted of discrete and coalescing
erythematous papules on the face. The lesions were photodistributed and appeared within hours
after intense sun exposure in the spring.
Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org.
364
Phototoxic eruption
Diffuse, sunburn-like erythema is present on the face and ears.
365
Photoallergic eruption
This 45-year-old woman developed an acute, well-demarcated, erythematous plaque with vesicles
after topical application of ketoprofen gel followed by sun exposure. The patient wore socks, which
protected the foot from the sun, creating the line of demarcation that is visible in the image.
366
Poikiloderma of Civatte
Chronic sun damage is associated with the development of poikiloderma of Civatte, which typically
presents as redness, telangiectasias, and mottled hyperpigmentation on the lateral neck.
367
Acute cutaneous lupus erythematosus
Malar erythema and subtle edema are present in this patient with systemic lupus erythematosus.
368
Heliotrope eruption in dermatomyositis
Violaceous erythema is present on the periorbital skin in this patient with dermatomyositis.
369
Heliotrope eruption in dermatomyositis
Violaceous erythema and edema are present on the upper eyelid in this patient with
dermatomyositis.
370
Erythema infectiosum
Redness appears acutely on one or both cheeks ("slapped cheek" appearance). The redness may be
reticulated.
371
Measles
Numerous erythematous macules are present on the face and trunk.
372
Measles
Numerous erythematous macules are present on the face.
373
Erysipelas
Erysipelas lesions are raised above the level of surrounding skin, and there is a clear line of
demarcation between involved and uninvolved tissue.
374
Lupus erythematosus tumidus
Inflammatory plaques consistent with lupus erythematousus tumidus (tumid lupus erythematosus)
are present on the face.
375
Jessner's lymphocytic infiltration of the skin
Annular, erythematous plaques are present on the face.
376
Jessner's lymphocytic infiltration of the skin
An erythematous, round plaque is present on the lateral forehead.
377
Granuloma faciale
A red-brown plaque is present on the face.
378
Tinea faciei
An erythematous, oval plaque and pustules on the face.
379
380
Keratosis pilaris rubra faciei
Multiple small, follicularly-based, rough, keratotic papules are present on the cheeks. As shown here,
background erythema may also be present in patients with this condition.
Comparison of representative topical corticosteroid preparations (classified according to the US

system)
Potency Corticosteroid Vehicle Brand names Available

group* type/form (United States) strength(s),
percent
(except as
noted)
Super- Betamethasone Gel, lotion, Diprolene 0.05

high dipropionate, ointment
potency augmented (optimized)
(group
1) Clobetasol propionate Cream, gel, Temovate 0.05
ointment,
solution
(scalp)
Cream, Temovate E 0.05

emollient base
381
emollient base
Lotion, Clobex 0.05

shampoo,
spray aerosol
Foam aerosol Olux-E, Tovet 0.05
Solution Cormax 0.05

(scalp)
Diflucortolone valerate Ointment, oily Nerisone Forte 0.3

(not available in cream (United Kingdom,
United States) others)
Fluocinonide Cream Vanos 0.1
Flurandrenolide Tape (roll) Cordran 4 mcg/cm2
Halobetasol Cream, lotion, Ultravate 0.05

propionate ointment
High Amcinonide Ointment Cyclocort¶, Amcort¶ 0.1

potency
(group Betamethasone Ointment Diprosone¶ 0.05
2) dipropionate
Cream, Diprolene AF 0.05
augmented
formulation
(AF)
Clobetasol propionate Cream Impoyz 0.025
Desoximetasone Cream, Topicort 0.25

ointment,
spray
Gel Topicort 0.05
Diflorasone diacetate Ointment ApexiCon¶, Florone¶ 0.05
Cream, ApexiCon E 0.05

emollient
Fluocinonide Cream, gel, Lidex¶ 0.05

ointment,
solution
Halcinonide Cream, Halog 0.1

ointment
H l b t l L ti B h li 0 01
382
Halobetasol Lotion Bryhali 0.01
propionate
High Amcinonide Cream Cyclocort¶, Amcort¶ 0.1

potency
(group Lotion Amcort¶ 0.1
3)
Betamethasone Cream, Diprosone¶ 0.05
dipropionate hydrophilic
emollient
Betamethasone Ointment Valisone¶ 0.1

valerate
Foam Luxiq 0.12
Desoximetasone Cream Topicort LP¶ 0.05
Diflorasone diacetate Cream Florone¶ 0.05
Diflucortolone valerate Cream, oily Nerisone (Canada, 0.1

(not available in cream, United Kingdom,
United States) ointment others)
Fluocinonide Cream Lidex-E¶ 0.05

aqueous
emollient
Fluticasone Ointment Cutivate 0.005

propionate
Mometasone furoate Ointment Elocon 0.1
Triamcinolone Cream, Aristocort HP¶, 0.5

acetonide ointment Kenalog¶, Triderm
Medium Betamethasone Spray Sernivo 0.05

potency dipropionate
(group
4) Clocortolone pivalate Cream Cloderm 0.1
Fluocinolone Ointment Synalar¶ 0.025

acetonide
Flurandrenolide Ointment Cordran 0.05
Hydrocortisone Ointment Westcort 0.2

valerate
Mometasone furoate Cream, lotion, Elocon¶ 0.1

ointment,
solution
383
Triamcinolone Cream Kenalog¶, Triderm 0.1
acetonide
Ointment Kenalog¶ 0.1
Ointment Trianex 0.05
Aerosol spray Kenalog 0.2 mg per

2 second
spray
Dental paste Oralone 0.1
Lower- Betamethasone Lotion Diprosone¶ 0.05

mid dipropionate
potency
(group Betamethasone Cream Beta-Val, Valisone¶ 0.1
5) valerate
Desonide Ointment DesOwen, Tridesilon¶ 0.05
Gel Desonate 0.05
Fluocinolone Cream Synalar¶ 0.025

acetonide
Flurandrenolide Cream, lotion Cordran 0.05
Fluticasone Cream, lotion Cutivate 0.05

propionate
Hydrocortisone Cream, lotion, Locoid, Locoid 0.1

butyrate ointment, Lipocream
solution
Hydrocortisone Cream Pandel 0.1

probutate
Hydrocortisone Cream Westcort¶ 0.2

valerate
Prednicarbate Cream Dermatop 0.1

(emollient),
ointment
Triamcinolone Lotion Kenalog¶ 0.1

acetonide
Ointment Kenalog¶ 0.025
Low Alclometasone Cream, Aclovate 0.05

potency dipropionate ointment
384
potency dipropionate ointment
(group
6) Betamethasone Lotion Beta-Val¶, Valisone¶ 0.1
valerate
Desonide Cream DesOwen, Tridesilon¶ 0.05
Lotion DesOwen, LoKara 0.05
Foam Verdeso 0.05
Fluocinolone Cream, Synalar¶ 0.01

acetonide solution
Shampoo Capex 0.01
OilΔ Derma-Smoothe/FS 0.01

Body, Derma-
Smoothe/FS Scalp
Triamcinolone Cream, lotion Kenalog¶, Aristocort¶ 0.025

acetonide
Least Hydrocortisone (base, Cream, Hytone, Nutracort¶ 2.5

potent ≥2%) ointment
(group
7) Lotion Hytone, Ala Scalp, 2
Scalacort
Solution Texacort 2.5
Hydrocortisone (base, Ointment Cortaid, Cortizone 10, 1

<2%) Hytone, Nutracort
Cream Cortaid¶, Cortizone 10, 1

Hytone, Synacort
Gel Cortizone 10 1
Lotion Aquanil HC, Sarnol- 1

HC, Cortizone 10
Spray Cortaid 1
Solution Cortaid, Noble, Scalp 1

Relief
Cream, Cortaid 0.5

ointment
Hydrocortisone Cream MiCort-HC 2.5

t t
385
acetate
Lotion Nucort 2
Data from:
1. Lexicomp Online. Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
2. Tadicherla S, Ross K, Shenefelt D. Topical corticosteroids in dermatology. Journal of Drugs in
Dermatology 2009; 12:1093.
3. U.S. Food & Drug Administration Approved Drug Products with Therapeutic Equivalence
(Orange Book). Available at: https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
(Accessed on June 18, 2017).
Mark V Dahl, MDNothing to discloseErik Stratman, MDNothing to discloseAbena O Ofori, MDNothing
to disclose
386
Approach to the patient with pustular skin lesions
uptodate.com/contents/approach-to-the-patient-with-pustular-skin-lesions/print
Authors:
Beth G Goldstein, MD
Adam O Goldstein, MD, MPH
Section Editors:
Moise L Levy, MD
Deputy Editor:
INTRODUCTION Pustules are circumscribed collections of white blood

cells and serous fluid. It is important to recognize the morphologic pattern of pustules because it
may imply a different spectrum of differential diagnosis as well as treatment.
While the differential diagnosis of pustules is broad (table 1), most diagnoses will fit one of the
diseases below. Several defining features can aid in narrowing down the possibilities in an efficient
manner:
●The patient's age and general health
●The distribution of lesions
●The duration of the lesions
Simple procedures can confirm the diagnosis when questions persist.
DISTRIBUTION
Face
Acne vulgaris — Acne vulgaris is the most common skin disorder affecting adolescents
and young adults [1]. Patients typically have pustules and/or inflamed papules on the face and, less
frequently, on the back and chest (picture 1). Acne vulgaris is discussed in detail separately. (See
387
"Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Treatment of acne
vulgaris".)
Acneiform eruptions — Acneiform eruptions may be induced by exposure to drugs

(table 2), cosmetics containing comedogenic ingredients, industrial chemicals (eg, cutting oils, coal
tar, chlorinated hydrocarbons), or environmental factors (eg, elevated temperatures, ionizing
radiations). (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on
'Acneiform eruptions' and "Acneiform eruption secondary to epidermal growth factor receptor
(EGFR) and MEK inhibitors".)
Acne keloidalis nuchae — Acne keloidalis nuchae is a condition involving

chronic inflammation and scarring of the hair follicles of the posterior neck that is seen more
frequently in dark-skinned patients [2]. Follicular papules, pustules, and hypertrophic scars may
result (picture 2). The clinical manifestations, diagnosis, and treatment of acne keloidalis nuchae are
discussed in detail separately. (See "Acne keloidalis nuchae".)
Rosacea — Rosacea is a common chronic disorder that may present with pustular eruptions,
particularly in moderate and severe cases [3]. Pustular rosacea is found frequently on the central
face and neck and, occasionally, in atypical locations, such as the retroauricular area or scalp [4].
Look for telangiectasia, erythema, papules, nodules, thickening of the soft tissue, and sebaceous
prominence of the central face (picture 3A-C). Exacerbating factors for rosacea that have been
anecdotally reported include alcohol, spicy food, hot beverages, temperature extremes, and
psychologic stress. (See "Rosacea: Pathogenesis, clinical features, and diagnosis" and
"Management of rosacea".)
Perioral dermatitis — Perioral dermatitis (ie, periorificial dermatitis) presents as

small papules, vesicles, and/or tiny pustules with erythema and scaling around the mouth, nose, or
periorbital region (picture 4A-C) [5]. When in a perioral distribution, the eruption classically spares
the skin immediately surrounding the vermilion border of the lips. A burning sensation or pruritus
may be present [6]. (See "Perioral (periorificial) dermatitis".)
Bacterial folliculitis and impetigo — Bacterial folliculitis may occur

anywhere on the body, including the face. It is in most cases caused by Staphylococcus aureus.
Folliculitis is typically characterized by isolated pustules with a hair piercing the central aspect
(picture 5). (See "Infectious folliculitis", section on 'Bacterial folliculitis'.)
Gram-negative folliculitis may occur on the face as a sudden pustular flare of acne previously
controlled by chronic oral antibiotics [7]. It can be caused by Klebsiella, Enterobacter, and Proteus
species. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on
'Gram-negative folliculitis'.)
388
Impetigo occurs most commonly on the face and can present with bullae, honey-colored crusts,
erythema, edema, and exudate (picture 6) [8]. (See "Impetigo".)
Fungal folliculitis — Tinea barbae is a fungal infection of the beard region that can
present with a significant pustular component (picture 7A-B). There is usually scaling and eventually
a circular configuration. Early or mild cases may not have pustules and can have an appearance
similar to tinea corporis. (See "Infectious folliculitis", section on 'Fungal folliculitis'.)
Herpes simplex — Herpes simplex eruptions can present as grouped pustules or

vesicles on an erythematous base typically located on the vermilion border of the lips (picture 8).
They may present similarly in the genital or sacral areas, particularly with recurrent disease. Patients
frequently have a history of a prodrome prior to the onset of lesions. Precipitating factors include
fever, wind or sunburn, trauma, or stress. (See "Epidemiology, clinical manifestations, and diagnosis
of herpes simplex virus type 1 infection".)
Herpes zoster — Herpes zoster may present early on as isolated pustules or vesicles on
the face in association with significant discomfort. Look for grouped pustules and/or vesicles on an
erythematous base that occur in a dermatomal distribution (picture 9A-B). Whether zoster occurs on
the face, trunk, or extremities, it is usually associated with symptoms of pain, aching, and burning.
(See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
Pityrosporum folliculitis — Pityrosporum or Malassezia folliculitis is a fungal

acneiform disorder that can present as fine pustules, often pruritic, on the face (picture 10). It tends
to be unresponsive to traditional acne therapies and worsens with humidity and heat. A KOH
examination will reveal copious budding yeast and pseudohyphae. (See "Infectious folliculitis",
section on 'Fungal folliculitis'.)
Trunk and extremities

Acne vulgaris — Patients with acne vulgaris often have pustules and/or inflamed
papules on the back and upper chest (picture 11). Acne vulgaris is discussed in detail separately.
(See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Treatment of acne
vulgaris".)
Acneiform eruptions — Acneiform eruptions may be induced by exposure to drugs

(table 2), cosmetics containing comedogenic ingredients, industrial chemicals (eg, cutting oils, coal
tar, chlorinated hydrocarbons), or environmental factors (eg, elevated temperatures, ionizing
radiations). (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on
'Acneiform eruptions' and "Acneiform eruption secondary to epidermal growth factor receptor
(EGFR) and MEK inhibitors".)
389
Keratosis pilaris — Keratosis pilaris, while often asymptomatic, may produce pruritic
and pustular lesions of the lateral face, trunk, upper and lower arms, thighs, and buttocks. It is
caused by the plugging of the follicle by keratin that has failed to exfoliate, leading to a sterile,
papular or pustular eruption (picture 12A-B). Prepubertal children can have significant involvement
of the lateral cheeks. (See "Keratosis pilaris".)
Miliaria — Miliaria is a transient skin disorder caused by accumulation of sweat beneath

eccrine sweat ducts obstructed by keratin. Depending on the level of duct obstruction, miliaria is
divided into miliaria crystallina, the most superficial form (picture 13A-B); miliaria rubra (picture 14A-
B); and miliaria profunda (picture 15). The clinical manifestations, diagnosis, and treatment of
miliaria are discussed in detail elsewhere. (See "Miliaria".)
Bacterial folliculitis — S. aureus folliculitis can involve the upper trunk, buttocks,
and legs (picture 16A-B). Gram-negative folliculitis is often seen as a generalized, pustular eruption
that ranges from mildly symptomatic to being associated with considerable pain and pruritus.
Truncal involvement is typically seen in healthy patients after use of recreational hot tubs, with
Pseudomonas aeruginosa identified as the pathogen on culture (picture 17) [9]. (See "Pseudomonas
aeruginosa skin and soft tissue infections", section on 'Hot tub-associated eruptions'.)
Dyshidrotic eczema — Hand and foot eczema typically presents with vesicles,
bullae, erythema, scale, and intense itching (picture 18A-B). Isolated pustules also may occur but
rarely are the predominant primary lesions. A KOH preparation is needed to rule out underlying
fungal infection. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
Palmoplantar pustulosis — Palmoplantar pustulosis (PPP) is a chronic,

pustular skin disorder of unknown etiology that usually occurs in adults. PPP presents as recurrent
crops of pustules on the palms and/or soles (picture 19), sometimes associated with nail dystrophy
and psoriasis-like skin lesions. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and
diagnosis".)
Hidradenitis suppurativa — Hidradenitis suppurativa occurs in areas of

hormonally influenced apocrine sweat glands, including the axillae, mammary, and inguinal regions,
frequently in patients who are obese (picture 20). Pustules may be evident in early lesions. Follicular
rupture and involvement of the apocrine gland occurs deeply, resulting over time in extensive
scarring and sinus tract formation in many patients (picture 21). Comedonal lesions are usually
present as well and help to define the diagnosis, with chronic, recurrent disease as the norm. (See
"Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis" and "Hidradenitis
suppurativa: Treatment".)
Fungal infections
390
Pityrosporum folliculitis — Pityrosporum or Malassezia folliculitis is a fungal
acneiform disorder that manifests with asymptomatic or pruritic, pustular lesions typically involving
the trunk and upper arms, especially in patients with a history of exposure to an extremely humid
environment (picture 22A-B). The lesions represent an overgrowth of normal yeast flora. Extensive
lesions may require treatment with oral antifungal drugs. More limited involvement often responds
to topical therapy (eg, ketoconazole, ciclopirox cream). (See "Infectious folliculitis", section on
'Fungal folliculitis'.)
Candida infection — Candida infections tend to be associated with beefy red areas with
scaling, predominantly in areas of moisture, such as the inframammary folds (picture 23), neck
folds, inguinal folds (picture 24), and axillae (picture 25). Satellite pustules may occur, particularly
beyond the erythematous plaques (picture 26). A KOH preparation of the roof of the pustule will
demonstrate the characteristic organisms. (See "Intertrigo".)
Dermatophyte infection — Dermatophyte (superficial fungal) infections, such as tinea

pedis or corporis, typically occur with papules, plaques, and peripheral scale (picture 27). Pustules
may also be a key primary lesion when follicular units are involved, particularly on the legs, scalp, or
forearms. A KOH preparation of the roof of the pustules will demonstrate hyphae (picture 28) [10].
(See "Dermatophyte (tinea) infections".)
Scabies — Scabietic infestations can produce isolated papules, vesicles, and pustules that
are intensely pruritic, particularly located in the interdigital web spaces, volar wrists, axillae, breasts,
umbilical, and groin areas (picture 29A-B). Family members are often symptomatic. Scrapings from
the base of isolated, nonexcoriated pustules, vesicles, or papules may reveal mites, eggs, or fecal
material. (See "Scabies: Epidemiology, clinical features, and diagnosis".)
Fire ant bites — Fire ant bites are painful and may cause isolated or grouped pustules
(picture 30), especially in patients with a history of outdoor exposure. Significant erythema and
edema can occur in patients who have a hypersensitivity reaction to the insect venom. (See "Stings
of imported fire ants: Clinical manifestations, diagnosis, and treatment".)
PUSTULES IN PATIENTS WITH

FEVER OR OTHER SYSTEMIC
SYMPTOMS
Eosinophilic folliculitis — Eosinophilic folliculitis is a pustular skin
eruption predominantly located on the scalp, face, neck, and upper chest that occurs in
immunosuppressed patients, particularly in those with advanced human immunodeficiency virus
391
infection (picture 31A-B). (See "HIV-associated eosinophilic folliculitis".)
Varicella — Varicella lesions may present with both vesicles and pustules in a generalized
fashion. Look for lesions that occur in varying stages in febrile patients (picture 32). Oral lesions
also can occur (picture 33A-B). Secondary staphylococcal infection may result in a pustular eruption
of not only a viral but also a bacterial origin. (See "Clinical features of varicella-zoster virus infection:
Chickenpox".)
Acute generalized exanthematous

pustulosis — Acute generalized exanthematous pustulosis is a rare drug eruption most
often caused by antibiotics (picture 34). Patients experience the rapid onset of a widespread
pustular eruption approximately 24 hours after ingesting the drug. (See "Acute generalized
exanthematous pustulosis (AGEP)".)
Disseminated gonococcemia — Disseminated gonococcemia can

present with lesions that initially begin as papules and vesicles, ultimately causing no more than 10
pustules that occur along with a necrotic base (picture 35). In addition to the rash, patients may have
a fever, migratory polyarthritis, or tenosynovitis. A Gram stain obtained after unroofing the pustule
reveals the causative organism. (See "Disseminated gonococcal infection".)
Secondary syphilis — Rash is the most characteristic finding of secondary

syphilis. The rash is classically a symmetric papular eruption involving the entire trunk and
extremities including the palms and soles. Individual lesions are discrete red or reddish-brown and
measure 0.5 to 2 cm in diameter (picture 36). They are often scaly but may be smooth and rarely
pustular. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-
uninfected patients".)
Pustular psoriasis — Pustular psoriasis is typically localized to the palms and

soles but may rarely occur in an acute, generalized form (von Zumbusch-type). Acute, generalized
pustular psoriasis is characterized by the abrupt development of widespread, painful, erythematous
patches that rapidly become studded with hundreds of pinhead-sized, sterile pustules (picture 37).
Systemic symptoms include fever, malaise, and arthralgias. (See "Pustular psoriasis: Pathogenesis,
Pyoderma gangrenosum — Pyoderma gangrenosum is an

inflammatory skin disease often associated with underlying systemic disorders such as
inflammatory bowel disease, arthritis, and lymphoproliferative disorders. The eruption may begin as
an isolated pustule or scattered lesions on the trunk or extremities (picture 38). There is surrounding
edema and purplish induration with rapid progression into a large ulcer, which heals ultimately with
392
cribriform scars (picture 39). The diagnosis is typically made after all infectious etiologies have been
ruled out. Histologic examination is helpful but not diagnostic in characterizing this disease. (See
"Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)
Sweet syndrome — Sweet syndrome (acute febrile neutrophilic dermatosis) is an

uncommon inflammatory disorder characterized by the abrupt appearance of painful, edematous,
and erythematous papules, plaques, or nodules on the skin, accompanied by fever and leukocytosis.
In some patients, it can present with vesicular or bullous lesions (picture 40). Sweet syndrome can
be idiopathic or associated with infections, inflammatory bowel disease, medications, or
malignancy. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical

●Basics topic (see "Patient education: Rosacea (The Basics)")
SUMMARY
●Pustules are elevated skin lesions containing collections of purulent fluid. A variety of skin
conditions may present with pustules, including both infectious and noninfectious disorders. (See
'Introduction' above.)
●Knowledge of the history and distribution of skin lesions, as well as patient demographics and
comorbidities, is useful for narrowing the differential diagnosis of a pustular eruption. In cases in
which infection is suspected, microbial cultures can assist in the identification of a causative
organism. A potassium hydroxide preparation is a quick procedure that is useful for the diagnosis of
superficial fungal infections. (See 'Introduction' above and 'Distribution' above and "Office-based
dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)
393
●Acute generalized exanthematous pustulosis is a drug-induced eruption in which widespread
pustules rapidly appear. Examples of other conditions that may present with generalized pustules
include varicella and pustular psoriasis. (See "Acute generalized exanthematous pustulosis (AGEP)"
and "Clinical features of varicella-zoster virus infection: Chickenpox" and "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis" and "Dermatoses of pregnancy", section on
'Pustular psoriasis of pregnancy'.)
●Pyoderma gangrenosum is an inflammatory disorder of the skin that clinically may resemble an
infectious process. The diagnosis of pyoderma gangrenosum is made only after infectious
processes have been excluded. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and
diagnosis".)

GRAPHICS
394
Differential diagnosis of pustules
Acne vulgaris
Arthropod bite (fire ants)
Drug eruption
Erythema toxicum neonatorum
Folliculitis
Fungal or yeast infections (especially tinea capitis and Majocchi's granuloma)
Furunculosis
Gonorrhea (disseminated)
Herpes simplex/zoster
Impetigo
Keratosis pilaris
Neonatal pustulosis
Pustular psoriasis
Rosacea/perioral dermatitis
Syphilis
Varicella
395
Inflammatory acne
Erythematous papules and pustules.
396
Major causes of drug-induced acne
Glucocorticoids
Phenytoin
Lithium
Isoniazid
Epidermal growth factor receptor inhibitors
Iodides
Bromides
Androgens
Progestin-only contraceptive agents
Corticotropin
Cyclosporine
Disulfiram
Psoralens
Thiourea
Vitamins B2, B6, and B12
Azathioprine
397
Acne keloidalis nuchae
Inflamed papules and keloidal papules on the posterior scalp. Coalescence of keloidal papules into a
plaque is present in the upper portion of the image.
398
Rosacea
Multiple erythematous papules on the cheek.
399
Rosacea
Inflammatory papules and pustules are present on the nose and cheeks.
400
Rhinophyma in rosacea
Marked distortion of the nose is present

in this patient with severe
rhinophymatous rosacea.

401
Perioral dermatitis
Tiny papules and pustules grouped on the chin.
402
Periorificial dermatitis
Multiple erythematous papules are present in the periorbital region.
403
Periorificial dermatitis
Multiple erythematous papules and mild scale are present on the perinasal skin.
Reprinted by permission of Edizioni Minerva Medica from G Ital Dermatol Venereol 2010; 145:433.
Copyright © 2010. All rights reserved.
404
Bacterial folliculitis
Isolated pustules on erythematous base with a hair piercing the center.
405
Impetigo
"Honey-crusted" plaques on the face of a

child with impetigo.

Stedman's Medical Dictionary. Copyright
© 2008 Lippincott Williams & Wilkins.
Tinea barbae
Follicular pustules and crusted lesions in a patient with tinea barbae.
406
Tinea barbae
Erythematous plaques studded with pustules on the chin of a patient with tinea barbae.
407
Herpes simplex infection of the lip (herpes labialis)
Grouped pustules on the vermilion border of the upper lip.
408
Herpes zoster
Grouped vesicles and pustules on the forehead.
409
Herpes zoster face
Grouped vesicles on erythematous base on the right cheek.
410
Pityrosporum folliculitis
Numerous tiny pustules on the forehead.
411
Acne vulgaris
The upper back of males with acne vulgaris frequently presents pustular and cystic lesions.
412
Keratosis pilaris
Keratosis pilaris. Multiple mildly erythematous, follicularly based papules on the lower leg.
413
Keratosis pilaris
Keratosis pilaris. Close view of multiple follicularly based, hyperpigmented papules on arm.
414
Multiple vesicles with clear fluid on the neck.
415
Clear, superficial vesicles on the shoulder.
Courtesy of Alan S Boyd, MD.
416
Miliaria rubra
Infant with widely spread, nonfollicularly based erythematous papules.
Courtesy of Kenneth Greer, MD.
417
Miliaria rubra
Multiple erythematous papules and papulovesicles. The erythema is subtle in this patient with dark
skin.
418
Miliaria profunda
Multiple subtle skin-colored papules.
Courtesy of Barbara Wilson, MD.
419
Staphylococcal folliculitis
Small, inflammatory pustules and papules on the chest.
420
Staphylococcal folliculitis
Multiple follicularly-based inflammatory papules and pustules are present on the leg.
421
Pseudomonas folliculitis (hot tub folliculitis)
Multiple erythematous papules and pustules.
422
Dyshidrotic eczema
Pinpoint vesicles, some of which are coalescing into larger ones, are visible on the lateral and dorsal
aspects of the fingers of a patients with acute palmoplantar eczema (dyshidrotic eczema).
423
eczema.
424
Palmoplantar pustulosis
Pustules, scale, and erythema on the palm of the hand.
425
Hidradenitis suppurativa
Hurley stage I disease. An inflamed nodule (arrow) and an open comedo (arrowhead) are visible.
Sinus tracts and fibrosis are absent.
426
Hidradenitis suppurativa
Hurley stage III disease involving the axilla. Diffuse involvement of the axilla with deep-seated
inflamed nodules, interconnecting sinus tracts, purulent drainage, and rope-like scars.
427
Follicular papules and pustules on the upper back of a patient with Pityrosporum folliculitis.
428
Pinpoint follicular papules and pustules are characteristic of Pityrosporum folliculitis. The eruption
most often involves the upper trunk.
429
Inframammary candidal intertrigo
Inframammary erythema in an obese, diabetic woman with candidal intertrigo.
Reproduced with permission from Ted Rosen, MD.
430
Candidal intertrigo
An erythematous plaque with satellite pustules in the groin.
Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
431
Candidal intertrigo
Severe axillary intertrigo with erythema, skin breakdown, and satellite papules and pustules.
Courtesy of Eva Rawlings Parker, MD.
432
Intertrigo
Severe intertrigo of the abdominal and inguinal folds in an older adult patient.
Courtsey of Eva Rawlings Parker, MD.
433
Acute tinea pedis
The medial aspect of the left great toe demonstrates erythematous, papulovesicular lesions caused
by Trichophyton mentagrophytes.
Acute tinea pedis
Segmented, branched dermatophyte hyphae are visible on this potassium hydroxide (KOH)
preparation from a patient with acute tinea pedis infection. KOH preparations of skin scrapings from
all dermatophyte infections show similar hyphal structures.
434
Interdigital lesions of scabies
The essential lesion is

a small, erythematous,
nondescript papule.
Courtesy of John T
Crissey, MD.
Graphic 51161 Version

2.0
Penile scabies
Small erythematous papule is visible on the glans penis.
435
Fire ant stings, dorsum of hand
436
HIV-associated eosinophilic folliculitis
Multiple erythematous papules and excoriated papules are present on the back.
437
HIV-associated eosinophilic folliculitis is

characterized by recurrent, pruritic crops
of discrete, erythematous, urticarial
follicular papules and rare pustules, with
a diameter of 3 to 5 mm.
Courtesy of Toby Maurer, MD.
Primary varicella lesions
Vesicular lesions on an erythematous base are characteristic of chickenpox. The lesions occur in
crops and are present in a variety of stages from maculopapular to vesicular or even pustular.
Central necrosis and early crusting is also visible.
Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT
Jr (Eds), Williams & Wilkins, Baltimore 1995.
http://www.lww.com
438
Oral manifestation of varicella (chickenpox)
Vesicles on the hard palate of a child with chickenpox.
439
Oral manifestations of varicella (chickenpox)
Gingival vesicle in a patient with chickenpox.
440
Acute generalized exanthematous pustulosis (AGEP)
Confluent nonfollicular pustules superimposed on edematous erythema in a 46-year-old woman with

AGEP. A skin biopsy showed intracorneal pustules with numerous neutrophils and neutrophilic
infiltration of the epidermis and upper dermis.
Copyright © Vincent CB Lin, MD, Dermatlas; http://www.dermatlas.org.
441
Skin lesions in disseminated gonococcal infection
Typical small pustular skin lesion in a patient with disseminated gonococcal infection.
Courtesy of Don L Goldenberg, MD.
Secondary syphilis: Rash
The rash of secondary syphilis

characteristically involves the palms and
soles. It may have a variety of appearances
but is usually pigmented and macular.
Courtesy of Charles B Hicks, MD.
442
Generalized pustular psoriasis
Pustules, erythema, and scale in generalized pustular psoriasis.
Early lesion in pyoderma gangrenosum

presenting as a pustular and violaceous
plaque with incipient breakdown.
Courtesy of Cynthia Magro, MD.
443
Multiple active and healing lesions of pyoderma

gangrenosum with cribriform scarring in patient with
inflammatory bowel disease.
Courtesy of Samuel Moschella, MD.
Sweet syndrome
Vesicles and inflammatory papules and plaques are present in this patient with Sweet syndrome.
444
Beth G Goldstein, MDNothing to discloseAdam O Goldstein, MD, MPHNothing to discloseRobert P
Dellavalle, MD, PhD, MSPHEquity Ownership/Stock Options: Altus Labs [Itch, eczema].
Grant/Research/Clinical Trial Support: Pfizer [Patient decision aids, inflammatory and immune-
mediated skin disease]. Consultant/Advisory Boards: Altus Labs [Itch, eczema]; ParaPRO [Scabies,
lice]. Other Financial Interest: Journal of Investigative Dermatology; Journal of the American
Academy of Dermatology [Stipends]; Cochrane Council meetings [Expense reimbursement].Moise L
Levy, MDGrant/Research/Clinical Trial Support: Galderma [Atopic dermatitis (Investigational drug)];
Janssen Pharmaceutica [Psoriasis (Investigational drug)]; Pfizer [Atopic dermatitis (Investigational
drug)]. Consultant/Advisory Boards: Cassiopea [Pediatric and adolescent acne]; Regeneron
Pharmaceuticals [Atopic dermatitis (Dupilumab)]; UCB [Psoriasis (Certolizumab pegol)]. Patent
Holder: Incontinentia pigmenti (NEMO gene mutations). Other Financial Interest: Novan [Data safety
monitoring board for molluscum contagiosum trial (Investigational drug)].Rosamaria Corona, MD,
DScNothing to disclose
445
Approach to the patient with retiform (angulated) purpura
uptodate.com/contents/approach-to-the-patient-with-retiform-angulated-purpura/print
INTRODUCTION Purpura are nonblanchable, hemorrhagic skin lesions

that result from the leakage of red blood cells into the skin. The term "retiform purpura" describes
lesions that demonstrate an angulated or branched configuration (picture 1A-C). Retiform purpura
can occur in a variety of disorders; thus, identifying the underlying cause is an important component
of patient management.
The potential causes of retiform purpura and the approach to the assessment of patients with these
lesions will be reviewed here. Additional details on the pathogenesis, clinical manifestations, and
treatment of disorders that present with retiform purpura are discussed elsewhere in UpToDate. (See
'Associated disorders' below.)
Cutaneous vasculitis, a potential cause of purpura (including retiform purpura), is reviewed in greater
detail separately. The differential diagnosis of purpura in children is also reviewed separately. (See
"Overview of cutaneous small vessel vasculitis" and "Evaluation of adults with cutaneous lesions of
vasculitis" and "Evaluation of purpura in children".)
CLINICAL FINDINGS Retiform purpura are nonblanchable,

persistent, dark red to dark purple, hemorrhagic patches or plaques that occur on the skin and
exhibit a characteristic branched configuration (picture 1A). Lesions may be relatively small (eg, 1 to
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2 cm) or more than 10 cm in diameter and may be limited to a focal area of skin, particular body
region, or widespread (picture 1B, 1D-E).
Prominent, peripheral erythema may occur in lesions that develop secondary to inflammatory
processes and areas of necrosis due to tissue infarction may be present (picture 2). Pain within
lesions is common and may be severe.
PATHOPHYSIOLOGY Retiform purpura develop as a

consequence of complete vascular occlusion and vascular damage involving blood vessels in the
skin. Lesions may occur in the setting of intravascular abnormalities in which thrombi, proteins, or
emboli obstruct cutaneous vessels, or may involve direct damage to vessel walls, as occurs in
vasculitis, calciphylaxis, and some severe opportunistic infections.
As in livedo reticularis (picture 3A-B) and livedo racemosa (picture 4) (additional disorders
associated with vasculopathy or vasculitis), the angulated or branched shape of retiform purpura
reflects the vascular architecture in the skin (see 'Differential diagnosis' below). The hemorrhagic
appearance of purpura results from the local extravasation of red blood cells. Skin necrosis results
from infarction.
ASSOCIATED DISORDERS Multiple vasculopathic

disorders may present with retiform purpura [1].
Intravascular abnormalities — Thrombosis, intravascular deposition

of abnormal proteins, and embolic phenomena may result in the development of retiform purpura.
Thrombotic and coagulopathic disorders

●Disseminated intravascular coagulation (DIC) – DIC may occur in the setting of sepsis, organ
failure, trauma, malignancy, and other severe disorders, such as homozygous C deficiency in
neonates. Patients with DIC exhibit clinical manifestations of both hemorrhage and thrombosis.
Purpura may be widespread (purpura fulminans), and the disorder can be fatal(picture 1B, 1F) [2,3].
Meningococcemia is a common cause of DIC. (See 'Recognition of life-threatening emergencies'
below and "Disseminated intravascular coagulation (DIC) in adults: Evaluation and management"
and "Disseminated intravascular coagulation in infants and children".)
●Hypercoagulable states – Hypercoagulable states, such as antiphospholipid syndrome, may lead

to retiform purpura. The mechanisms through which antiphospholipid antibodies in serum lead to
thrombosis are not completely understood (picture 1C-D). Common additional features of
antiphospholipid syndrome include livedo reticularis, livedo racemosa, cutaneous infarctions or
ulceration, recurrent venous or arterial thromboses, and fetal loss [4-7]. Examples of other
hypercoagulable states that may present with retiform purpura include antithrombin III deficiency,
447
protein C/S deficiency, prothrombin III mutation, factor V Leiden, and hyperhomocysteinemia [1].
(See "Clinical manifestations of antiphospholipid syndrome" and "Diagnosis of antiphospholipid
syndrome".)
●Thrombotic thrombocytopenic purpura (TTP) – TTP is a rare, idiopathic disorder characterized by

microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, and renal disease
[8,9]. Nonretiform purpura related to thrombocytopenia are often present. (See "Acquired TTP:
●Warfarin-induced skin necrosis – This condition results from the development of a transient,
hypercoagulable state secondary to warfarin-induced reduction of protein C (an anticoagulant) early
in the course of warfarin therapy. Purpura are extensive and demonstrate a predilection for areas
with significant adipose tissue (eg, thighs, buttocks, abdomen, breasts (picture 5A-C)). Patients with
underlying protein C deficiency are at increased risk for this disorder [10-12]. (See "Protein C
deficiency", section on 'Warfarin-induced skin necrosis'.)
●Heparin-induced thrombocytopenia –Heparin-induced thrombocytopenia is an immune-mediated

disorder that usually occurs 5 to 10 days after treatment with heparin [13,14]. Necrotic, purpuric
lesions may occur at sites of subcutaneous heparin injection or in areas distant from the site of
administration (heparin necrosis). Patients may also exhibit large vessel venous or arterial
thromboses[13,14](see "Management of heparin-induced thrombocytopenia"). Heparin necrosis may
also occur in the absence of thrombocytopenia (picture 6A-B).
●Paroxysmal nocturnal hemoglobinuria – This rare disorder due to a defect in the PIG-A gene is
characterized by venous thrombosis and hemolysis, resulting in hemoglobinuria. In addition to
retiform purpura, patients may present with bullae, petechiae, or ulcerations. (See "Clinical
manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and
prognosis of paroxysmal nocturnal hemoglobinuria".)
Intravascular protein deposition

●Cryoglobulinemia (type I) – In type 1 cryoglobulinemia, retiform purpura develop in the setting of
blood hyperviscosity and blood vessel occlusion due to the precipitation of immunoglobulins in
response to cold. Lesions are often found on acral areas; livedo reticularis, acrocyanosis, and
infarction may also be present (picture 7) [15,16]. (See "Overview of cryoglobulins and
cryoglobulinemia".)
●Cryofibrinogenemia – Cryofibrinogenemia results from the precipitation of fibrin, fibrinogen, and/or

fibronectin in plasma during cold exposure. Like cryoglobulinemia, retiform purpura are often acral.
Additional findings may include livedo reticularis, livedo racemosa, and painful ulcerations [17]. (See
"Cryofibrinogenemia".)
●Paraproteinemia – Rarely, paraproteinemia induces blood hyperviscosity and plugging of vessels,

resulting in the development of retiform purpura [18].
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Embolic disorders — Embolic disorders that may lead to retiform purpura include
cholesterol emboli, septic emboli, atrial myxoma, and other disorders:
●Cholesterol emboli – Retiform purpura associated with cholesterol embolization are often located
on the distal lower extremities (picture 8). Other cutaneous features include livedo reticularis, livedo
racemosa, gangrene, cutaneous infarction, ulceration, and cyanosis (blue toe syndrome) (picture 9).
Renal, gastrointestinal, ocular, or central nervous system abnormalities may also occur. Many
patients exhibit eosinophilia [19,20]. (See "Embolism from atherosclerotic plaque: Atheroembolism
(cholesterol crystal embolism)".)
●Septic emboli – Purpura due to septic emboli most commonly occur in the setting of infectious
endocarditis but may also occur in other forms of septicemia. Lesions are typically acral. Other
cutaneous findings, such as petechiae or Janeway lesions, may be present. (See "Clinical
manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
●Atrial myxoma – Atrial myxomas are benign tumors of the heart. Tumor fragments may embolize
systemically, and patients often exhibit constitutional symptoms (eg, fever, weight loss) [21,22]. As
with other embolic phenomena, lesions are often acral. (See "Cardiac tumors", section on
'Myxomas'.)
●Other –Emboli resulting in vessel occlusion and retiform purpura may also occur in nonbacterial
thrombotic endocarditis (marantic endocarditis, Libman-Sacks endocarditis) and hypereosinophilic
syndrome. (See "Nonbacterial thrombotic endocarditis" and "Hypereosinophilic syndromes: Clinical
manifestations, pathophysiology, and diagnosis".)
Vessel wall pathology — Damage to vessel walls resulting in retiform

purpura may occur in vasculitis, various opportunistic infections, calciphylaxis, and primary
hyperoxaluria:
●Vasculitis – Vasculitis is defined by the presence of an inflammatory infiltrate invading blood

vessel walls and fibrinoid necrosis (fibrin deposition within vessel walls or lumina). Retiform purpura
are classically seen in vasculitides that affect medium-sized cutaneous vessels. In contrast, small
vessel vasculitis most often presents with nonretiform palpable purpura. (See "Evaluation of adults
with cutaneous lesions of vasculitis", section on 'Diagnostic criteria' and "Evaluation of adults with
cutaneous lesions of vasculitis".)
Examples of vasculitides that may present with retiform purpura include:
•Septic vasculitis – Vasculitis presenting with retiform purpura may occur in meningococcemia,
gonococcemia, pseudomonal or streptococcal septicemia, rickettsial infections, infective
endocarditis, and other infectious states [23-25]. In the setting of severe infection, retiform purpura
may also result from DIC. (See "Clinical manifestations of meningococcal infection" and 'Recognition
of life-threatening emergencies' below.)
449
•Vasculitis related to autoimmune disease or primary systemic vasculitis (eg, rheumatoid arthritis,
systemic lupus erythematosus, cutaneous or systemic polyarteritis nodosa, granulomatosis with
polyangiitis, eosinophilic granulomatosis with polyangiitis [Churg-Strauss]). (See "Evaluation of
adults with cutaneous lesions of vasculitis".)
•Cryoglobulinemic vasculitis (cryoglobulinemia types 2 and 3) [15,26]. (See "Overview of

cryoglobulins and cryoglobulinemia" and "Mixed cryoglobulinemia syndrome: Clinical manifestations
and diagnosis".)
●Opportunistic infections –In immunocompromised patients, invasion of infectious organisms into

blood vessel walls and lumina may result in vessel occlusion and the development of retiform
purpura. This phenomenon may be seen in association with pseudomonal infection (ecthyma
gangrenosum (picture 10)), invasive fungal infections (eg, mucormycosis, aspergillosis, candidiasis),
disseminated strongyloidiasis, and in lepromatous leprosy as a feature of the Lucio phenomenon.
•(See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Ecthyma
Gangrenosum'.)
•(See "Mucormycosis (zygomycosis)".)
•(See "Epidemiology and clinical manifestations of invasive aspergillosis".)
•(See "Strongyloidiasis".)
•(See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type
2 reaction (T2R, erythema nodosum leprosum, ENL)'.)
●Calciphylaxis – Calciphylaxis is a life-threatening disorder characterized by the deposition of

calcium in blood vessels (picture 2). This condition almost always occurs in the setting of advanced,
chronic renal failure. Extremely painful retiform purpura may develop; lesions frequently occur in
adipose-rich areas, such as the buttocks, abdomen, or thighs. Other cutaneous features include
livedo reticularis, livedo racemosa, and cutaneous infarction [27,28]. (See "Calciphylaxis (calcific
uremic arteriolopathy)".)
●Primary hyperoxaluria – Primary hyperoxaluria is a rare, autosomal recessive, metabolic disorder

that results in the overproduction of oxalate. Patients develop renal stones and calcium oxalate
deposits in multiple tissues, including blood vessels [29,30]. The cutaneous lesions of primary
hyperoxaluria are similar to calciphylaxis. (See "Primary hyperoxaluria".)
Other — Examples of other conditions that may present with retiform purpura include livedoid
vasculopathy, pyoderma gangrenosum, and vasculopathy or vasculitis due to levamisole-
contaminated cocaine:
450
●Livedoid vasculopathy –Livedoid vasculopathy (also known as atrophie blanche) is a cutaneous
disease characterized by the development of fibrin thrombi in cutaneous vessels. The condition
typically manifests as recurrent, small, purpuric, ulcerative lesions on the distal lower extremities
(picture 11). Pale scars with stippled telangiectasia are left after healing [31-33]. (See "Livedoid
vasculopathy".)
●Pyoderma gangrenosum – Pyoderma gangrenosum is an inflammatory skin disorder that typically

presents with ulceration. Infrequently, it may present with retiform purpura that evolve into ulcers
that exhibit the violaceous edges classically seen in this disorder. Pyoderma gangrenosum may
occur in association with inflammatory bowel disease, inflammatory arthritis, or hematologic
malignancies [34-36]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and
diagnosis".)
●Thrombotic vasculopathy or vasculitis due to levamisole-contaminated cocaine –Use of cocaine

contaminated with levamisole has been associated with the development of tender purpura on the
ears and necrotic, retiform purpura on the trunk or extremities (picture 12A-C).
DIFFERENTIAL DIAGNOSIS Retiform purpura must be

distinguished from nonpurpuric skin disorders that may exhibit a branched configuration, such as
livedo reticularis and livedo racemosa, as well as other types of purpuric lesions.
Livedo reticularis and livedo racemosa are nonpurpuric disorders that present with accentuated
vascular patterns in the skin. Livedo reticularis, which results from the slowing of blood flow through
cutaneous vessels, presents as a blanchable, reticulated vascular pattern with a red-blue or
violaceous hue (picture 3A-B). Livedo racemosa, which develops in the setting of irregular
impairment of blood flow, is characterized by a more abrupt, patchy, and broken vascular pattern
with or without areas of necrosis (picture 4). In some conditions, retiform purpura may coexist with
livedo reticularis or livedo racemosa. (See 'Associated disorders' above and "Evaluation of adults
with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)
The configuration of retiform purpura distinguishes these lesions from petechiae and purpura due to
trauma or bleeding diatheses. Such lesions typically lack the angulated shape of retiform purpura
(picture 13A-B).
PATIENT ASSESSMENT The assessment of patients with

retiform purpura focuses on early recognition of patients with acute, life-threatening disease that
requires immediate intervention and the detection of the underlying cause of purpura formation [1].
In general, the evaluation should include at least a patient history, physical examination, skin biopsy,
and select laboratory tests. The need for additional microbiologic and radiologic testing is based
upon the clinical presentation.
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Recognition of life-threatening
emergencies — Examples of acute and immediately life-threatening conditions that
may present with retiform purpura include disseminated intravascular coagulation (DIC; a disorder
that may occur due to sepsis, trauma, malignancy, obstetric emergencies, neonatal homozygous C
deficiency, or other causes) and opportunistic infections. Mortality from these conditions can be
high, and prompt evaluation is necessary for these patients.
Findings that should prompt investigation for these disorders include:
●Purpura fulminans (acute development of widespread retiform purpura (picture 1A, 1E, 1G))
●Signs or symptoms of sepsis and/or shock
●Other signs of severe illness (fever, organ failure, altered mental status)
●Acute development of retiform purpura in an immunocompromised patient
Immediate initial tests for such patients should include [1]:
●Complete blood count with differential
●Comprehensive metabolic panel
●Urgent skin biopsy (see 'Skin biopsy' below)
●Erythrocyte sedimentation rate and/or C-reactive protein level
●Urine toxicology
In addition, the presence of purpura fulminans should prompt:
●Laboratory evaluation for DIC (see "Disseminated intravascular coagulation (DIC) in adults:
Evaluation and management", section on 'Diagnostic evaluation' and "Disseminated intravascular
coagulation in infants and children", section on 'Diagnosis')
There should be a high suspicion for infection in patients with purpura fulminans or with signs of
sepsis and in immunocompromised patients with retiform purpura. The initial evaluation of these
patients should include:
●Lesional punch biopsy for tissue culture (see 'Assessment for infection' below)
●Evaluation for sepsis (cultures [blood and other suspected sites of infection], blood tests, and
radiologic imaging, as indicated) and consideration of broad-spectrum antibiotic and antifungal
coverage while awaiting results
•(See "Evaluation and management of suspected sepsis and septic shock in adults".)
452
•(See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions,
epidemiology, clinical manifestations, and diagnosis".)
●Tests for specific suspected infections (eg, invasive aspergillosis)
Patient history — The medical history should be obtained with particular emphasis
on factors that may assist with the identification of the underlying disorder, such as:
●Symptoms of infection
●History of thrombotic disease, which may suggest antiphospholipid syndrome or genetic disorders
characterized by hypercoagulability:
•Deep venous thromboses or pulmonary emboli
•Recurrent, spontaneous abortions
•Family history of thrombotic events
●Drug history, which may suggest warfarin-induced skin necrosis, heparin-induced

thrombocytopenia, or vasculopathy or vasculitis due to levamisole-contaminated cocaine
●History of organ dysfunction:
•Renal failure, which may suggest calciphylaxis
•History of heart murmur or valve dysfunction, which may suggest endocarditis or atrial myxoma
●History of myeloproliferative conditions and blood dyscrasias, which may suggest occlusion
related to blood hyperviscosity
●History of hyperlipidemia, ischemic heart disease, or peripheral vascular disease, which may
suggest atheroemboli
●History of or symptoms of connective tissue disease or primary systemic vasculitis, which may
suggest vasculitis related to rheumatoid arthritis, systemic lupus erythematosus, polyarteritis
nodosa, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis (EGPA;
Churg-Strauss)
●Exacerbation of lesions with cold exposure, which may suggest cryoglobulinemia or

cryofibrinogenemia
Physical examination — A full physical examination and skin examination

should be performed. The examination confirms that the cutaneous findings are consistent with
retiform purpura and allows for the detection of features suggestive of an underlying cause. In
453
particular, the skin examination should assess the appearance, palpability, and distribution of
purpuric lesions, as well as the presence of other cutaneous findings.
Lesion color and palpability — Retiform purpura are typically dark red to
dark purple, and unlike erythema associated with nonpurpuric, inflammatory skin disorders, the color
of purpura fails to blanch under pressure. Diascopy (application of pressure to a lesion with a glass
slide) can be used to confirm the nonblanchable nature of a purpuric lesion.
In some cases, early lesions demonstrate significant erythema, which suggests the presence of a
primary inflammatory process [37]. These inflammatory lesions are frequently palpable and may
appear in the following conditions:
●Vasculitis
●Livedoid vasculopathy
●Pyoderma gangrenosum
Retiform purpura associated with noninflammatory, intravascular, occlusive vasculopathies may be

palpable or macular but typically lack prominent erythema. (See 'Intravascular abnormalities' above.)
Areas of necrosis due to tissue infarction may occur in both noninflammatory and inflammatory
lesions.
With time and the breakdown of extravasated hemoglobin, purpura may develop a greenish or
yellow-brown color.
Lesion distribution — The clinical distribution of lesions may assist in diagnosis

(table 1). As examples:
●Retiform purpura in areas with significant adipose tissue, such as the buttocks, thighs, and
abdomen, may occur in warfarin-induced skin necrosis or calciphylaxis.
●Retiform purpura predominantly involving lower extremities may occur in vasculitis, livedoid
vasculopathy, cholesterol emboli, or calciphylaxis.
●Retiform purpura primarily involving acral areas may occur in septic vasculitis, embolic disorders,
cryoglobulinemia, or cryofibrinogenemia.
●Widespread, extensive purpura (purpura fulminans) may occur in DIC or warfarin-induced skin
necrosis.
●The presence of unilateral lesions may suggest embolic phenomena.
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Associated physical findings — The presence of additional cutaneous or
extracutaneous findings should be assessed. As examples, the detection of a heart murmur, splinter
hemorrhages (picture 14), Osler nodes (picture 15), or Janeway lesions (picture 16) suggests
infectious endocarditis, and respiratory symptoms may occur in patients with EGPA or
granulomatosis with polyangiitis (table 2).
The detection of additional cutaneous findings may also assist with diagnosis. As an example,
livedo reticularis (picture 3A-B) is a common feature of several disorders that may present with
retiform purpura, such as antiphospholipid antibody syndrome, polyarteritis nodosa, cholesterol
emboli, and cryoglobulinemia.
Skin biopsy — Skin biopsies offer insight into the pathogenic mechanism of retiform
purpura and, therefore, can be useful for diagnosis. We advocate the performance of skin biopsies in
most patients.
Type and location of biopsy — Evaluation of vessels in the dermis and

subcutis is important in retiform purpura. Thus, punch or incisional wedge biopsies are performed,
rather than more superficial shave biopsies. (See "Skin biopsy techniques".)
Preferred sites for biopsies for histopathologic examination include areas that are painful or tender;
biopsying both from the center and the edge of a lesion may also increase the diagnostic yield [38].
Areas of frank necrosis or ulceration should be avoided, since necrotic tissue may fail to
demonstrate diagnostic histopathologic findings. In addition, biopsies of necrotic areas may
demonstrate an inflammatory response resembling primary vasculitis in patients with nonvasculitic
disorders [37].
The approach to biopsies for tissue culture for patients with findings suggestive of infection differs.
(See 'Assessment for infection' below.)
Vasculitis is a common cause of inflammatory retiform purpura. The approach to the biopsy of
lesions that are suspicious for vasculitis is reviewed separately. (See "Evaluation of adults with
cutaneous lesions of vasculitis", section on 'Skin biopsy to confirm vasculitis'.)
Assessment of biopsy results — Several histopathologic patterns are

associated with retiform purpura; a table correlating histopathologic findings with specific disorders
is provided (table 3).
Assessment for infection — When infection is suspected, a tissue specimen

should also be sent for culture. A punch biopsy from the center of a retiform purpura lesion that
shows early signs of necrosis is ideal [1].
455
Other techniques that may be helpful for assessing for infection include aspiration and culture of
fluid within hemorrhagic bullae, scraping of the roof of bullae for potassium hydroxide preparations,
and smearing of tissue specimens on a glass slide for a touch preparations [1]. (See "Office-based
Laboratory tests — Routine initial laboratory studies for the stable patient with
noninflammatory retiform purpura include [37] (see 'Intravascular abnormalities' above):
●Complete blood count with platelets and differential
●Blood smear
●Partial thromboplastin time
●Hepatic and renal function tests
●Cryoglobulins in patients with lesions and symptoms suggestive of this disorder (eg, acral lesions
exacerbated by cold exposure) (see "Overview of cryoglobulins and cryoglobulinemia", section on
'Detection of cryoglobulins')
●Antineutrophil cytoplasmic antibodies
The diagnostic utility of these laboratory studies is described in a table (table 4). Additional tests
may be ordered based upon the results of these studies, skin biopsy findings, and suspicion of the
underlying disorder. In cases in which infection is suspected, blood and/or urine cultures should be
obtained.
Patients with inflammatory retiform purpura should be evaluated for the possibility of vasculitis.
(See 'Lesion color and palpability' above and "Evaluation of adults with cutaneous lesions of
vasculitis".)
Patients with purpura fulminans require assessment for DIC. (See 'Recognition of life-threatening
emergencies' above and "Disseminated intravascular coagulation (DIC) in adults: Evaluation and
management", section on 'Diagnostic evaluation' and "Disseminated intravascular coagulation in
infants and children", section on 'Diagnosis'.)
MANAGEMENT The treatment of retiform purpura is dependent upon

correction of the underlying etiology. (See 'Associated disorders' above.)
SUMMARY AND
RECOMMENDATIONS
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●Retiform purpura are hemorrhagic skin lesions characterized by an angulated or branched
appearance. The shape of retiform purpura is reflective of the pattern of the underlying vascular
network. (See 'Clinical findings' above and 'Pathophysiology' above.)
●Retiform purpura occur as a consequence of disrupted vascular flow in the skin or subcutis.
Disorders that cause vessel occlusion through thrombosis, intravascular protein deposition, emboli,
or vessel wall destruction are associated with the development of these lesions. (See
'Pathophysiology' above.)
●The acute appearance of extensive purpura, termed "purpura fulminans," is a life-threatening

disorder that occurs in the setting of disseminated intravascular coagulation (DIC). Identification of
the underlying cause of DIC is essential for management. Retiform purpura may also occur in the
setting of life-threatening, opportunistic infections. Prompt evaluation of patients with purpura
fulminans, with signs of sepsis or severe illness, or in immunocompromised states is essential. (See
'Recognition of life-threatening emergencies' above.)
●A thorough history and physical examination may provide valuable clues for diagnosis and should
be performed in all patients who present with retiform purpura. The skin examination should include
assessment of the color and distribution of purpura. (See 'Patient assessment' above.)
●Skin biopsies of retiform purpura can provide useful diagnostic information (table 3). We perform a
skin biopsy in almost all patients. A punch or excisional wedge biopsy should be performed to allow
for adequate evaluation of vessels in the dermis and subcutis. Areas of necrosis should be avoided.
A tissue culture should be performed if infection is suspected. (See 'Skin biopsy' above.)
●An appropriate initial laboratory workup for stable patients with noninflammatory retiform purpura
includes a complete blood count with differential and platelets, blood smear, partial thromboplastin
time, hepatic and renal function tests, cryoglobulins in patients with acral lesions exacerbated by
cold exposure, and antineutrophil cytoplasmic antibodies (table 4). Additional tests may be added
based upon these results, skin biopsy findings, and the likelihood of specific disorders. If infection is
suspected, blood, tissue, and/or tissue cultures should be performed. (See 'Laboratory tests' above.)
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Approach to the differential diagnosis of leg ulcers
uptodate.com/contents/approach-to-the-differential-diagnosis-of-leg-ulcers/print
INTRODUCTION Leg ulcers are an increasing problem worldwide and

represent a major health care burden [1]. Patients with leg ulcers are managed by clinicians in
multiple specialties, including primary care, vascular surgery, plastic surgery, podiatry, wound care,
and dermatology.
A leg ulcer is a physical finding that can result from multiple etiologies, rather than a diagnosis (table
1). Thus, determination of the cause is essential for selecting appropriate treatment and determining
the need for further evaluation. The most common causes of leg ulcers are venous insufficiency,
arterial insufficiency, and neuropathic disease (table 2).
The etiologies and approach to the differential diagnosis of leg ulcers will be reviewed here. Specific
etiologies of leg ulcers and wound management are reviewed in detail separately.
458
●(See "Overview of lower extremity chronic venous disease".)
●(See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
●(See "Evaluation of the diabetic foot".)
●(See "Screening for diabetic polyneuropathy".)
●(See "Clinical assessment of chronic wounds".)
●(See "Basic principles of wound management".)
●(See "Overview of treatment of chronic wounds".)
DEFINITION The term "ulcer" describes destruction of the epidermis that

extends into the dermis and may reach subcutaneous fat or deeper tissues.
COMMON CAUSES Venous, arterial, and neuropathic ulcers account

for up to 90 percent of leg ulcers. In a survey study in which wound care professionals in Germany
reported the etiologies of chronic leg ulcers in over 31,000 patients, venous insufficiency, arterial
insufficiency, and mixed venous and arterial insufficiency accounted for 48, 15, and 18 percent of
chronic ulcers, respectively [2]. Ulcers caused by a combination of venous insufficiency and
peripheral arterial disease (PAD) are increasingly diagnosed, an observation related to the increasing
incidence of atherosclerosis and obesity.
Venous insufficiency — Chronic venous disease is the most common cause

of leg ulcers. Examples of risk factors include advancing age, female sex, obesity, pregnancy,
prolonged standing, and a history of deep venous thrombosis. (See "Overview of lower extremity
chronic venous disease", section on 'Epidemiology and risk factors' and "Overview of lower extremity
chronic venous disease", section on 'Risk factors'.)
●Clinical features –Venous insufficiency ulcers frequently affect the "gaiter" area of the leg, which
extends from the mid-calf to ankle (table 2). The skin immediately above the medial or lateral
malleolus is the most common site, with the medial aspect affected most frequently. Ulcers are
typically shallow with irregular borders with yellow, fibrinous exudate overlying the wound bed. Pain
is mild to moderate. Arterial pulses are normal unless there is concomitant arterial insufficiency.
(See 'Arterial insufficiency' below.)
Additional clinical findings in chronic venous disease include telangiectasias of the feet and ankles,
peripheral edema, venous varicosities, and brown discoloration of the lower legs and feet due to
hemosiderin deposition in tissue macrophages. Venous stasis dermatitis characterized by erythema
and scaling may develop around ulcers (picture 1). Lipodermatosclerosis, also known as sclerosing
panniculitis, may develop in the setting of long-standing venous hypertension and insufficiency.
459
Lipodermatosclerosis presents as induration and fibrosis of the lower medial leg, which may be
erythematous and painful and mistaken for cellulitis (picture 2). (See "Clinical manifestations of
lower extremity chronic venous disease" and "Stasis dermatitis".)
●Diagnosis – Venous ulcers are diagnosed by clinical examination. Noninvasive venous imaging
with duplex ultrasonography assesses reflux and obstruction in the superficial, deep, and perforating
veins and is indicated if the diagnosis is not clear or if surgical intervention is being considered. (See
"Diagnostic evaluation of lower extremity chronic venous insufficiency" and "Medical management
of lower extremity chronic venous disease".)
Arterial insufficiency — Peripheral arterial disease (PAD), a manifestation of

atherosclerosis, leads to reduced blood flow to the extremities and may result in tissue necrosis and
leg ulcers. Examples of risk factors for PAD include diabetes, smoking, hypertension, and
hyperlipidemia [3]. Patients may have a history of myocardial infarction, angina, or stroke. (See
"Clinical features and diagnosis of lower extremity peripheral artery disease", section on
'Epidemiology and risk factors'.)
●Clinical features – Arterial insufficiency (ischemic) ulcers typically occur distally on the toes or on
pressure areas, such as the heel, malleoli, and shin (table 2). Ulcers have well-demarcated edges,
giving them a "punched-out" appearance, often with an overlying necrotic eschar (picture 3). Unlike
venous ulcers, arterial ulcers typically are very painful.
Patients with PAD may complain of intermittent claudication or, later, rest pain. On examination,
decreased hair density, shiny and thin skin, diminished or absent peripheral pulses, or prolonged
capillary refill time (>3 to 4 seconds) may be present. Prolonged pallor with leg elevation to 45° for 1
minute (Buerger's test) supports vascular compromise. Peripheral dry gangrene may occur with
disease progression. (See "Clinical features and diagnosis of lower extremity peripheral artery
disease", section on 'Clinical features'.)
●Diagnosis – Peripheral arterial disease should be confirmed with ankle-brachial index (ABI) testing.
(See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on
'Diagnosis of lower extremity PAD'.)
Neuropathy — Diabetic neuropathy is responsible for the vast majority of neuropathic

ulcers. Diabetic patients may have up to a 25 percent lifetime risk of developing a foot ulcer. Other
causes of peripheral neuropathy (eg, spinal cord disorders [injury or spina bifida], tabes dorsalis,
alcohol abuse, nutritional deficiencies, and autoimmune diseases) may result in similar ulcerations.
●Clinical features – Neuropathic ulcers are painless and occur over pressure points on the foot or
heel (table 2). Ulcers have a punched-out morphology and typically occur within a thick callus
(picture 4). Associated clinical findings of diabetic neuropathy include claw toes, neuropathic
(Charcot) arthropathy, and reduced sweating resulting in dry, scaly feet (picture 5). (See "Evaluation
of the diabetic foot", section on 'Inspection'.)
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●Diagnosis –Sensory examination confirms decreased sensation in the involved areas. Ulcers can
become deep, and underlying osteomyelitis should be considered when ulcers do not heal with off-
loading therapies. (See "Management of diabetic foot ulcers".)
LESS COMMON CAUSES There are multiple less common

causes of leg ulcers, including physical injury, infection, vasculopathy, pyoderma gangrenosum (PG),
panniculitis, malignancy, medications, and brown-recluse spider envenomation (table 1).
Physical injury — Physical injury to the skin may cause ulceration. Ulcers may
result from pressure, thermal injury (burns or cold injury), radiation exposure, iatrogenic injury, or
factitial (self-induced) injury. Of note, traumatic ulcers on the lower legs can demonstrate prolonged
healing in older individuals and patients with underlying venous hypertension or arterial
insufficiency.
●Clinical features – Ulcer features vary depending on the inciting injury. In particular, pressure
ulcers often occur in sites overlying bony prominences; on the lower extremity, the heels are
common sites [4]. The appearance of pressure ulcers ranges from shallow open ulcers to deep
ulcers that expose bone, tendon, or muscle (picture 6 and figure 1). (See "Clinical staging and
management of pressure-induced skin and soft tissue injury" and "Assessment and classification of
burn injury".)
●Diagnosis – With the exception of factitial ulcers, diagnosis is largely straightforward and relies on
historical evidence of skin trauma.
Infection — Primary infectious ulcers may result from bacterial, fungal, spirochete, or
protozoal infections, either by direct inoculation or systemic spread.
Staphylococcal and streptococcal skin infections are common bacterial infections that may result in
ulceration. Cutaneous ulcers also may result from atypical mycobacterial infections, late-stage
syphilis (gummas) (picture 7), deep fungal infections (eg, coccidioidomycosis, blastomycosis,
histoplasmosis), and protozoal infections (eg, leishmaniasis (picture 8)). These infections most
commonly, but not exclusively, occur in immunosuppressed patients.
●Clinical features – Clinical features vary according to the type of infection. Furuncles secondary to
methicillin-resistant Staphylococcus aureus (MRSA) may progress to form larger abscesses, cellulitis,
or ulcerative, necrotic plaques. Ecthyma, a form of nonbullous impetigo caused by Streptococcus
pyogenes (with frequent contamination with S. aureus), produces punched-out shallow ulcers with a
purulent necrotic crust and surrounding erythema (picture 9). Ecthyma gangrenosum, a
Pseudomonas aeruginosa infection characterized by bacterial invasion of the media and adventitia of
arteries and veins, results in the rapid development of gangrenous ulcers with black eschar (picture
10). Ecthyma gangrenosum usually occurs in immunocompromised patients. (See "Impetigo" and
"Pseudomonas aeruginosa skin and soft tissue infections", section on 'Ecthyma Gangrenosum'.)
461
●Diagnosis – The diagnosis of infectious ulcers requires identification of the causative organism via
swab cultures for aerobic bacteria or tissue culture for bacteria, fungi, and atypical mycobacteria.
For tissue culture, incisional or punch biopsies should be obtained from the edge of the ulcer, placed
on a sterile gauze pad moistened with non-bacteriostatic saline, and sent for culture in a sterile urine
cup. In addition, ulcer edge tissue should be sent for histopathologic examination, including special
stains for infectious organisms, since this may yield a more rapid diagnosis than culture. Culture can
take up to six weeks for certain mycobacteria and fungi.
In addition, secondary bacterial infection can complicate chronic ulcers caused by venous
insufficiency, arterial insufficiency, neuropathic disease, or other etiologies. Clinical signs such as
exacerbations of erythema, warmth, edema, and exudate warrant investigation for secondary
infection. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the
lower extremities" and "Infectious complications of pressure-induced skin and soft tissue injury".)
Vasculopathy — Vasculopathic disorders can cause lower extremity ulcers by

means of inflammatory processes that cause destruction of blood vessel walls (vasculitis) or vessel
occlusion leading to ischemia.
Vasculitis — Vasculitis of small or medium-sized cutaneous blood vessels can result in leg
ulcers. Small-vessel vasculitis can be idiopathic or a consequence of infections, drugs, mixed
cryoglobulinemia, autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis,
Sjögren syndrome), or malignancies (particularly hematologic malignancies). Inflammation of both
small and medium-sized cutaneous blood vessels is associated with anti-neutrophil cytoplasmic
antibody (ANCA)-associated vasculitides, including granulomatosis with polyangiitis (formerly
Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and
microscopic polyangiitis. Inflammation of medium-sized blood vessels occurs in cutaneous and
systemic polyarteritis nodosa. (See "Evaluation of adults with cutaneous lesions of vasculitis".)
●Clinical features – The characteristic clinical finding of cutaneous small-vessel vasculitis is

palpable purpura. Palpable purpura may develop an overlying necrotic vesicle or bulla that becomes
ulcerative. Subcutaneous nodules, necrotic ulcerations, retiform purpura, and livedo racemosa are
features of medium-sized vessel involvement. (See "Evaluation of adults with cutaneous lesions of
vasculitis", section on 'When to suspect cutaneous vasculitis'.)
●Diagnosis – A diagnosis of vasculitis requires a skin biopsy that reaches the subcutis. In
cutaneous small-vessel vasculitis, biopsy of an early but palpable lesion is most informative [5].
Biopsies demonstrate leukocytoclastic vasculitis (infiltration of postcapillary venules by neutrophils
undergoing degranulation and fragmentation) and fibrinoid necrosis of the involved vessels. Similar
changes occur in vasculitis of medium-sized vessels involving the small arteries in the deep reticular
dermis and fat. Performance of direct immunofluorescence studies to identify immunoglobulin or
complement deposits is an important component of the evaluation of cutaneous vasculitis. (See
"Evaluation of adults with cutaneous lesions of vasculitis".)
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Livedoid vasculopathy — Livedoid vasculopathy (LV) is a chronic, painful,
ulcerative skin condition, most common in young and middle-aged women [6]. While the
pathogenesis of LV is not clearly understood, hypercoagulable states and impaired fibrinolysis have
been implicated [7]. (See "Livedoid vasculopathy".)
●Clinical features – LV is characterized by crusted, painful, stellate, shallow ulcerations that are slow
to heal (picture 11). The disease is often bilateral, involving the skin around the ankle and dorsal
foot. The ulcers heal with white, atrophic, stellate scars with telangiectasia, known as atrophie
blanche. The terms atrophie blanche and livedoid vasculopathy have been used interchangeably in
older literature; however, atrophie blanche is now recognized as a healing pattern that can occur as a
result of both LV and chronic venous insufficiency. (See "Livedoid vasculopathy", section on 'Clinical
features'.)
●Diagnosis – A skin biopsy is used to confirm the diagnosis. Characteristic findings are hyaline
thrombi in the mid and upper dermal blood vessels with fibrinoid changes in vessel walls. Further
evaluation for hypercoagulable states, paraproteinemias, cryoprecipitable proteins (cryoglobulins or
cryofibrinogen), and collagen vascular disease may be helpful as indicated by history and physical
examination. (See "Livedoid vasculopathy", section on 'Diagnosis'.)
Thromboangiitis obliterans — Thromboangiitis obliterans (TAO, Buerger's

disease) is a vaso-occlusive inflammatory vasculopathy affecting small and medium-sized arteries,
veins, and nerves of the extremities. The pathophysiology of TAO is characterized by inflammatory
thrombi occluding vessels, with sparing of the vessel walls.
A rare disorder, TAO most commonly affects young to middle-aged male smokers. Exposure to
tobacco is considered essential to initiation and progression of the disorder. (See "Thromboangiitis
obliterans (Buerger's disease)".)
●Clinical features – The legs are affected more often than the arms. Affected individuals present
with ischemic symptoms of the extremities, which may progress to digital gangrene and ulcerations
(picture 12A-B). Raynaud phenomenon and superficial thrombophlebitis are other common features
[8]. (See "Thromboangiitis obliterans (Buerger's disease)", section on 'Clinical features'.)
●Diagnosis – TAO is a clinical diagnosis requiring a compatible history (including tobacco use),
physical findings, and diagnostic changes on angiography. Angiography demonstrates involvement
of the small and medium-sized arteries, segmental occlusions, and "corkscrew"-shaped collateral
vessels around areas of occlusion (image 1). (See "Thromboangiitis obliterans (Buerger's disease)",
section on 'Diagnosis'.)
Microvascular occlusion disorders — Occlusion of small cutaneous

blood vessels may occur by multiple mechanisms, such as platelet plugging (eg, thrombocythemia,
heparin-induced necrosis), cryoagglutination (eg, cryoglobulinemia, cryofibrinogenemia), bacterial
infection (eg, ecthyma gangrenosum), embolism (eg, cholesterol emboli, oxalosis), coagulopathies
(eg, antiphospholipid syndrome, protein C or S deficiency, warfarin necrosis), and calciphylaxis [9].
463
The clinical features vary with etiology. Overall, cutaneous ulcerations resulting from microvascular
occlusion typically are very painful and retiform purpura are a common associated finding (picture
13A-B). The approach to diagnosis is also dependent on the etiology; histologic examination often is
useful.
Examples of clinical and histologic findings of specific microvascular occlusion disorders include:
●Cryoglobulinemia (type I) and cryofibrinogenemia – Patients with type I cryoglobulinemia or

cryofibrinogenemia may exhibit retiform acral purpura or skin necrosis leading to ulceration (picture
14). Involvement of other acral sites including ears and nose may also occur, especially with
cryoglobulinemia. Livedo reticularis, the Raynaud phenomenon, and acral cyanosis are additional
common clinical findings. Histopathologic examination of early sites of involvement reveals bland
hyaline thrombi or red cell occlusion of superficial dermal blood vessels. (See "Overview of
cryoglobulins and cryoglobulinemia", section on 'Type I cryoglobulinemia' and "Cryofibrinogenemia".)
●Cholesterol emboli – An abrupt onset of widespread livedo reticularis plus distal retiform purpura
is strongly suggestive of cholesterol emboli (more common) or oxalate emboli (rare). Peripheral
gangrene and ulcerations occur in a subset of patients [10]. (See "Embolism from atherosclerotic
plaque: Atheroembolism (cholesterol crystal embolism)".)
Cholesterol embolization is most common in men over age 50 with atherosclerotic disease.
Cholesterol emboli may occur spontaneously, but are more commonly seen within hours to days of
arterial catheterization. Thrombolytic therapy and starting anticoagulation therapy (warfarin blue toe
syndrome) have also been implicated, but a causal relationship is not well established. Full-
thickness punch or incisional biopsies to fat in sites of retiform purpura may demonstrate
characteristic elongated clefts in deep dermal arterioles.
●Oxalosis – Oxalate embolism can occur in patients with primary hyperoxaluria. Patients develop
hyperoxalemia and hyperoxaluria leading to recurrent urolithiasis that begins in childhood and
subsequent progression to renal failure. Skin manifestations of oxalosis present after the onset of
renal failure and include acrocyanosis, livedo reticularis, and cutaneous necrosis. Histopathologic
examination reveals birefringent yellow-brown crystals within and around vessels in the deep dermis
or fat. (See "Primary hyperoxaluria".)
●Calciphylaxis – Calciphylaxis, also referred to as calcific uremic arteriolopathy, presents with

painful indurated reticulate purpuric plaques that progress to necrosis and ulceration (picture 13A,
13C). Calciphylaxis is most commonly seen in patients with renal failure, often in the setting of
diabetes. Prognosis is poor [11]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)
Biopsies of involved skin must include the subcutaneous tissue; calcium deposits are found in the
media of blood vessels in the fat. Perieccrine calcium deposition may be a highly specific but not
sensitive finding in calciphylaxis [12]. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on
'Diagnosis'.)
464
Sickle cell disease — Leg ulcers can occur as a complication of sickle cell disease.
The ulcers most commonly occur on the medial and lateral malleoli and are usually painful and
intractable [13,14]. The mechanism for ulcer development is not fully understood but may involve
impaired blood flow, endothelial dysfunction, thrombosis, inflammation, and delayed healing [15].
(See "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)
Pyoderma gangrenosum — Pyoderma gangrenosum (PG) is a

neutrophilic dermatosis often associated with an underlying systemic disorder, such as
inflammatory bowel disease, arthritis, or hematologic disease (eg, acute and chronic myelogenous
leukemia, hairy cell leukemia, myelodysplasia, IgA monoclonal gammopathy) [16]. (See "Pyoderma
gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Associated disorders'.)
●Clinical features – PG classically presents as single or multiple rapidly progressive painful leg
ulcers with necrotic borders and surrounding erythema (picture 15A-B). The initial clinical finding is
a pustule, which then develops an overlying necrotic bulla that ulcerates with purulent drainage. The
lower leg is a common site of involvement [17]. PG may exhibit pathergy, the induction or worsening
of PG in sites of trauma.
In its acute phase, PG may be accompanied by systemic symptoms or signs, such as fever and
leukocytosis. In addition to the classic form, there are bullous, pustular, superficial granulomatous,
and peristomal variants. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and
diagnosis", section on 'Clinical manifestations'.)
●Diagnosis – PG is a diagnosis of exclusion, since there are no specific clinical, pathologic, or

laboratory findings. Biopsies of an acute PG ulcer may demonstrate a neutrophilic infiltrate in the
dermis, often with a surrounding mononuclear cell infiltrate. (See "Pyoderma gangrenosum:
Pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)
Panniculitis — Panniculitides are disorders characterized by inflammation of the

subcutaneous fat. Panniculitides associated with lower extremity ulcers include erythema induratum
(nodular vasculitis) and panniculitis caused by alpha-1-antitrypsin deficiency or pancreatic disease.
(See "Panniculitis: Recognition and diagnosis".)
●Erythema induratum – Erythema induratum typically occurs in young or middle-aged women and
involves the lower legs, especially the posterior calves. The disorder presents with tender
subcutaneous nodules and plaques that may ulcerate and drain (picture 16A-B).
Biopsy demonstrates a mixed septal and lobular inflammatory cell infiltrate with vasculitis in most
cases. Erythema induratum was classically described as a tuberculid associated with M.
tuberculosis; however, erythema induratum may also be idiopathic or associated with other
infections or drugs. (See "Cutaneous manifestations of tuberculosis", section on 'Erythema
induratum of Bazin'.)
465
●Alpha-1-antitrypsin deficiency –Alpha-1-antitrypsin deficiency produces a neutrophil panniculitis
in a small subset of patients [18]. Patients develop tender erythematous or purpuric nodules and
plaques on the lower trunk and extremities. The nodules and plaques may ulcerate, drain an oily
discharge, and heal with scarring. (See "Extrapulmonary manifestations of alpha-1 antitrypsin
deficiency", section on 'Skin disease'.)
Biopsies of early alpha-1-antitrypsin deficiency panniculitis demonstrate a neutrophilic infiltrate of

the fat followed by necrosis and destruction of fat lobules. Diagnosis is confirmed by serum
evaluation of alpha-1-antitrypsin activity and genotype analysis. (See "Clinical manifestations,
diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
●Pancreatic panniculitis – Suppurative panniculitis is a rare complication of benign or malignant

pancreatic disease [19]. Subcutaneous painful nodules develop on the lower extremities and trunk
and may drain an oily material (picture 17). Systemic symptoms may include fever, abdominal pain,
and arthritis; ascites and pleural effusions may also be present.
Histopathologic examination of pancreatic panniculitis demonstrates septal and lobular

inflammation, plus the diagnostic changes of fat necrosis and characteristic "ghost cells" and
saponification of the fat. (See "Panniculitis: Recognition and diagnosis".)
Malignancy — Leg ulcers may arise as a feature of a primary cancer or as a result of

malignant transformation of a chronic ulcer. Various cutaneous malignancies can cause ulcers. In a
prospective study of 154 chronic leg ulcers in 144 patients that were diagnosed as venous ulcers but
failed to respond to three months of standard treatment, biopsies revealed skin cancer in 16 ulcers
(10 percent) [20]. Of the 16 malignant ulcers, there were 9 squamous cell carcinomas, 5 basal cell
carcinomas, 1 melanoma, and 1 leiomyosarcoma. Cutaneous lymphomas (both B and T cell) and
Kaposi's sarcoma may also cause leg ulcerations.
Malignant ulcers often are not recognized immediately. Primary malignant ulcers may be assumed
to result from other causes of ulceration, and malignant transformation of a chronic ulcer may
become apparent only after an ulcer fails to respond as expected to treatment. Diagnosis is
dependent upon histologic confirmation of malignancy. Ulcers that are enlarging or failing to heal
despite treatment, occurring in scars, or with exophytic or irregular wound edges probably warrant
biopsy to rule out malignancy, but a standard of care has not been determined in large studies.
Drugs — Drugs associated with the development of leg ulcers include warfarin, heparin, and
hydroxyurea.
●Warfarin– Warfarin skin necrosis is a microvascular occlusion syndrome that begins two to five
days after beginning warfarin without concomitant heparin therapy and results from a transient
hypercoagulable state [21,22]. Pain is the initial symptom, followed by erythema, which then
becomes hemorrhagic and necrotic (picture 18A-B). Retiform purpura may be adjacent to sites of
skin necrosis. Warfarin-induced skin necrosis is more common in women than men and is most
466
likely to occur in fatty areas, such as breasts, hips, buttocks, and thighs. A biopsy of involved skin
demonstrates bland thrombi in dermal blood vessels. (See "Protein C deficiency", section on
'Warfarin-induced skin necrosis'.)
●Heparin – Heparin-induced thrombocytopenia is a thrombotic complication of heparin therapy

resulting from the production of autoantibodies against platelet factor 4 in complex with heparin.
Patients with heparin-induced thrombocytopenia may develop microvascular occlusion resulting in
skin necrosis at sites of heparin injection or other sites, such as the distal extremities or nose
(picture 19). The initial manifestation is erythema that evolves to purpura, hemorrhage, and necrosis.
(See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
●Hydroxyurea–Hydroxyurea-related leg ulcers may occur in patients receiving chronic hydroxyurea

therapy. The ulcers are clinically similar to ulcers of livedoid vasculopathy: painful, fibrous,
persistent ulcers with surrounding atrophie blanche changes, typically near the malleoli or on the
anterior lower leg [23]. The mechanism for ulcer development may involve drug-induced cytologic
damage [23].
Brown recluse spider bite — Loxosceles reclusa envenomation is a rare

cause of dermonecrotic lesions resulting in painful leg ulcers. The venom contains
sphingomyelinase D, which may be responsible for neutrophil activation and skin necrosis (necrotic
arachnidism). (See "Bites of recluse spiders".)
●Clinical features – The actual bite is often minimally painful; however, it is followed by the
appearance of a tender erythematous plaque. The plaque develops central pallor followed by painful
blistering and/or necrosis in about 40 percent of cases (picture 20A-B) [24]. (See "Bites of recluse
spiders", section on 'Clinical manifestations of bites'.)
●Diagnosis – The diagnosis is based upon witnessing the spider bite and correct identification of
the spider. Most ulcers suspected to be caused by spider bites are actually due to infection or
pyoderma gangrenosum. In the absence of a witnessed bite and identification of the spider, other
etiologies should be considered. (See "Bites of recluse spiders", section on 'Diagnosis'.)
PATIENT EVALUATION The evaluation of patients with leg

ulcers begins with a clinical evaluation aimed at narrowing the differential diagnosis. Given that the
vast majority of ulcers are caused by venous insufficiency, arterial insufficiency, or neuropathy, the
initial goal should be to identify patients with these conditions. Alternative diagnoses should be
considered when patients have features that are not consistent with these etiologies or fail to
respond to appropriate treatments.
History — Key aspects of the patient history that should raise suspicion for venous, arterial,
or neuropathic ulcers are reviewed in a table (table 2). Additional information that may aid in
identifying other causes includes:
467
●History of trauma at ulcer site (traumatic ulcers, pyoderma gangrenosum [PG])
●Severe pain (ulcers due to arterial insufficiency, microvascular occlusion disorders, or PG)
●Rapid ulcer development (infectious ulcers, PG, brown recluse spider bite ulcer)
●Underlying thrombosis or coagulopathies (venous insufficiency ulcers, microvascular occlusion

disorder ulcers, livedoid vasculopathy [LV])
●Underlying autoimmune disease or hematologic disease (ulcers due to vasculitis, PG, LV)
●Other chronic disease (ulcers due to arterial insufficiency [atherosclerosis], diabetic neuropathy
[diabetes], PG [inflammatory bowel disease, arthritis], panniculitides [pancreatitis, alpha-1-antitrypsin
deficiency, tuberculosis])
●Medication exposure (warfarin-, heparin-, or hydroxyurea-induced ulcers)
●Poor mobility (pressure ulcers)
●Smoking (ulcers due to thromboangiitis obliterans)
In addition, the clinician should review prior ulcer treatments. A failure to respond to treatment may
suggest an incorrect diagnosis or malignant ulcer. (See 'Malignancy' above.)
Physical examination — The physical examination serves to identify

physical features of the ulcer (eg, location, size, shape) and associated cutaneous or non-cutaneous
features that may aid in diagnosis. Findings that should raise suspicion for venous insufficiency,
arterial insufficiency, and neuropathic ulcers are reviewed in a table (table 2). Because arterial
insufficiency ulcers are common, routine palpation of pedal pulses is prudent. (See "Clinical
assessment of chronic wounds", section on 'Vascular assessment'.)
Additional physical examination findings that may help to narrow the differential diagnosis include:
●Palpable purpura (ulcers due to small or small- and medium-vessel vasculitis)
●Retiform purpura or livedo racemosa (ulcers due to microvascular occlusion disorders or medium-
vessel vasculitis)
●Nodules (ulcer due to medium-vessel vasculitis or panniculitis)
●Predilection for high-fat areas (ulcers due to calciphylaxis or warfarin)
●Atrophie blanche (livedoid vasculopathy or venous insufficiency ulcers)
●Livedo reticularis (ulcers due to microvascular occlusion disorders)
●Oily drainage (ulcers due to pancreatic panniculitis or alpha-1-antitrypsin panniculitis)
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The physical examination should also include an assessment for clinical signs of secondary
infection (eg, warmth, erythema, swelling, purulent drainage, malodor) or osteomyelitis (eg, visible
bone, ability to probe to bone). (See "Clinical manifestations, diagnosis, and management of diabetic
infections of the lower extremities", section on 'Clinical manifestations' and "Osteomyelitis in adults:
Biopsy — Biopsies are not necessary for the diagnosis of most ulcers, but can be helpful
when the diagnosis is unclear or ulcers fail to respond to therapy. Histopathologic examination may
be particularly helpful when vasculitis, microvascular occlusion disorders, panniculitis, infection, or
malignancy are in the differential diagnosis.
In general, biopsies for diagnosis are performed from the edge of an ulcer. A punch biopsy to
subcutaneous fat or a wedge biopsy from the ulcer edge are recommended. A biopsy from purpura
or early necrosis at the ulcer edge may be particularly informative. A biopsy site may subsequently
ulcerate in cases of PG (pathergy) and patients should be informed of this risk.
Biopsies to provide tissue for culture are also useful for evaluating ulcers for primary or secondary
infection. (See 'Infection' above.)
Additional tests — The need for serologic, radiologic, or microbiologic studies is

determined by the disorders being considered. Such studies may be performed to confirm ulcer
etiology or to evaluate for an associated underlying disease. (See 'Common causes' above and 'Less
common causes' above.)
Additional tests also may serve to evaluate for complications such as wound infection or
osteomyelitis. However, routine wound swab cultures are not recommended in the absence of
clinical signs of infection because bacterial colonization of ulcers is common [4]. (See 'Physical
examination' above and "Clinical assessment of chronic wounds", section on 'Wound assessment'
and "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
INDICATIONS FOR REFERRAL Leg ulcers that do

not heal within three months of conservative wound care, are associated with livedo
racemosa/reticularis or purpura, increase rapidly in size, or worsen with debridement should be
referred to dermatology for further assessment. Classic venous ulcers or worsening arterial ulcers
should be referred to vascular surgery.
SUMMARY AND
RECOMMENDATIONS
469
●Leg ulcers are a common condition that can result in significant morbidity. The causes of leg ulcers
are diverse (table 1). The most common causes are venous insufficiency, arterial insufficiency, and
neuropathy. Physical injury, infection, vasculopathies, pyoderma gangrenosum (PG), panniculitis,
malignancies, drugs, and spider bites are less common etiologies. (See 'Common causes' above and
'Less common causes' above.)
●Although the differential diagnosis of leg ulcers is broad, the high frequency of venous
insufficiency, arterial insufficiency, and neuropathic ulcers warrant strong consideration of these
etiologies during patient evaluation (table 2). If findings are not consistent with these etiologies, less
common causes of leg ulcers should be considered. (See 'Patient evaluation' above.)
●Clinical findings that suggest venous insufficiency ulcers include location on the lower leg,
particularly near the medial or lateral malleoli, and signs of chronic venous disease, such as edema,
varicosities, hemosiderin deposition, or stasis dermatitis. Venous ulcers are usually shallow with
irregular borders and overlying yellow, fibrinous exudate. (See 'Venous insufficiency' above.)
●Clinical findings that suggest arterial insufficiency ulcers are painful, well-demarcated ulcers with a
"punched-out" appearance located on toes or pressure areas. Associated clinical findings may
include a shiny appearance to the skin, local hair loss, diminished pulses, and dry gangrene. (See
'Arterial insufficiency' above.)
●Clinical findings that suggest neuropathic ulcers include painless, "punched-out" ulcers occurring
over pressure points, usually on the foot or heel. A surrounding callus is common. Patients with
diabetic neuropathy may also have claw toes, neuropathic (Charcot) arthropathy, and reduced
sweating on the feet resulting in dry, scaly feet. (See 'Neuropathy' above.)
●Careful assessment of the patient history and physical findings is often helpful for identifying less
common causes of leg ulcers. Historical information such as the time course of ulcer development,
underlying disease, or medication exposure can be useful. Recognition of associated physical
findings such as palpable purpura, retiform purpura, or nodules can also aid in diagnosis. (See
'Patient evaluation' above.)
●Biopsies are not necessary for the diagnosis of most ulcers, but can be helpful when the diagnosis
is uncertain. In particular, histopathologic examination may be helpful when the differential
diagnosis includes vasculitis, microvascular occlusion syndromes, panniculitis, or malignancy.
Additional laboratory or radiologic studies may be helpful for confirming the cause of an ulcer or
evaluating for a suspected infection or associated underlying disease. (See 'Patient evaluation'
above.)
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Evaluation of adults with cutaneous lesions of vasculitis
uptodate.com/contents/evaluation-of-adults-with-cutaneous-lesions-of-vasculitis/print
INTRODUCTION Cutaneous vasculitis comprises a diverse group of

conditions characterized by acute, relapsing, or chronic inflammatory damage to small or medium-
sized blood vessels in the skin or subcutaneous tissue. Cutaneous vasculitis can occur as a feature
of multiple disorders and exhibits a wide variety of clinical manifestations. Examples of clinical
findings include petechiae, palpable purpura, hemorrhagic bullae, nodules, ulcers, livedo reticularis,
livedo racemosa, and urticaria.
Although cutaneous vasculitis can be a benign, transient condition, it may also be an indicator of
underlying disease or systemic vasculitis. Careful assessment is essential for accurate diagnosis
and optimal management. A typical initial evaluation includes a skin biopsy to confirm vasculitis,
careful review of the patient history to assess for the etiology of vasculitis, and laboratory tests to
assess for systemic involvement. When the cause of vasculitis is uncertain, additional tests may be
helpful.
The general approach to the evaluation of adults with cutaneous lesions suggestive of vasculitis will
be reviewed here. Overview discussions of vasculitis in adults and children and in-depth discussions
of specific forms of vasculitis are provided separately. (See "Overview of and approach to the
vasculitides in adults" and "Vasculitis in children: Evaluation overview" and 'Types of cutaneous
vasculitis' below.)
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TYPES OF CUTANEOUS
VASCULITIS The dermatologic addendum to the 2012 Revised International
Chapel Hill Consensus Conference Nomenclature of Vasculitides provides a framework for the
classification of vasculitides affecting the skin [1]. Major groupings are based upon the size of
vessels involved, propensity to affect other organs, and associated causes:
●Small vessel vasculitis (primarily affects dermal vessels [arterioles, capillaries, venules]):
•Immune complex vasculitis:
-Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) (see "IgA vasculitis (Henoch-

Schönlein purpura): Clinical manifestations and diagnosis")
-Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) (see "Urticarial vasculitis")
-Cryoglobulinemic vasculitis (see "Overview of cryoglobulins and cryoglobulinemia")
•Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis:
-Microscopic polyangiitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis:

Clinical manifestations and diagnosis")
-Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (see "Clinical features and
diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)")
-Granulomatosis with polyangiitis (see "Granulomatosis with polyangiitis and microscopic

polyangiitis: Clinical manifestations and diagnosis")
●Medium vessel vasculitis (primarily affects arteries in subcutaneous tissue):
•Cutaneous polyarteritis nodosa (see "Cutaneous polyarteritis nodosa")
•Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults")
●Variable-vessel vasculitis (may affect any type of vessel):
•Behçet disease (see "Clinical manifestations and diagnosis of Behçet syndrome")
•Cogan's syndrome (see "Cogan's syndrome")
●Cutaneous single-organ vasculitis (skin-limited vasculitis that exhibits no association with

systemic vasculitis):
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•Cutaneous immunoglobulin M (IgM)/immunoglobulin G (IgG) immune complex vasculitis
(leukocytoclastic vasculitis with IgG/IgM deposits that does not fit into another defined immune
complex vasculitis)
•Nodular cutaneous vasculitis (erythema induratum of Bazin) (see "Erythema induratum (nodular
vasculitis)")
•Erythema elevatum diutinum (see "Erythema elevatum diutinum")
Additional defined variants include vasculitis associated with systemic disease (eg, rheumatoid
vasculitis, lupus vasculitis, etc) and vasculitis associated with a probable etiology (ie, associated
with a specific drug, infection, sepsis, neoplasm, etc).
Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, typically do not affect
vessels in the skin. Occasionally, giant cell arteritis results in cutaneous necrosis related to vascular
compromise of vessels proximal to the skin [1]. Rarely, giant cell arteritis involves vessels in the
panniculus [1]. Kawasaki disease, a form of medium vessel vasculitis, also does not typically involve
vessels in the skin. (See "Overview of and approach to the vasculitides in adults", section on 'Major
categories of vasculitis'.)
WHEN TO SUSPECT CUTANEOUS

VASCULITIS Suspicion for cutaneous vasculitis typically arises based upon the
detection of suggestive cutaneous findings.
Suggestive findings — Cutaneous vasculitis may exhibit a variety of

morphologies, which usually correlate with the pathologic processes occurring in the skin [2-4].
Clinical features can include manifestations typical of small vessel involvement (eg, petechiae,
palpable purpura, hemorrhagic bullae, superficial ulceration, urticaria) or medium vessel involvement
(eg, subcutaneous nodules, deep ulcers, livedo reticularis, livedo racemosa). The skin lesions are
often asymptomatic but may be associated with pruritus, burning sensations, or pain.
Examination of the entire skin surface can be helpful for the assessment for cutaneous vasculitis.
Cutaneous vasculitis most commonly occurs in a symmetrical distribution on the lower legs,
dependent areas, or on areas of constrictive clothing due to increased hydrostatic pressure in these
locations.
●Petechiae – Petechiae are nonblanchable and nonpalpable, pinpoint macules (less than a few
millimeters in diameter) that result from capillary inflammation and red blood cell extravasation
(picture 1) [2]. Petechiae are nonblanchable due to the presence of extravasated erythrocytes in the
dermis due to damaged vessel walls. Diascopy (the application of pressure to a skin lesion with a
glass slide) is a helpful technique for identifying nonblanchable lesions.
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●Palpable purpura – Brisk inflammation of venules and arterioles initially manifests as infiltrated,
erythematous papules and plaques. These progress to raised, nonblanchable (purpuric) lesions as
damage to vessel walls increases (picture 2A-B) [2]. As with petechiae, diascopy can be used to
confirm nonblanchable lesions.
●Hemorrhagic bullae – Small vessel involvement in the dermis can result in necrosis of overlying
skin with associated blisters and extravasation of red blood cells (picture 3) [2].
●Subcutaneous nodules – Intense inflammation of medium-sized vessels (vessels with muscular

walls in the deep dermis and subcutis) can lead to the formation of nodular lesions (picture 4).
●Ulceration or digital necrosis – Ulceration and tissue necrosis occur when vasculitis results in
reduced vascular perfusion in the skin (picture 5A-B) [2]. Superficial ulcers can occur in patients with
small vessel vasculitis; deep ulcers are usually the result of medium vessel disease [5].
●Livedo reticularis and livedo racemosa – Livedo reticularis presents as a localized or widespread,
patchy, reticulated, vascular network with a red-blue or violaceous hue (picture 6A-B). It results from
compromise of blood flow in medium-sized vessels and can occur in the setting of vasculopathy due
to vasospasm, hypercoagulable states, thrombosis, increased blood viscosity, or embolic
phenomena, as well as in association with vasculitis. Livedo racemosa presents with a more abrupt
and broken vascular pattern than livedo reticularis (picture 7). It is strongly associated with Sneddon
syndrome, a nonvasculitic disorder characterized by livedoid skin lesions and cerebrovascular
accidents, but may also occur as a manifestation of medium vessel vasculitis and other disorders
[6].
●Urticaria – Unlike nonvasculitic urticaria, lesions of urticarial vasculitis usually persist for more
than 24 hours and are frequently associated with a burning sensation or pain, rather than pruritus.
Lesions may contain purpuric areas and can resolve with hyperpigmentation (picture 8). (See
"Urticarial vasculitis".)
Mimickers — The presence of a petechial or purpuric eruption does not always indicate
vasculitis. Examples of other disorders that may present with these findings include [7,8]:
●Common vasculitis mimickers:
•Pigmented purpuric dermatoses (eg, nonblanchable pinpoint macules, patches, or plaques, often on
the lower legs) (picture 9) (see "Pigmented purpuric dermatoses (capillaritis)", section on
'Schamberg's disease (progressive pigmentary purpura)')
•Macular purpura due to chronic sun exposure, glucocorticoid therapy, trauma, or anticoagulants
(picture 10)
•Inflammatory disorders on the lower extremities or other dependent sites (eg, hemorrhagic macules
or papules due to stasis dermatitis or maculopapular drug eruptions) (picture 11A-B)
474
•Arthropod bites (eg, bedbugs) (picture 12)
●Less common vasculitis mimickers:
•Scurvy (perifollicular hemorrhage) (picture 13) (see "Overview of water-soluble vitamins", section on
'Deficiency')
•Platelet deficiencies or dysfunction (petechiae or macular purpura) (picture 14)
•Hypercoagulable and thrombotic disorders (noninflammatory retiform purpura) (picture 15A-B) (see
"Approach to the patient with retiform (angulated) purpura")
•Cholesterol emboli (noninflammatory retiform purpura, digital gangrene, livedo reticularis) (picture
16) (see "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)")
•Septic emboli (petechiae on the distal extremities, noninflammatory retiform purpura) (picture 17)
(see "Complications and outcome of infective endocarditis", section on 'Metastatic infection')
•Systemic amyloidosis (periorbital and pinch purpura) (picture 18) (see "Cutaneous manifestations
of amyloidosis")
•Strongyloidiasis (periumbilical purpura) (see "Strongyloidiasis")
•Purpura fulminans (sharply demarcated retiform purpura in the setting of disseminated

intravascular coagulation or sepsis) (picture 19) (see "Disseminated intravascular coagulation (DIC)
in adults: Evaluation and management" and "Clinical manifestations of meningococcal infection",
section on 'Purpura fulminans')
•Calciphylaxis (painful retiform purpura in adipose-rich areas, livedo reticularis) (see "Calciphylaxis
(calcific uremic arteriolopathy)")
In addition, livedoid vasculopathy (also known as atrophie blanche) may be confused with vasculitis.
Livedoid vasculopathy presents with punched-out ulcers on the lower legs with surrounding livedo
reticularis or livedo racemosa (picture 20). (See "Livedoid vasculopathy".)
PATIENT ASSESSMENT The evaluation of patients with

cutaneous lesions of vasculitis focuses on confirming the presence of vasculitis, evaluating for
extracutaneous involvement, and identifying the underlying cause. This typically involves
consideration of a skin biopsy (or biopsies), careful review of the patient history and review of
systems, and performance of select laboratory tests.
Skin biopsy to confirm vasculitis
475
Indications for biopsy — A diagnosis of cutaneous vasculitis may be strongly
suspected based upon the physical examination; however, a biopsy is necessary for a definitive
diagnosis.
In general, a skin biopsy for routine histopathologic examination should be performed whenever
feasible. However, clinicians with expertise in the evaluation of cutaneous vasculitis may elect to
delay a biopsy for patients with classic presentations of acute small vessel cutaneous vasculitis that
have persisted for less than four weeks, have a clear removable or treatable inciting factor (eg, drug
or infection), and exhibit no clinical or laboratory evidence of systemic involvement because many
such cases resolve spontaneously within a few weeks. If the vasculitis fails to improve within four
weeks (ie, new lesions developing or persistence of red or purple lesions), performance of a skin
biopsy is indicated. Of note, residual, macular or patchy hyperpigmentation is common after
resolution of vasculitis lesions.
An additional skin biopsy for direct immunofluorescence (DIF) may be performed at the same time
as the biopsy for routine histopathologic examination but is not always necessary. (See 'Direct
immunofluorescence' below.)
Diagnostic criteria — A histologic diagnosis of cutaneous vasculitis is confirmed by

the identification of findings that indicate an inflammatory process that results in damage to vessel
walls [2,4]. Small vessels (venules and arterioles) require two out of three of the following criteria for
a definitive diagnosis of vasculitis [9]:
●Angiocentric and/or angioinvasive inflammatory infiltrates
●Disruption and/or destruction of vessel walls by the inflammatory infiltrate
●Fibrinoid necrosis (fibrin deposition within the vessel wall or lumen; results from the accumulation
and conversion of plasma proteins [2])
Medium-sized vessels (small arteries and veins) in the deep dermis and subcutaneous tissue require
both of the following criteria to confirm vasculitis:
●Inflammatory infiltrate infiltrating the muscular vessel wall
●Fibrinoid necrosis
Additional supportive findings — Other histopathologic findings that

support but are not diagnostic for vasculitis include the presence of extravasated erythrocytes,
nuclear debris (leukocytoclasia), necrosis of eccrine glands, endothelial cell damage swelling or
necrosis, and cutaneous ulceration, infarction, or necrosis [9]. Findings that suggest particular forms
of vasculitis (eg, granulomas in granulomatosis with polyangiitis or eosinophilic granulomatosis
with polyangiitis [Churg-Strauss syndrome] and interface dermatitis in vasculitis associated with
lupus erythematosus or dermatomyositis) represent additional helpful information that can be
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gleaned from a biopsy. "Leukocytoclastic vasculitis" is a pathologic term that describes the
microscopic findings of a neutrophilic small vessel vasculitis, a characteristic feature of multiple
forms of cutaneous small vessel vasculitis.
Procedure — Optimizing the timing of the biopsy, biopsy depth, and biopsy location
increases the likelihood of identifying diagnostic features.
Timing — The histologic characteristics of vasculitic lesions evolve quickly. Selection of a lesion
that the patient estimates has been present for 24 to 48 hours for biopsy may optimize both the
detection of vasculitis and assessment of the type of inflammatory infiltrate, a feature that can be
helpful for diagnosis. Lesions that are between 24 and 48 hours old are the most likely to
demonstrate diagnostic findings. Biopsies of leukocytoclastic vasculitis taken prior to 24 hours are
likely to have some infiltration of neutrophils but often do not yet exhibit fibrinoid necrosis. Beyond
48 hours, the inflammatory infiltrate in leukocytoclastic vasculitis begins to shift from a neutrophilic
infiltrate to lymphocytes and macrophages, and then eventually clears, leaving only evidence of
fibrinoid necrosis. (See 'Diagnostic criteria' above and 'Additional supportive findings' above.)
Type of biopsy — The cutaneous features dictate the type of biopsy that should be
performed. In general, shave biopsies should be avoided, as they prevent the evaluation of vessels in
the mid-dermis and deep dermis. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)
The following principles are helpful for guiding the selection of the appropriate procedure:
●Cutaneous findings suggestive of involvement of the vessels in the superficial to mid-dermis

(petechiae, palpable purpura, or urticarial papules or plaques) should be evaluated with a punch
biopsy that is 4 mm in diameter or larger. This allows for evaluation of vessels throughout the
dermis.
●Cutaneous findings suggestive of involvement of the vessels in the mid-dermis to the

subcutaneous tissue (livedo racemosa, subcutaneous nodules, ulcers) require a large punch biopsy
(8 to 10 mm) or wedge biopsy that includes the subcutaneous tissue.
Location — The cutaneous features determine the optimal location of the biopsy within the
involved area. Biopsies of petechial lesions or palpable purpura can be taken from any site within the
lesion.
The ideal location of the biopsy differs in patients with livedo racemosa or ulcerations. In livedo
racemosa, biopsy should be performed within the pale center of an erythematous ring [2]. This is
where the responsible vessel is likely to be located. When ulceration is present, the biopsy should be
taken from the edge of the ulcer, rather than the ulcer itself. A biopsy taken from the base of an ulcer
can reveal purely incidental findings of vascular injury that resemble the histopathologic findings of
vasculitis [9]. Biopsies of nodular lesions should be centered over a tender nodule.
477
Biopsies of infarcted digits are generally low yield for evaluation for vasculitis, as the infarcted area
is simply a manifestation of underlying vessel obstruction.
Biopsies of livedo reticularis, a feature that may accompany vasculitis, demonstrate nonspecific
histopathologic findings and are usually not indicated.
Direct immunofluorescence — Although an additional skin biopsy for direct

immunofluorescence (DIF) is commonly performed at the same time as the biopsy for routine
histopathologic examination in patients with findings suggestive of small vessel vasculitis, an
immediate biopsy for DIF is not mandatory when small vessel vasculitis is acute (duration <4 weeks)
in the absence of symptoms or signs suggestive of systemic involvement because many of these
cases resolve spontaneously. Reserving a biopsy for DIF for patients with small vessel vasculitis of
unclear cause that persists for ≥4 weeks is a reasonable alternative. (See 'Biopsy for direct
immunofluorescence' below.)
Evaluation for etiology and extracutaneous

involvement
Initial assessment — The initial assessment focuses on identifying readily
identifiable causes of vasculitis and systemic involvement. Appropriate initial steps include an
assessment for risk factors for vasculitis and performance of a review of systems and select
laboratory tests.
Review of risk factors — Although the cause of vasculitis can be elusive, the patient
history is an important method for identifying the etiology of vasculitis. In particular, the history
should assess for recent infections (particularly upper respiratory infections), drug exposure,
connective tissue disease, and malignancy [2,9,10]. In a study that pooled data from over 2000
patients in studies that reported triggering factors or associated conditions in patients with
vasculitis, the frequencies of idiopathic disease, infections, drugs, connective tissue disease, IgA
vasculitis, malignancy, and primary systemic vasculitides were 39, 23, 20, 12, 10, 4, and 4 percent,
respectively [9]. Other systemic disorders were less frequently reported. Rates of failure to identify
the cause of vasculitis ranged from 3 to 72 percent of patients [9].
In particular, when evaluating for drug-induced vasculitis, the timing of the development of vasculitis
can be helpful. Drug-induced vasculitis most often occurs 7 to 10 days after the introduction of the
inciting medication, with the exception of drug-induced antineutrophil cytoplasmic antibody (ANCA)-
associated vasculitis, which usually occurs a year or more after starting the causative medication
[9].
Review of systems — Single-organ vasculitis limited to the skin is a diagnosis of

exclusion. Patients should be questioned regarding signs or symptoms that could suggest systemic
vasculitis or underlying disease (table 1). Examples of potentially helpful findings include:
478
●Weight loss
●Fatigue, chills, night sweats
●Myalgias or arthralgias
●Tea-colored urine or gross hematuria
●Abdominal pain or melena
●Chest pain
●Dyspnea, cough, or hemoptysis
●New-onset or worsening asthma
●Nasal symptoms
●Peripheral neuropathy
If these or other symptoms suggestive of systemic vasculitis or underlying disease are present,
further testing guided by the specific symptoms present are indicated. (See "Overview of and
approach to the vasculitides in adults", section on 'Clinical features suggestive of systemic
vasculitis' and 'Additional studies' below.)
Laboratory tests — Routine initial laboratory tests suggested for all patients with
cutaneous vasculitis include:
●Complete blood count with differential and platelets – Cytopenias may suggest underlying
connective tissue disease, leukocytosis can suggest infection or hematologic malignancy, and
platelet abnormalities may reflect nonvasculitic causes of skin lesions.
●Comprehensive metabolic panel – Evaluates for renal and hepatic abnormalities.
●Urinalysis with microscopy – Identifies hematuria due to renal involvement.
Additional studies — Additional evaluation is indicated for patients in whom the

cause of persistent vasculitis (duration ≥4 weeks) is unclear or who present with symptoms, signs,
or laboratory results suggestive of extracutaneous involvement or underlying disease. This may
include screening laboratory tests, other tests directed by patient symptoms or test results, and a
skin biopsy for DIF (if biopsy for DIF was not already performed).
Laboratory and other tests — Typical laboratory tests obtained to evaluate patients
with either persistent vasculitis of unknown cause or systemic symptoms include:
●Hepatitis B and C serologies
479
●Serum complement levels (total hemolytic complement [CH50], C3, and C4)
●Antinuclear antibody (ANA) and anti-dsDNA, anti-Ro, anti-La, anti-RNP, and anti-Smith antibodies
●Rheumatoid factor
●Serum cryoglobulins
●ANCA
●HIV antibody
Positive ANCAs are helpful in the correct clinical context but do not confirm or eliminate a diagnosis
of an ANCA-associated vasculitis. (See "Clinical spectrum of antineutrophil cytoplasmic
autoantibodies", section on 'Disease associations'.)
Additional laboratory tests or imaging studies are selected based upon the results of these tests and
the presence of worrisome signs or symptoms (table 1). For example, review of systems that detects
weight loss, joint pain, sicca symptoms, oral or nasal ulcerations, hair loss, photosensitivity, or
Raynaud phenomenon supports a thorough evaluation for underlying connective tissue disorders.
Pulmonary symptoms support performance of a chest radiograph and further evaluation as needed.
ANCA-associated vasculitis can affect the small and medium vessels of the lung, causing
inflammation and hemorrhage. Additionally, hypocomplementemic urticarial vasculitis syndrome, a
subset of urticarial vasculitis, may present with hemoptysis, pleural effusion, and severe chronic
obstructive pulmonary disease [11,12].
Unexplained weight loss, fevers, chills, and night sweats may signify a malignancy and should
prompt further evaluation. However, an extensive search for malignancy is not warranted in patients
without signs or symptoms suggestive of malignancy given the rarity of this association (less than 5
percent of all patients with cutaneous vasculitis [13-15]). Patients should be up-to-date on age-
appropriate malignancy screening. Also, in addition to the standard complete blood count with
differential, our evaluation of patients over the age of 60 who lack another identifiable cause of small
vessel vasculitis includes serum protein electrophoresis and immunofixation and serum free light
chains. Limiting imaging studies to those indicated based upon the presence of suggestive signs
and symptoms is appropriate in this situation.
Biopsy for direct immunofluorescence — Direct immunofluorescence (DIF)

is an essential component of the evaluation of cutaneous vasculitis in adults with small vessel
vasculitis of unclear cause that persists for ≥4 weeks. DIF utilizes labeled antibodies to identify
immunoglobulin and complement deposits within the skin.
Value — DIF can aid in the identification of the underlying etiology of the vasculitis. DIF is
particularly important for the diagnosis of IgA vasculitis (Henoch-Schönlein purpura). Renal
involvement is common in IgA vasculitis, warranting additional monitoring. Only the identification of
perivascular IgA deposition with DIF confirms the diagnosis of IgA vasculitis [16]. (See "IgA
480
vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Diagnosis'
and "IgA vasculitis (Henoch-Schönlein purpura): Management" and "IgA vasculitis (Henoch-
Schönlein purpura): Renal manifestations".)
DIF is also of value for distinguishing immune complex-mediated vasculitides (such as most cases
of cutaneous leukocytoclastic vasculitis, IgA vasculitis [Henoch-Schönlein purpura],
cryoglobulinemic vasculitis, urticarial vasculitis, and vasculitis secondary to autoimmune connective
tissue disease) from pauci-immune vasculitis (granulomatosis with polyangiitis, eosinophilic
granulomatosis with polyangiitis, microscopic polyangiitis, and polyarteritis nodosa) (table 1) [17]. A
negative DIF in the setting of histopathologically confirmed vasculitis should increase suspicion of
these pauci-immune primary systemic vasculitides, and an appropriate work-up for systemic
involvement should be undertaken. (See "Granulomatosis with polyangiitis and microscopic
polyangiitis: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Clinical features and
diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Evaluation
and diagnosis' and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section
on 'Diagnosis'.)
Predominant deposition of IgM around vessel walls suggests the possibility of vasculitis related to
type 2 or type 3 cryoglobulinemia or rheumatoid vasculitis (table 1). Patients with
hypocomplementemic urticarial vasculitis may have deposition of IgG, complement, and fibrin on
vessel walls, as well as along the dermal-epidermal junction [9]. (See "Clinical manifestations and
diagnosis of rheumatoid vasculitis", section on 'Diagnosis' and "Overview of cryoglobulins and
cryoglobulinemia", section on 'Biopsy' and "Urticarial vasculitis".)
Procedure — Ideally, DIF is performed on a lesion that is less than 24 hours old. The
inflammatory reaction stimulated by the deposition of immunoglobulins in vessel walls quickly
results in the destruction of both the vessel wall and the immune complexes, resulting in negative
immunofluorescence.
In contrast to the biopsies for DIF performed for the evaluation of blistering skin diseases, which are
taken from perilesional skin, specimens from vasculitic lesions should be taken from within the
lesions. DIF studies cannot be performed on the formalin-fixed tissue obtained for hematoxylin and
eosin staining, and a separate tissue specimen should be obtained.
Specimens can be placed in Michel's transport medium (a fixative) or normal saline, or can be flash-
frozen with liquid nitrogen. Tissue submitted in saline must be processed within 24 hours.
Examination of the specimen by a pathologist experienced in DIF microscopy is preferred.

provided separately. (See "Society guideline links: Vasculitis".)
481
SUMMARY AND
RECOMMENDATIONS
●Cutaneous vasculitis occurs as a result of inflammatory processes that target and damage small
or medium-sized blood vessels in the skin (table 1). Cutaneous manifestations of vasculitis may
include petechiae, palpable purpura, nodules, ulcers, digital necrosis, livedo reticularis, livedo
racemosa, or urticaria. (See 'Types of cutaneous vasculitis' above and 'When to suspect cutaneous
vasculitis' above.)
●A wide variety of disorders can lead to the development of cutaneous vasculitis. Infections and
medications are the most common etiologies of cutaneous small vessel vasculitis. (See 'When to
suspect cutaneous vasculitis' above and 'Evaluation for etiology and extracutaneous involvement'
above.)
●The initial evaluation of patients with cutaneous lesions suggestive of vasculitis incorporates
confirmation of the presence of vasculitis, assessment for the underlying cause, and the
identification of extracutaneous involvement. This includes consideration of a skin biopsy, analysis
of the patient history and review of systems, and basic laboratory tests (complete blood count with
differential and platelets, comprehensive metabolic panel, and urinalysis with microscopy). (See
'Patient assessment' above.)
●A skin biopsy is required to confirm a diagnosis of cutaneous vasculitis. Ideally, biopsies for routine
histopathologic examination should be taken from a lesion that is 24 to 48 hours old. The best type
of biopsy and location for the biopsy depends upon the clinical manifestations. Histopathologic
features of vasculitis include fibrinoid necrosis and an inflammatory infiltrate invading or damaging
the vessel wall. (See 'Skin biopsy to confirm vasculitis' above.)
●Additional evaluation is indicated for patients with cutaneous vasculitis of uncertain etiology that
persists for four or more weeks or who exhibit signs or symptoms suggestive of systemic vasculitis
or an associated underlying disease. For patients with vasculitis of uncertain etiology, this typically
includes tests for hepatitis B and C, autoimmune disease, and other disorders associated with
vasculitis and a skin biopsy for direct immunofluorescence (DIF) testing (if not already performed).
(See 'Additional studies' above.)
●DIF testing can be a valuable tool for the diagnosis of small vessel vasculitis, as it can help to
distinguish immune complex-mediated vasculitides from pauci-immune vasculitis. Because many
cases of small vessel vasculitis spontaneously resolve within a few weeks, DIF testing is most
useful for the evaluation of vasculitis that persists for more than four weeks. Ideally, the biopsied
lesion should be less than 24 hours old. Biopsy specimens for DIF should not be placed in formalin.
(See 'Biopsy for direct immunofluorescence' above.)
482
Office-based dermatologic diagnostic procedures - UpToDate
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INTRODUCTION Several dermatologic diagnostic procedures (eg, Wood's

lamp examination, potassium hydroxide preparation, Tzanck smear) can be performed at the
bedside, in the clinic, or in the doctor's office to confirm or exclude a suspected diagnosis or to
differentiate among diagnoses [1,2]. Although additional tests, such as histopathology, cultures, or
polymerase chain reaction, are usually performed for a more precise diagnosis, the simple
procedures reviewed in this topic represent valuable diagnostic tools for several infectious and
noninfectious diseases, especially in limited-resource settings.
A number of dermatologic diagnostic procedures will be described here. Dermoscopy, skin biopsy,
and nail biopsy are discussed separately. (See "Overview of dermoscopy" and "Dermoscopic
evaluation of skin lesions" and "Skin biopsy techniques" and "Intralesional corticosteroid injection".)
483
WOOD'S LAMP EXAMINATION
(BLACK LIGHT) The Wood's lamp is a device that emits ultraviolet (UV)
light using a filter selective for wavelengths in the 320 to 400 nm region of the UV spectrum, with a
peak at 365 nm [3]. Under Wood's light, normal skin has a blue fluorescent appearance, whereas
different skin diseases have characteristic fluorescent patterns. These include vitiligo, progressive
macular hypomelanosis, melasma, tinea capitis, erythrasma, and pityriasis versicolor [4,5].
●Under Wood's light, vitiligo lesions (picture 1) appear bright white and sharply delineated, as a
result of the autofluorescence of dermal collagen. (See "Vitiligo: Pathogenesis, clinical features, and
diagnosis".)
●The hypopigmented lesions of progressive macular hypomelanosis (picture 2) demonstrate a

characteristic punctiform, orange-red, follicular fluorescence when examined under Wood's light.
(See "Acquired hypopigmentation disorders other than vitiligo", section on 'Progressive macular
hypomelanosis'.)
●Only some of the dermatophytes that cause tinea capitis (picture 3A-B) produce fluorescence.
These include members of the genus Microsporum (eg, Microsporum audouinii and Microsporum
canis). Infected hairs produce a blue-green fluorescence under the Wood's light. Members of the
genus Trichophyton, such as Trichophyton schoenleinii, produce only a faint, dull blue fluorescence.
(See "Tinea capitis".)
●In erythrasma, a superficial bacterial infection caused by Corynebacterium minutissimum most often
involving the intertriginous areas (picture 4A-B), examination with the Wood's lamp reveals a coral-
red fluorescence due to bacterial coproporphyrin III (picture 5). (See "Erythrasma".)
●In pityriasis versicolor, a common superficial fungal skin infection caused by yeasts in the genus
Malassezia (picture 6A-B), theyeasts emit a yellow-orange fluorescence. Pseudomonas reveals a
yellow-green fluorescence. (See "Tinea versicolor (pityriasis versicolor)".)
●The use of the Wood's lamp may improve the detection of the borders of lentigo maligna (picture 7)
before surgical excision by accentuating the hyperpigmentation in the epidermis. (See "Lentigo
maligna: Clinical manifestations, diagnosis, and management".)
●A presumptive diagnosis of porphyria cutanea tarda (picture 8), a metabolic disorder caused by the
altered activity of enzymes in the heme biosynthetic pathway, is possible if pink or orange-red
fluorescence is seen in urine examined under a Wood's light. (See "Porphyria cutanea tarda and
hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)
Equipment
●Wood's lamp or hand-held black light source
484
●Electrical source
●Darkened room
Technique
●The examination with a Wood's lamp should be performed in a dark room, with the light source at 4
to 5 inches from the skin surface.
●If the patient has recently bathed, fluorescence may be reduced.
●Topical medications, fabric fibers, and scale also may fluoresce.
DERMOSCOPY The principles of dermoscopy and dermoscopic

examination of cutaneous lesions are discussed in detail separately. (See "Overview of dermoscopy"
and "Dermoscopic evaluation of skin lesions".)
GRAM STAIN Gram stain is widely used for the rapid identification of bacteria
in skin lesions and for guiding empiric antibiotic treatment for gram-positive and gram-negative
bacterial infections. The technique and interpretation of Gram staining are described in detail
elsewhere. (See "Approach to Gram stain and culture results in the microbiology laboratory".)
POTASSIUM HYDROXIDE
PREPARATION The potassium hydroxide (KOH) preparation is the simplest
method to microscopically identify fungi or yeasts from epidermal skin scrapings, hair roots, or nail
clippings. KOH dissolves epidermal keratinocytes, allowing for easier demonstration and
identification of organisms. KOH preparation is indicated to identify fungal infections (eg, tinea
pedis, manus, corporis, cruris, capitis, onychomycosis) and yeast infections (eg, tinea versicolor,
candidiasis). KOH examination may yield false-negative results in 12 to 24 percent of cases [6-8].
Equipment
●Alcohol preparations.
●No. 15 blade or glass slide for scraping.
●Glass slide and coverslip.
●KOH 20% solution with or without dimethylsulfoxide (DMSO); heating is not needed if DMSO is
used.
485
●Alcohol lamp.
●Microscope.
●Hemostats or 2x2 gauze for scalp lesions, tongue blade for oral lesions, and nail clippers or curette
for subungual debris for nail lesions.
Technique
●Clean the skin of any lotions or creams with an alcohol preparation.
●Obtain a specimen. For the skin, use either a no. 15 blade or the side of a glass slide to scrape
material loose from a leading edge; if there are pustules or vesicles, scrape the roof onto a glass
slide. For oral candidiasis, use a tongue blade to scrape white plaques onto a slide. For nail
infections, remove as much nail as possible with nail clippers to expose the most proximally
involved area, then scrape the subungual debris onto a slide with a 1 to 2 mm curette or a no. 15
blade. For hair infections, pluck 5 to 10 hairs from an active scaling area with a hemostat and place
them on a slide or rub a 2x2 gauze vigorously on an area of alopecia and scaling, placing the broken-
off hairs onto a glass slide.
●Apply two or three drops of KOH to the slide, then apply the coverslip.
●If KOH without DMSO is used, heat the slide gently over an alcohol lamp or with a lighter for two or
three seconds until just before it starts to boil. This will hasten the breakdown of cell wall
components and make it easier to see fungal remnants.
●Examine at 10 times magnification, using the lowest light possible (lowering the condenser is
helpful). Examine at 40 times magnification, if necessary, to confirm the presence of hyphae in
dermatophyte infections (picture 9A) and pseudohyphae or yeast forms for Candida or Pityrosporum
infections (picture 9B). Use the fine focus to demonstrate refractile properties of organisms
compared with epidermal cell walls.
For nail specimens, if the KOH with DMSO does not show the organism, you can allow the
preparation to sit for several hours, then re-examine. This helps the thick keratin dissolve and aids in
examination of fungal elements.
FUNGAL CULTURE Fungal cultures are especially useful in hair or

nail infections to identify the fungal species or differentiate fungal from yeast or mold infections.
This differentiation can influence therapy. As an example, nail infections due to molds will not
respond to oral therapies but may respond to nail removal. In contrast, fungal cultures are rarely
needed to diagnose fungal or yeast infections of the skin. Fungal cultures may yield false-negative
results in over 40 percent of cases [6-8].
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Equipment
●Alcohol preparation
●No. 15 blade or glass slide for scraping
●Glass slide and coverslip
●Alcohol lamp
●Microscope
●Hemostats or gauze for scalp lesions, tongue blade for oral lesions, and nail clippers/curette to
collect subungual debris for nail lesions
●Dermatophyte test medium for cultures
Technique
●Obtain a specimen. For hair, remove 5 to 10 hairs from an involved, scaling area with one quick
motion using a hemostat or rub a 2x2 gauze vigorously on an area of alopecia and scaling, placing
the broken-off hairs into the media. After placing the hairs in the culture medium, loosely recap the
bottle and store it in a dark cabinet. For nails, remove a portion of the involved nail with nail clippers
to expose the most proximal involved area. Using a no. 15 blade or a curette, scrape the proximal
subungual debris into the culture medium. Nail clippers can be used to remove the involved proximal
areas but cover the nail with 4x4 gauze to avoid having a specimen fly across the room. After
embedding some of the specimen in the medium, apply the cap loosely and store in a dark cabinet.
●Examine the specimen every two weeks for four to eight weeks, looking for the phenol indicator in
the test medium to turn from yellow to red.
●Monomorphous colony growth indicates a dermatophyte infection. Yeast looks like creamy,
discrete colonies (picture 10). Bacterial contaminants and nonpathogenic molds also can grow; it
may be necessary to send the specimen to a mycology laboratory if the diagnosis is in doubt.
TZANCK SMEAR The Tzanck smear, first introduced in 1947, is a

simple, rapid, and inexpensive test that can be easily performed in the clinic or clinician's office.
Although it is typically employed for a rapid diagnosis of herpes simplex virus (HSV) infections, it
can also be used as an initial diagnostic test for other viral and bacterial infections and for several
noninfectious inflammatory conditions [1,9-12]. A number of stains for Tzanck smear are
commercially available.
Equipment
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●Alcohol preparation
●No. 15 blade
●Cotton swab
●Glass slide and coverslip
●Mineral oil
●Microscope
●For modified, quick Tzanck – spray-on cytology fixative and ready-to-use urine sediment stain
●For routine staining – 95% methanol; distilled water; and Giemsa, Wright's, or Hansel stain
Technique
●Clean an area with an intact vesicle or blister for best results. If no intact vesicles are present, use
the edge of the most recently appearing erosion or ulcer.
●Remove a blister roof with a no. 15 blade, blot any excess blister fluid, then scrape the base of the
vesicle, erosion, or ulcer with the scalpel blade, spreading a thin layer of the resultant material onto a
glass slide.
●For a modified, quick Tzanck test, immediately fix the slide with spray cytology fixative and air dry
for 5 to 10 minutes. Flood the slide with urine sediment stain for 30 to 60 seconds, rinse gently with
tap water, and air dry. The modified test is easier, quicker, and utilizes fewer supplies than the
traditional test.
●For routine staining, fix the specimen by flooding the slide with 95% methanol for five seconds, then
air dry for one to two minutes. Flood the slide with nuclear stain (Wright's, Giemsa, or Hansel stain)
for 30 to 60 seconds. Add distilled water to the slide for 30 seconds, then flood it with distilled water
to remove any remaining stain. Flood the slide again with 95% methanol for Hansel stain. Air dry
without blotting.
●Observe the slide initially at 40 times magnification to find areas where individual cells are best
identified (ie, not clumped together). Then, use oil immersion at 100 times magnification to identify
multinucleated giant cells (ie, where nuclei are molded together in giant epithelial cells). Using
microscope settings under high light and with the condenser up is most helpful.
Viral infections — Typical cytologic findings in HSV infection include

multinucleated giant cells, acantholytic cells, keratinocyte ballooning, and nuclear molding (picture
11) [11]. Tzanck smear's sensitivity for the diagnosis of HSV infection varies from 40 to over 80
percent, depending upon the experience of the examiner, and is generally lower than viral cultures
488
[1]. Tzanck smear cannot distinguish among herpes simplex virus type 1 (HSV-1), herpes simplex
virus type 2 (HSV-2), and varicella zoster virus. Although the diagnosis of a specific HSV infection
can be confirmed by viral culture, direct fluorescent antibody testing, and type-specific serology, real-
time polymerase chain reaction (PCR) has emerged as the most sensitive method to confirm HSV
infection in clinical specimens obtained from mucocutaneous sites or cerebrospinal fluid. (See
"Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection",
The Tzanck smear can be used to confirm the diagnosis of molluscum contagiosum (MC) when the
clinical presentation is atypical or, in immunosuppressed patients, to differentiate MC from deep
fungal infections (eg, cryptococcosis, histoplasmosis, coccidioidomycosis) that present with
umbilicated papules mimicking MC [13].
For the Tzanck smear, the central part of the lesion is scraped with a no. 15 scalpel blade and
applied in a thin layer on a glass slide. The characteristic molluscum bodies present as large, ovoid,
eosinophilic, cytoplasmic inclusions and may be easily identified with hematoxylin and eosin stain.
(See "Molluscum contagiosum", section on 'Diagnosis'.)
Bacterial infections — In bacterial infections, such as bullous impetigo,

cytologic findings include dyskeratotic acantholytic cells, abundant neutrophils, and clumps of
cocci.
Leishmaniasis — Rapid bedside diagnosis of cutaneous leishmaniasis (picture 12)

can be performed using a Tzanck preparation obtained by scraping the lesion using a scalpel and
pushing in one direction until blood oozes from the inflamed border of the lesion; the blood drops are
then applied to a slide as a thin smear or "thick drop" that is let dry at room temperature [14]. The
amastigote protozoa can be easily identified by Wright-Giemsa stains as blue, "swarm of bees,"
round or oval bodies (Leishman-Donovan bodies) in the cytoplasm of macrophage mononuclear
cells (picture 13). In a study including 72 patients with cutaneous leishmaniasis who underwent
lesion scraping, biopsy, and PCR for diagnostic confirmation, the thick drop Tzanck was more
sensitive than biopsy and thin smear for the diagnosis of leishmaniasis (64, 44, and 39 percent,
respectively) [14]. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)
Noninfectious diseases — Tzanck smear is the test of choice for the

diagnosis of the benign pustuloses of the newborn [15]. Moreover, it can be used as an initial
screening test for patients with suspected autoimmune blistering diseases [2,11].
●In neonates with erythema toxicum neonatorum (picture 14A-B), a common pustular eruption
affecting neonates in the first few days of life, a Tzanck smear will a reveal the presence of
numerous eosinophils and absent bacteria. In acropustulosis of infancy and transient pustular
melanosis, Tzanck smear demonstrates abundant neutrophils, few eosinophils, and absent bacteria.
(See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Benign
vesiculopustular eruptions'.)
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●On a Tzanck smear, lesions of pemphigus vulgaris (picture 15) typically show numerous round,
acantholytic cells with enlarged nuclei and basophilic cytoplasm with a more intensely stained
peripheral rim [11]. In contrast, in lesions of bullous pemphigoid, acantholytic cells are absent and
there are abundant eosinophils. The definitive diagnosis of pemphigus vulgaris and bullous
pemphigoid requires a skin biopsy for histopathology and direct immunofluorescence and the
demonstration of circulating autoantibodies by enzyme-linked immunosorbent assay. (See
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Diagnosis' and
"Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section
on 'Diagnosis'.)
SCABIES PREPARATION The scabies preparation is

described in detail separately. (See "Scabies: Epidemiology, clinical features, and diagnosis", section
on 'Scabies preparation'.)
SKIN BIOPSY Skin biopsy techniques are discussed in detail separately. (See
"Skin biopsy techniques".)
SUMMARY
●Several dermatologic diagnostic procedures (eg, Wood's lamp examination, potassium hydroxide
[KOH] preparation, Tzanck smear) can be performed at the bedside, in the clinic, or in the clinician's
office to confirm or exclude a suspected diagnosis or to differentiate among diagnoses. (See
●The Wood's lamp is a device that emits ultraviolet (UV) light in the 320 to 400 nm region of the UV
spectrum. Examination under the Wood light may assist in the diagnosis of several skin diseases,
including vitiligo, melasma, tinea capitis, erythrasma, and pityriasis versicolor. (See 'Wood's lamp
examination (black light)' above.)
●Dermoscopic examination of pigmented and nonpigmented skin lesions is discussed separately.

(See "Overview of dermoscopy" and "Dermoscopic evaluation of skin lesions".)
●The technique and interpretation of Gram staining for the rapid identification of bacteria in skin
lesions are described in detail elsewhere. (See "Approach to Gram stain and culture results in the
microbiology laboratory".)
●The KOH preparation is the simplest method to microscopically identify fungi or yeasts from
epidermal skin scrapings, hair roots, or nail clippings (picture 9A-C). (See 'Potassium hydroxide
preparation' above.)
490
●Fungal cultures (picture 10) are especially useful in hair or nail infections to identify the fungal
species or differentiate fungal from yeast or mold infections. However, the sensitivity of culture may
not be much better than KOH examination, and results are not available for four to six weeks. (See
'Fungal culture' above and "Onychomycosis: Epidemiology, clinical features, and diagnosis", section
on 'Diagnosis' and "Tinea capitis", section on 'Culture'.)
●The Tzanck smear is a simple, rapid, and inexpensive test typically employed for a rapid diagnosis
of herpes virus infections. However, it can also be used as a diagnostic test for a number of other
infectious and noninfectious skin diseases presenting with vesiculopustular or bullous lesions. (See
'Tzanck smear' above.)
●The scabies preparation is described in detail separately. (See "Scabies: Epidemiology, clinical
features, and diagnosis", section on 'Scabies preparation'.)
●Skin biopsy techniques are discussed in detail separately. (See "Skin biopsy techniques".)
491
Longitudinal melanonychia - UpToDate
uptodate.com/contents/longitudinal-melanonychia/print
Literature review current through: Apr 2020. | This topic last updated: Feb 12, 2020.
INTRODUCTION Longitudinal melanonychia, also called "melanonychia

striata," describes a pigmented, brown to black, longitudinal streak of the nail plate due to increased
activity of melanocytes or melanocytic hyperplasia in the nail matrix, with increased melanin
deposition in the nail plate [1,2]. The most common type of longitudinal melanonychia due to
melanocytic activation is ethnic melanonychia, which typically presents in dark-skinned individuals
as multiple bands affecting multiple nails. Other causes of melanocytic activation include
pregnancy, chronic local trauma or inflammation, systemic conditions, and drugs (table 1). Nail
lentigo, nail melanocytic nevus, and nail melanoma are causes of longitudinal melanonychia due to
melanocytic hyperplasia.
492
This topic will discuss the pathophysiology, clinical presentation, diagnosis, differential diagnosis,
and management of longitudinal melanonychia. Other nail disorders are discussed separately. The
dermoscopic examination of nail pigmentations, nail biopsy and nail surgery techniques, and
surgical management of nail melanoma are also discussed separately.
●(See "Overview of nail disorders".)
●(See "Nail biopsy: Indications and techniques".)
●(See "Principles and overview of nail surgery".)
EPIDEMIOLOGY The prevalence of longitudinal melanonychia ranges

from approximately 1 percent in white and Asian populations to more than 70 percent in populations
with darker skin phototypes [3-5]. In a cross-sectional study of nearly 2500 Chinese outpatients,
longitudinal melanonychia was noted in 0.6 percent of patients aged 20 to 29 years and 1.7 percent
of those aged ≥50 years [4]. In a Japanese population, the prevalence of longitudinal melanonychia
was 11 percent. In another study of 482 Brazilian patients with skin phototypes IV to VI, longitudinal
melanonychia was present in 58 patients (12 percent).
PATHOPHYSIOLOGY The number of melanocytes in the nail unit

is low compared with normal skin. Melanonychia usually originates in the distal nail matrix because
melanocytes located in the proximal matrix are dormant, while approximately one-half of those
located in the distal matrix have the potential to become activated. Longitudinal melanonychia
results from either activation of previously dormant melanocytes or by proliferation (hyperplasia) of
melanocytes in the distal nail matrix [1,6-8].
Melanocytic activation occurs physiologically in dark-skinned individuals, hormonally driven during

pregnancy, or in response to a variety of stimuli, including inflammation or infection of the nail unit
(eg, nail psoriasis, nail lichen planus, onychomycosis), exposure to certain drugs, due to minor
repetitive trauma (frictional melanonychia), or in the setting of systemic disorders (eg, Addison
disease, Laugier-Hunziker syndrome, Peutz-Jeghers syndrome) (table 1). Melanocytic activation
(also termed "functional melanonychia," "melanocytic stimulation," or "hypermelanosis") causes an
increase in melanic pigmentation of the nail matrix epithelium without a concurrent increase in the
number of melanocytes [7].
Melanocytic hyperplasia (matrix melanocyte proliferation) is a less frequent cause of longitudinal

melanonychia and occurs in only three situations: nevus, lentigo, and melanoma. Benign
melanocytic hyperplasia results in lentigines and nevi of the nail matrix. Malignant melanocytic
hyperplasia includes in situ and invasive melanoma of the nail apparatus.
493
CLINICAL PRESENTATION
General features — Longitudinal melanonychia presents with one or more
longitudinal, pigmented bands running from the proximal nail fold to the distal free edge of the nail
plate (picture 1) [2]. Occasionally, the band can be wide or involve the entire nail plate (picture 2 and
picture 3). The color varies, from gray to light or dark brown to black. It occurs more frequently on
the thumbnail or the big toenail but may involve other nails or multiple nails (picture 4 and picture
5A-B).
Melanonychia due to melanocytic

activation — Melanonychia due to melanocytic activation, also called "functional
melanonychia," is the most common type of melanonychia seen in both adults and children. It
presents with regular, homogeneous, thin bands of brown color involving one or more nails.
Longitudinal melanonychia due to melanocytic activation is common in individuals with darker skin
types (ethnic melanonychia (picture 5A-B)). The number and width of the bands increases with age
[7]. Of note, a periungual hyperpigmentation (pseudo-Hutchinson sign) may be present [9]. (See
'Hutchinson sign and pseudo-Hutchinson sign' below.)
Longitudinal melanonychia can be seen in patients with chronic nail trauma (eg, nail biting,
onychotillomania), onychomycosis, and inflammatory skin diseases involving the nails (eg,
psoriasis, lichen planus (picture 6)) as well as in patients with a number of systemic diseases (eg,
Addison disease, Cushing syndrome, Peutz-Jeghers syndrome) (table 1). Exposure to certain drugs
and, in particular, to chemotherapeutic agents may also cause melanonychia due to melanocytic
activation [10]. In all these situations, multiple nails are typically involved.
Melanonychia due to melanocytic hyperplasia

Nail lentigo and nevus — Nail lentigines and nevi present as single-digit bands,
usually <5 mm in width, and light brown to dark brown or black in color (picture 7A-B) [7,11]. Nail
lentigines are seen more often than nevi in adults, while nail nevi are the most common cause of
longitudinal melanonychia in children [12,13]. In a review of 40 patients younger than 16 years with
longitudinal or total melanonychia, the histopathologic diagnosis was nevus in 19 patients, lentigo in
12, and melanocytic activation in 9 [12].
Nevi usually occur on the fingernails, with the thumbnail being most commonly affected. In some
cases, the pigmented band may be visible through the thin cuticle, resulting in an apparent
periungual pigmentation (pseudo-Hutchinson sign (picture 8)). (See 'Hutchinson sign and pseudo-
Hutchinson sign' below.)
494
Nail melanoma — Nail unit melanoma, also called subungual melanoma, is rare,
accounting for 1 to 3 percent of all melanomas occurring in white populations and 15 to 30 percent
of melanomas occurring in dark-skinned populations [14]. In approximately two-thirds of cases, nail
melanoma presents as a brown to black, longitudinal band involving a single nail [15]. The band is
generally wider than 3 mm; shows proximal widening and irregular or blurred, lateral borders; and
may be associated with nail plate dystrophy (picture 9A-C) [2]. A periungual pigmentation
(Hutchinson sign) may be present and supports the clinical diagnosis of melanoma (picture 9D and
picture 9C). (See 'Hutchinson sign and pseudo-Hutchinson sign' below.)
Early nail melanoma may appear as a narrow melanonychia band with subtle variegation of color
that is difficult to differentiate clinically and dermoscopically from a benign lentigo or nevus [16].
(See 'Dermoscopic examination (onychoscopy)' below.)
In approximately one-third of cases, nail melanoma is hypomelanotic or amelanotic and presents as

a nail bed mass or nail plate abnormality (picture 10).
Hutchinson sign and pseudo-Hutchinson

sign — The Hutchinson sign is the periungual spread of pigment into the proximal or lateral nail
folds [9,17]. It has been historically considered a pathognomonic sign of subungual melanoma
(picture 11). However, a periungual pigmentation may be seen in approximately one-third of cases of
nail lentigines or nevi and in other benign conditions, such as ethnic melanonychia (picture 5A),
melanonychia associated with Laugier-Hunziker syndrome or Peutz-Jeghers syndrome, and
melanonychia associated with the use of certain medications (table 2) [18,19]. In these
circumstances, it is referred to as "pseudo-Hutchinson sign" [7,9,17]. Of note, in some cases and
especially in children with melanocytic nevi of the nail matrix, the cuticle pigmentation is illusory due
to the pigmented band that shows through the transparency of the cuticle (picture 8).
PATIENT EVALUATION AND

DIAGNOSIS Longitudinal melanonychia involving multiple nails is in most cases
diagnosed clinically, based on physical examination and history. In contrast, the diagnosis of
longitudinal melanonychia involving a single nail may be challenging, especially when the onset is in
adulthood or when the patient reports a change (eg, widening, darkening) in a previously stable
band. In these cases, a nail matrix biopsy is required for accurate diagnosis.
Dermoscopy, which allows for the visualization of morphologic features that are not visible to the
naked eye, may help the clinician in the decision on whether to perform a nail matrix biopsy. (See
'Dermoscopic examination (onychoscopy)' below and 'When to biopsy' below.)
The approach to the clinical diagnosis and management of longitudinal melanonychia involving one
or multiple nails is illustrated in the algorithm (algorithm 1).
495
Clinical examination and history — The diagnosis of
longitudinal melanonychia starts with a careful examination of all nails to assess [2]:
●Number of involved nails
●Color and width of the band(s)
●Color homogeneity
●Presence of signs of trauma
●Presence of periungual pigmentation
●Presence of nail dystrophy or subungual nail lesions
Information on onset, progression, and possible triggers of melanonychia should be obtained from
the patient. Medical and drug history, history of digital trauma, and history of exposure to exogenous
substances (eg, tar, tobacco, dyes) can provide clues to the etiology of melanonychia [8].
Physiologic longitudinal melanonychia (ethnic [racial] melanonychia, pregnancy associated);

melanonychia associated with signs of local trauma; and melanonychia associated with
concomitant systemic diseases, dermatologic conditions (eg, fungal melanonychia), or drugs are in
most cases diagnosed by clinical examination and history and do not require further examination
(algorithm 1).
In contrast, unexplained longitudinal melanonychia involving a single nail, especially if presenting in

an adult patient, can be a diagnostic challenge. The clinical features that raise suspicion of
melanoma are reviewed below. (See 'Clinical features suspicious for nail melanoma' below and
'When to biopsy' below.)
Clinical features suspicious for nail

melanoma — Clinical features that may suggest early nail melanoma and warrant a
biopsy of the nail matrix in patients with longitudinal melanonychia include (algorithm 1) [1,20,21]:
●Melanonychia that develops during adulthood, involves a single digit (in particular, the thumb, index
finger, or great toe), and enlarges rapidly
●Longitudinal melanonychia >3 mm in width (picture 11) with variegated pigmentation or proximal
widening (triangular shape) (picture 9A, 9D)
●Pre-existing longitudinal melanonychia that becomes darker or wider or demonstrates blurred,

lateral borders
●Longitudinal melanonychia associated with nail plate fissuring, splitting, or dystrophy (picture 9B)
496
●Melanonychia extending to the nail folds (Hutchinson sign (picture 9C))
The ABCDEF mnemonic may also be helpful in recalling clinical features that raise suspicion of
melanoma [22]:
●Age of patient (peak incidence in the fifth to seventhdecade)
●Band of brown/black color, breadth greater than 3 mm, border (irregular/blurred)
●Change in the band (rapid increase in size or growth rate)
●Digit involved (in order of decreasing frequency: thumb > hallux > index finger > single digit >
multiple digits)
●Extension of pigment to the proximal or lateral nail fold (Hutchison sign) or free edge of nail plate
●Family history of melanoma
Dermoscopic examination (onychoscopy) — Nail

plate dermoscopy (onychoscopy) may help the clinician with at least minimal training in
dermoscopy in recognizing benign lesions that do not require further histologic examination from
lesions that require biopsy or regular follow-up. However, clinicians should be cognizant that
dermoscopy is not a substitute for histopathologic diagnosis and that it is important to maintain a
low threshold of suspicion for performing a biopsy for histopathologic examination:
●Melanonychia due to melanocytic activation appears as a gray background with thin, gray, regular,
parallel lines (picture 12). In melanocyte activation caused by chronic trauma, tiny, dark red to brown
spots corresponding to extravasation of blood may also be seen [1]. (See "Dermoscopy of nail
pigmentations", section on 'Benign lesions'.)
●Nail lentigines generally appear as homogeneous, longitudinal, thin, gray or brown lines on a gray
or light brown background; nail lentigines are more common in adults than in children.
●Nail nevi, which are more common in children than in adults, appear as a band of regular lines of
light brown to black color on a brown background (picture 13 and picture 14) [16,23].
●Dermoscopic features associated with nail melanoma include (picture 15A-B) [16,23,24]:
•Brown background hue
•Presence of irregular, longitudinal lines (in their color, spacing, thickness, and parallelism)
•Micro-Hutchinson sign (pigmentation of the cuticle seen on dermoscopy but not with the naked
eye)
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It is important to note that irregular lines that would be considered suspicious for melanoma in an
adult can often be seen in children with nail matrix nevi (picture 16 and picture 17). (See
"Dermoscopy of nail pigmentations", section on 'Benign lesions' and "Dermoscopy of nail
pigmentations", section on 'Melanonychia in children'.)
The dermoscopic evaluation and differential diagnosis of longitudinal melanonychia are discussed
in greater detail separately (algorithm 2). (See "Dermoscopy of nail pigmentations", section on
'Differential diagnosis of nail pigmentations'.)
When to biopsy — In most patients presenting with stable longitudinal

melanonychia involving multiple nails, a biopsy is not required to confirm the clinical diagnosis
(algorithm 1). (See 'Melanonychia due to melanocytic activation' above.)
In contrast, a clinician's threshold for biopsy should be low when examining a patient with a single
digit longitudinal melanonychia, especially if (algorithm 1):
●Onset occurred in adulthood
●Lesion is located on the thumb, index finger, or big toenail
●Lesion shows clinical features that suggest melanoma (see 'Clinical features suspicious for nail
melanoma' above)
●Lesion shows dermoscopic features suspicious for melanoma (see 'Dermoscopic examination
(onychoscopy)' above)
●Lesion is rapidly enlarging
In children, longitudinal melanonychia is in most cases due to a nevus of the nail matrix, while nail
melanoma is exceedingly rare, with only a few cases reported in the literature [12,25,26]. Thus, some
experts suggest to avoid nail matrix biopsy in children where possible, with the exception of cases in
which the band enlarges and/or darkens rapidly or involves the whole nail [27].
The techniques for performing a nail matrix biopsy are described elsewhere. (See "Nail biopsy:
Indications and techniques".)
Histopathologic diagnosis — Histopathologic examination is the gold

standard for the diagnosis of longitudinal melanonychia. However, differentiating early melanoma of
the nail matrix from benign melanocytic lesions may be challenging, even for the expert pathologist,
as some features (eg, cellular atypia, pagetoid spread, nest formation) can be seen in lentigines, nevi,
and in melanoma in situ:
●Melanocytic activation – Melanocytic activation is characterized by nonspecific, melanic

pigmentation of the matrix epithelium without an increase in the number of melanocytes. The
Fontana-Masson stain is helpful when the pigmentation is barely visible. There are some
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melanocytes with pigmented dendrites in the suprabasal layer of the proximal matrix and basal layer
of the distal matrix and pigmented keratinocytes; a few melanophages can be seen in the superficial
dermis [28,29]. Cytologic atypia is absent.
●Lentigo – Lentigo is characterized by a slight to moderate increase in the number of matrix

melanocytes (10 to 31 per mm) that are individually aligned in the basal layer without confluence
[28,29]. Cytologic atypia is absent or mild; pagetoid spread is rare or focal. The pigmentation is
usually limited to the lower third of the nail epithelium but can be observed throughout its full
thickness. Fontana-Masson staining shows fine granularity of the melanin pigment.
●Nevus – On microscopic examination, a melanocytic nevus of the nail matrix is characterized by

hyperplasia of melanocytes with nest formation. A lentiginous pattern can be seen at the center of
the lesion, along with a suprabasal pagetoid spread tendency, mild nuclear pleomorphism, and nail
plate involvement [29]. Periungual pigmentation can also be observed.
●Melanoma – Melanoma in situ is characterized by an increased number of melanocytes in the

basal cell layer (39 to 136 per mm), with a predominance of single melanocytes and a few nests
[20,28]. Nuclear atypia and pagetoid spreading are present. Atypical melanocytes have large,
hyperchromatic, pleomorphic nuclei; prominent nucleoli; increased mitoses; and long, branching
dendrites [6]. A dermal lymphoid infiltrate is present. The detection of melanocytes in the nail plate
corresponding to the matrix keratogenous zone is an important finding for malignancy [29].
Invasive melanoma is characterized by atypical melanocytes invading the dermis. The commonest
histogenic subtype is acral lentiginous, followed by nodular and desmoplastic [28]. (See "Pathologic
characteristics of melanoma", section on 'Acral lentiginous melanoma'.)
DIFFERENTIAL DIAGNOSIS Several nonmelanic

pigmentations of the nail plate may be confused with longitudinal melanonychia. These include (see
"Overview of nail disorders"):
●Subungual hematoma (picture 18)
●Exogenous discoloration
●Splinter hemorrhage (picture 19A-C)
●Fungal melanonychia (picture 20)
●Longitudinal erythronychia
●Onychopapilloma (picture 21)
●Pigmented onychomatricoma
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MANAGEMENT Longitudinal melanonychia is in most cases a benign
condition. A wait-and-see approach with periodic clinical and, if available, dermoscopic monitoring
may be appropriate in adults and children when clinical and dermoscopic features indicate a low risk
of melanoma [2,13,30]. (See 'Monitoring' below.)
Melanonychia should be excised when worrisome features suspicious for melanoma (eg, wide band,
presence of the Hutchinson sign, or irregular dermoscopic features) are noted. Additional surgery is
generally needed if the initial biopsy shows melanoma. Wide surgical excision of the entire nail
apparatus with margin control is a conservative option for subungual melanoma in situ; digit
amputation is the traditional surgical approach for invasive melanoma [31,32]. (See "Surgical
management of primary cutaneous melanoma or melanoma at other unusual sites", section on
'Subungual'.)
There is very limited evidence to guide the management of biopsied lesions displaying atypical
melanocytic hyperplasia, especially in children [33,34]. Some experts suggest that adult patients
with melanocytic hyperplasia with moderate to severe melanocytic atypia on biopsy should undergo
complete resection with margin control [33]. In children, given the extreme rarity of subungual
melanoma, clinical and dermoscopic surveillance for enlargement or changes may be reasonable
[34].
MONITORING There is no consensus on the frequency and modalities of

follow-up for pigmented nail bands. Some experts recommend clinical and dermoscopic
examination every six months for lesions that have subtle, irregular features that do not require
immediate biopsy [1,16]. Baseline medical photography of the nail in question, including
dermoscopy photos when possible, can be very helpful when clinically monitoring over time the
patient with longitudinal melanonychia.
SUMMARY AND
RECOMMENDATIONS
●Longitudinal melanonychia, also called "melanonychia striata," describes a pigmented, brown to
black, longitudinal streak of the nail plate resulting from increased melanin production and
deposition within the nail plate. This may result from melanocytic activation, due to multiple causes,
or from benign or malignant hyperplasia of melanocytes in the nail matrix (table 1). (See
'Introduction' above and 'Pathophysiology' above.)
●Longitudinal melanonychia presents with one or more pigmented bands running from the proximal
nail fold to distal margin of the nail plate (picture 1):
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•Melanonychia due to melanocytic activation, also called "functional melanonychia," is the most
common type of melanonychia seen in adult patients. It includes ethnic melanonychia, commonly
seen in patients with darker skin tones, melanonychia due to repeated trauma (frictional
melanonychia), and melanonychia associated with skin diseases, systemic diseases, or exposure to
drugs. (See 'Melanonychia due to melanocytic activation' above.)
•Melanonychia due to melanocytic hyperplasia includes benign lesions (lentigines and nevi of the
nail matrix) and nail melanoma. Nail lentigines and nevi present as single-digit bands, <5 mm in
width, and light brown to dark brown or black in color (picture 7A-B). Lentigines are seen more often
than nevi in adults, while nail nevi are the most common cause of longitudinal melanonychia in
children. (See 'Nail lentigo and nevus' above.)
●Nail melanoma presents in most cases as a brown to black, longitudinal band involving a single
nail, usually wider than 3 mm, that shows proximal widening and irregular or blurred, lateral borders
(picture 9B and picture 9C). A periungual pigmentation (Hutchinson sign) may be present and
supports the clinical diagnosis of melanoma (picture 9C and picture 9D and picture 11). However,
early melanoma can be clinically indistinguishable from lentigo or nevus. (See 'Nail melanoma'
above and 'Hutchinson sign and pseudo-Hutchinson sign' above.)
●The diagnosis of longitudinal melanonychia is in many cases clinical; however, a nail matrix biopsy
may be required in the following circumstances (algorithm 1) (see 'Patient evaluation and diagnosis'
above):
•Melanonychia that develops during adulthood, involves a single digit (in particular, the thumb, index
finger, or great toe), and enlarges rapidly
•Longitudinal melanonychia >3 mm in width (picture 11) with variegated pigmentation or proximal
widening (triangular shape)
•Pre-existing longitudinal melanonychia that becomes darker or wider or demonstrates blurred,

lateral borders
•Longitudinal melanonychia associated with nail plate fissuring, splitting, or dystrophy (picture 9B)
•Melanonychia extending to the nail folds (Hutchinson sign (picture 9C))
●Longitudinal melanonychia is in most cases a benign condition. A wait-and-see approach with

periodic clinical and dermoscopic monitoring may be appropriate in adults and children when
clinical and dermoscopic features indicate a low risk of melanoma. Surgical excision of the entire
lesion should be performed when there are worrisome features suspicious for melanoma. (See
'Management' above.)
●Additional surgery is needed following an initial biopsy showing melanoma. Wide surgical excision
of the entire nail apparatus with margin control is a conservative treatment option for subungual
melanoma in situ; digit amputation is the traditional approach for invasive melanoma. (See "Surgical
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management of primary cutaneous melanoma or melanoma at other unusual sites", section on
'Subungual'.)
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Erythroderma in adults - UpToDate
uptodate.com/contents/erythroderma-in-adults/print
Literature review current through: Apr 2020. | This topic last updated: Aug 26, 2019.
INTRODUCTION Erythroderma (literally, "red skin"), also sometimes

called exfoliative dermatitis, is a severe and potentially life-threatening condition that presents with
diffuse erythema and scaling involving all or most of the skin surface area (≥90 percent, in the most
common definition). Erythroderma is a clinical sign and, as such, may be the clinical presentation of
a wide range of cutaneous and systemic diseases (including psoriasis and atopic dermatitis), drug
hypersensitivity reactions, and, more rarely, Sézary syndrome, a leukemic subtype of cutaneous T
cell lymphoma. Although uncommon in pediatric patients, erythroderma may similarly be the clinical
503
presentation of a wide range of acquired and inherited diseases. The differential diagnosis for
erythroderma in pediatric patients includes infections, inflammatory skin diseases, ichthyoses, and
congenital immunodeficiencies.
This topic will discuss the clinical manifestations, diagnosis, and treatment of erythroderma in
adults. Erythroderma in neonates and infants and Sézary syndrome are discussed separately. (See
"Neonatal and infantile erythroderma" and "Clinical presentation, pathologic features, and diagnosis
of Sézary syndrome".)
EPIDEMIOLOGY Erythroderma is a rare condition. The annual incidence

has been estimated to be approximately 1 per 100,000 in the adult population [1]. In a retrospective
study, erythroderma accounted for 13 in 100,000 patients presenting with skin diseases in China [2].
Erythroderma can occur at any age and in both sexes, but is more frequent in older adults (mean age
42 to 61 years) and in males [2-6]. Erythroderma is exceedingly rare in children; its prevalence is
estimated to be approximately 0.1 percent in pediatric dermatology clinic populations [7,8].
ETIOLOGY A wide range of cutaneous or systemic diseases can evolve to or cause

erythroderma (table 1):
●Exacerbation of a preexisting inflammatory dermatosis – The most common cause of

erythroderma is the exacerbation of a preexisting inflammatory dermatosis, most often psoriasis or
atopic dermatitis [3-6,9,10]. In patients with psoriasis, triggers of erythroderma include the abrupt
discontinuation of systemic corticosteroids or other immunosuppressant therapy, systemic
illnesses, phototherapy burns, medications (eg, lithium, antimalarials), or HIV infection [11].
●Hypersensitivity drug reaction – A hypersensitivity drug reaction is the second most frequent
cause of erythroderma (approximately 20 percent of cases). A wide variety of drugs have been
reported to be associated with erythroderma, including penicillins, sulfonamides, carbamazepine,
phenytoin, and allopurinol (table 2) [4,12]. Multiple patterns of drug reaction, from
maculopapular/morbilliform eruption to drug reaction with eosinophilia and systemic symptoms to
toxic epidermal necrolysis, may present with erythroderma.
●Uncommon causes – Uncommon causes of erythroderma include cutaneous T cell lymphoma and
other hematologic and systemic malignancies, immunobullous diseases, connective tissue
diseases, and infections (table 1).
●Idiopathic – In approximately 30 percent of cases of erythroderma, no underlying cause is

identified and erythroderma is classified as idiopathic (sometimes called "red man syndrome," a term
which is also used to describe an infusion reaction to vancomycin) [11,13,14].
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PATHOGENESIS The pathogenesis of erythroderma is incompletely
understood. A complex interaction of cytokines (eg, interleukin-1, -2 and -8 and tumor necrosis
factor), chemokines, and intercellular adhesion molecules is believed to play a role in the massive
recruitment of inflammatory cells to the skin and elevated epidermal turnover. The increased mitotic
rate and decreased transit time of epidermal cells through the skin layers results in exfoliation, with
significant loss of proteins, amino acids, and nucleic acids through the skin.
Increased circulating levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell
adhesion molecule-1, and E-selectin) have been demonstrated in patients with erythroderma
secondary to psoriasis or eczema and in patients with Sézary syndrome [15,16].
Immunohistochemical studies demonstrate a predominantly Th1 cytokine profile in the dermal

infiltrates of patients with erythroderma associated with inflammatory dermatoses and a Th2 profile
in the dermal infiltrates of patients with Sézary syndrome [17]. These findings suggest that different
pathophysiologic mechanisms may lead to the relatively uniform clinical presentation of
erythroderma.
CLINICAL MANIFESTATIONS
Onset — Erythroderma may develop acutely over hours or days or evolve gradually over
weeks to months.
The onset is usually abrupt in drug hypersensitivity reactions. A morbilliform or urticarial eruption
may first appear anywhere on the skin, then erythematous patches increase in size and coalesce
into a generalized bright red erythema with occasional islands of sparing (picture 1A-B). Organ
involvement (eg, hepatitis, nephritis, pneumonia) may occur in DRESS (drug reaction with
eosinophilia and systemic symptoms). (See "Exanthematous (maculopapular) drug eruption" and
"Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Erythroderma from underlying cutaneous or systemic diseases usually develops more gradually.
Erythematous patches may occur anywhere on the skin, enlarge and coalesce over hours to days to
weeks to involve nearly the entire skin surface. Initially, the erythematous patches may have the
characteristics of the underlying disease, but the specific features of the underlying diseases are
often lost after erythroderma has fully developed.
Cutaneous signs and symptoms — By definition, over 90

percent of the skin is involved; the skin is red and warm to the touch (picture 1B). In light-skinned
patients, the color of the skin varies from bright pink (characteristic of a drug reaction) to a dusky
red (characteristic of chronic erythroderma from many causes). In patients with darker skin tones,
these features may be more subtle. Most patients complain of severe skin pain or itching.
505
Linear crusted erosions and secondary lichenification may result from rubbing and scratching in
chronic erythroderma. On palpation, the skin may feel leathery and indurated. Scaling is a common
feature, particularly in erythroderma that has been present for more than a week. Scales can be
large, small, or bran-like, and are particularly abundant in patients with underlying psoriasis.
Palmoplantar keratoderma (hyperkeratosis of the palms and soles) is most often associated with
pityriasis rubra pilaris (picture 2A), but also may occur in patients with Sézary syndrome (picture 3).
Nail pitting is characteristic of psoriasis (picture 4).
Moist, crusted lesions on the face and upper trunk often precede the development of erythroderma
in patients with pemphigus foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations,
and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.)
Hair (eg, telogen effluvium, scaling of the scalp) and nail changes (paronychia, nail dystrophy, and
onychomadesis [nail shedding]) may be present. Involvement of the eyelids manifests with
blepharitis, epiphora (excessive tearing), and ectropion (eyelid eversion). These features may be
particularly prominent in patients with chronic erythroderma secondary to Sézary syndrome. (See
"Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Skin
lesions'.)
Extracutaneous findings — Patients with erythroderma often appear

uncomfortable, shiver, and complain of feeling cold. Constitutional symptoms (eg, malaise, fatigue,
fever, or hypothermia) and signs of high output cardiac failure (eg, peripheral edema, tachycardia)
also may be present. (See "Clinical manifestations, diagnosis, and management of high-output heart
failure", section on 'Clinical manifestations'.)
Lymphadenopathy and hepatomegaly or splenomegaly may be observed in chronic erythroderma.

Lymph node biopsy often shows only the features of dermatopathic lymphadenopathy (a benign
reactive lymph node enlargement), but may be diagnostic of lymphoma in patient with cutaneous T
cell lymphoma (CTCL). (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma", section
on 'Lymph node and tissue biopsy'.)
Laboratory abnormalities — Nonspecific laboratory abnormalities may

occur in patients with erythroderma due to various causes, including leukocytosis, anemia, and
elevated erythrocyte sedimentation rate. Eosinophilia may be found in patients with DRESS. (See
"Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Laboratory
abnormalities'.)
Atypical lymphocytes with cerebriform nuclei (Sézary cells) are often observed in erythroderma
regardless of cause. Counts of Sézary cells greater than 20 percent of the circulating peripheral
blood lymphocytes are found in Sézary syndrome, a leukemic variant of cutaneous T cell lymphoma.
(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on
'Peripheral blood'.)
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CLINICAL COURSE Depending upon the cause, the erythema may
become generalized in hours to days, weeks, or months. Exfoliation typically begins two to six days
after the onset of erythema, starts in flexural areas, and rapidly extends to the entire body surface.
Scaling is particularly pronounced in patients with underlying psoriasis. Over weeks to months, hair
and nail changes may occur. (See 'Cutaneous signs and symptoms' above.)
The duration of erythroderma is highly variable. Erythroderma due to drug reactions usually resolves
in two to six weeks after stopping the culprit drug. In patients with drug reaction with eosinophilia
and systemic symptoms (DRESS), resolution of erythroderma may require many weeks to months.
(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Erythroderma due to underlying cutaneous or systemic diseases may persist for weeks, months, or
years.
COMPLICATIONS Erythroderma is relatively well tolerated by many

patients. However, some patients, particularly those at the extremes of age and patients with
comorbidities, may experience complications. (See 'Hemodynamic and metabolic disturbances'
below and 'Infection' below.)
Hemodynamic and metabolic

disturbances — Profound disturbances in fluid and electrolyte regulation,
thermoregulation, and metabolic balance occur with erythroderma. Increased skin perfusion leads to
fluid loss by transpiration, and consequent electrolyte imbalance. Heat loss, hypothermia, and
compensatory hypermetabolism associated with hyperthermia may occur. The shunting of the blood
through the skin due to peripheral vasodilation may result in high-output cardiac failure, especially in
older or compromised patients. (See "Causes and pathophysiology of high-output heart failure".)
Exfoliation of the skin results in significant protein loss that may exceed 9 g/m2 body surface per
day, particularly in patients with erythrodermic psoriasis [18]. The protein loss causes negative
nitrogen balance, hypoalbuminemia, edema, and muscle wasting.
Infection — Inflammation, fissuring, and excoriation increase the susceptibility of the

erythrodermic skin to bacterial colonization. Sepsis from Staphylococcus aureus, including
methicillin-resistant S. aureus, has been reported in erythrodermic patients and is of particular
concern in those who are HIV positive [19-22]. Widespread superinfection with herpes simplex virus
(Kaposi varicelliform eruption) also has been reported in erythrodermic patients [23,24]. (See
"Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia" and
"Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection",
section on 'Eczema herpeticum'.)
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DIAGNOSIS The diagnosis of erythroderma is straightforward; it is made
clinically in a patient presenting with diffuse and generalized erythema and scaling involving 90
percent or more of the body surface area (picture 1A-B). Determining the cause of erythroderma is
more difficult and requires meticulous clinical assessment and clinicopathologic correlation.
DETERMINATION OF UNDERLYING
CAUSE The underlying cause of erythroderma is often difficult to determine and may
remain elusive. In approximately one third of patients, the cause cannot be determined and
erythroderma is classified as idiopathic. However, ongoing evaluation of patients with idiopathic
erythroderma is important, since the underlying cause may become apparent over time [13,14].
The evaluation of the erythrodermic patient to determine the underlying cause involves a detailed
history, physical examination, skin biopsies, and laboratory tests. Specific tests are performed based
upon the suspected cause.
History — A detailed history is of key importance in establishing the cause of erythroderma.

Important elements of history are:
●History of presenting illness – Onset of symptoms and course of erythroderma
●Past dermatologic and medical history – History of inflammatory skin disease (eg, psoriasis, atopic
dermatitis), preexisting systemic diseases or neoplasia
●Medication history, including over-the-counter medications and supplements
●Family history of inflammatory skin diseases
Physical examination — Physical examination should include a complete

examination of the skin, hair, nails, and mucosae for any sign of underlying skin disease. Lymph
node and organ enlargement should be assessed.
Clinical signs that are nonspecific but may be helpful in suggesting the cause of erythroderma
include:
●Color of erythema – In light-skinned patients, the color of the erythema may be helpful in
ascertaining the diagnosis. Salmon pink/orange color with islands of sparing is typical of pityriasis
rubra pilaris (picture 1A) [25]. A deeper red color associated with exfoliation is associated with
psoriasis or cutaneous T cell lymphoma (picture 1B).
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●Scaling – Severe scaling may indicate psoriasis. Crusted scales are seen in pemphigus foliaceus,
whereas exfoliation of large skin sheets is seen in drug reactions. Scaling between the fingers or
burrows involving the web spaces may indicate scabies.
●Bullae – The presence of bullae and the involvement of the mucous membranes may indicate
immunobullous disease (eg, pemphigus, bullous pemphigoid). Moist, crusted lesions on the face
and upper trunk often precede the development of erythroderma in patients with pemphigus
foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus",
section on 'Pemphigus foliaceus'.)
●Keratoderma – Waxy keratoderma of palms and soles with an orange hue is characteristic of
pityriasis rubra pilaris (picture 2A-B), but may also be observed in Sézary syndrome (picture 3).
●Nail abnormalities – Nail thickening, subungual hyperkeratosis, and splinter hemorrhages are
found in psoriasis and pityriasis rubra pilaris (picture 6) [2,26,27]. The presence of nail pitting is a
clue to the diagnosis of erythrodermic psoriasis (picture 4).
●Hair abnormalities – Diffuse alopecia is common in erythroderma from all causes but may be
particularly prominent in Sézary syndrome (picture 7) [28].
●Oral involvement – Oral mucositis is seen in most cases of erythroderma associated with
immunobullous disease, Stevens-Johnson syndrome/toxic epidermal necrolysis, and graft-versus-
host disease.
●Eye involvement – Conjunctival involvement is frequently seen in erythroderma associated with

immunobullous diseases, such as mucous membrane pemphigoid, and Stevens-Johnson
syndrome/toxic epidermal necrolysis. Chronic conjunctivitis may be complicated by the
development of trichiasis and symblepharon and may be associated with the development of sicca
syndrome and corneal perforation.
●Genitourinary involvement – The genitourinary tract may be involved in erythroderma associated

with mucous membrane pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis.
Skin biopsy and histopathologic

examination — Multiple skin biopsies may be necessary to identify the cause of
erythroderma. Skin samples are usually obtained by punch biopsy of multiple involved sites. (See
"Skin biopsy techniques", section on 'Punch biopsy'.)
The histopathology of erythroderma may reflect the underlying etiology. However, histology is more
often unrevealing or nonspecific. Hyperkeratosis, acanthosis, spongiosis, and perivascular
inflammatory infiltrate are frequent findings in erythroderma. The relative prominence of these
features may vary with the stage of the disease and the severity of inflammation (table 3) [29-31].
More specific histopathologic changes may become apparent later in the course of the disease.
Therefore, repeated skin biopsies over time may be needed to establish the diagnosis.
509
As an example, in the initial phase of Sézary syndrome histology may show a nonspecific
perivascular lymphocytic infiltrate without atypical lymphocytes and an overlying hyperplastic and
parakeratotic epidermis (picture 8) [29]. At a later stage, the infiltrate may become increasingly
pleomorphic and acquire specific diagnostic features, such as atypical cerebriform mononuclear
cells and Pautrier microabscesses (picture 8). (See "Clinical presentation, pathologic features, and
diagnosis of Sézary syndrome", section on 'Light microscopic findings'.)
Immunohistochemistry and T cell receptor gene rearrangement studies should be performed if

atypical lymphocytes are identified in the inflammatory infiltrate by routine histologic examination.
The demonstration of an immunophenotype of T cells lacking mature T cell antigens (CD3+, CD4+,
CD7-) and the clonality of the T cell receptor gene rearrangement support the diagnosis of Sézary
syndrome. The expression of the programmed death-1 (PD-1) may also be helpful in differentiating
Sézary syndrome from erythroderma associated with inflammatory skin diseases. In one study PD-1
was expressed by over 50 percent of neoplastic CD4+ T cells in 23 of 25 biopsies from patients with
Sézary syndrome and only in 4 of 30 biopsies from patients with erythroderma associated with
inflammatory skin diseases [32]. (See "Clinical presentation, pathologic features, and diagnosis of
Sézary syndrome", section on 'Immunophenotyping confirming T cell origin (CD3+, CD4+)' and
"Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Clonality
of the T cell receptor (TCR) gene rearrangement'.)
A predominance of CD8+ lymphocytes in the dermal infiltrate suggests chronic actinic dermatitis
(actinic reticuloid). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations,
diagnosis, and treatment", section on 'Chronic actinic dermatitis'.)
Direct immunofluorescence should be performed if an immunobullous disease is suspected based

upon the presence of intraepidermal bullae or subepidermal bullae or an urticarial appearance of the
erythroderma. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on
'Direct immunofluorescence' and "Clinical features and diagnosis of bullous pemphigoid and
mucous membrane pemphigoid", section on 'Direct immunofluorescence'.)
In approximately 30 percent of cases, the histologic features of erythroderma remain nonspecific

throughout its course and a precise diagnosis of the underlying condition cannot be made.
Laboratory and imaging tests — Laboratory testing is based upon

the patient's medical history, clinical presentation, and suspected cause of erythroderma. The initial
laboratory evaluation includes:
●Complete blood cell count and differential. Leukocytosis is common in all types of erythroderma.
Eosinophilia >700/microL may be found in drug reaction with eosinophilia and systemic symptoms
(DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on
'Laboratory abnormalities'.)
●Routine biochemistry tests including electrolytes, glucose, serum albumin, LDH, liver and kidney
function tests.
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●Examination of a peripheral blood smear for the presence of Sézary cells (atypical lymphocytes
with cerebriform nuclei). Counts of Sézary cells >20 percent of examined lymphocytes suggest
Sézary syndrome; counts <10 percent can be found in erythrodermas of different etiologies and are
considered nonspecific. (See "Clinical presentation, pathologic features, and diagnosis of Sézary
syndrome", section on 'Peripheral blood'.)
●Bacterial cultures and assessment of antimicrobial susceptibilities, fungal cultures, and swabs for
polymerase chain reaction tests for herpes simplex virus and varicella zoster virus should be
performed if superinfection of skin lesions is suspected. (See "Diagnosis of varicella zoster virus
infection", section on 'Polymerase chain reaction' and "Epidemiology, clinical manifestations, and
diagnosis of herpes simplex virus type 1 infection", section on 'Polymerase chain reaction'.)
Specific tests that may be helpful in determining the underlying cause of erythroderma include:
●Peripheral blood flow cytometry and T cell clonality – Immunophenotyping and T cell receptor
gene rearrangement studies should be performed to confirm or to rule out the diagnosis of Sézary
syndrome. Findings that support the diagnosis of Sézary syndrome include: absolute Sézary cell
count ≥1000/microL; CD4:CD8 ratio greater than 10; aberrant expression of pan-T cell markers
including CD2, CD3, CD7; deficient expression of CD26 and CD7 (CD4+CD26- ≥30 percent and
CD4+CD7- ≥40 percent); and evidence of a circulating T cell clone [33]. (See "Clinical presentation,
pathologic features, and diagnosis of Sézary syndrome", section on 'Peripheral blood'.)
●Studies for immunobullous and autoimmune disease – Direct immunofluorescence studies of skin
biopsy specimens are essential for the diagnosis of immunobullous disease. Biopsies should be
taken in perilesional skin (erythematous areas close to bullae or erosions). The detection of
circulating autoantibodies anti-desmoglein 1 and 3 or anti-bullous pemphigoid antigens BP180 or
BP230 confirms the diagnosis of pemphigus or bullous pemphigoid, respectively. (See
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Serology' and
on 'Antigen-specific serologic testing'.)
The presence of antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens
(ENA) suggests the diagnosis of lupus erythematosus or other autoimmune disease. (See "Overview
of cutaneous lupus erythematosus", section on 'Diagnosis'.)
Raised ANA and increased serum levels of muscle enzymes can confirm a clinical suspicion of
dermatomyositis; myositis-specific antibodies (eg, Jo-1 and other antisynthetases, anti-Mi-2, SRP,
PM-Scl) may be helpful in identifying subsets of dermatomyositis (picture 9). (See "Clinical
manifestations of dermatomyositis and polymyositis in adults".)
●Skin scrapings – Scrapings of burrows for mites should be performed and examined under a
microscope in patients with suspected crusted scabies. Potassium hydroxide (KOH) preparations
may be useful to identify hyphae and arthrospores if a generalized dermatophyte infection is
suspected. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Scabies
preparation' and "Dermatophyte (tinea) infections", section on 'Diagnosis'.)
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●Imaging studies – In patients in whom erythroderma is suspected to be the manifestation of occult
malignancy, radiologic workup may include chest radiograph, computed tomography (CT) or
magnetic resonance imaging (MRI) (or, alternatively, positron emission tomography/computed
tomography [PET/CT]) of the abdomen and pelvis, colonoscopy, mammography in women, or
ultrasonography of the prostate in men.
TREATMENT
Initial management — Patients with acute or symptomatic erythroderma and
patients who are in any way unstable (particularly patients who are hemodynamically unstable) may
require hospitalization for initial evaluation and treatment. Regardless of the specific etiology, the
initial management involves:
●Assessment and management of skin
●Symptomatic treatment of skin inflammation and pruritus
●Assessment and management of oral mucosa, eyes, genitourinary tract
●Monitoring of the hemodynamic status
●Replacement of fluid and electrolytes
●Monitoring of body temperature
●Nutritional support
●Treatment of cutaneous superinfections
Patients should be placed in a warm (30 to 32°C) and humid environment to prevent hypothermia.
Symptomatic relief of skin pain and itching may include intensive skin care with emollients and wet
dressings.
For the symptomatic treatment of skin inflammation and pruritus, we also suggest low- to mid-
potency topical corticosteroids. We generally use low-potency topical corticosteroids (groups six
and seven (table 4)) for the face and body folds and mid-potency corticosteroids (groups four and
five) for other body areas two to three times per day until improvement.
Oral antihistamines may be helpful in reducing itching in some patients. We prefer first-generation
antihistamines for their sedating effect, especially at night to help with sleep (eg, diphenhydramine
[25 to 50 mg orally every four to six hours for adults and children ≥12 years] or hydroxyzine [25 mg
orally three to four times per day for adults and children ≥6 years]).
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Cutaneous infection from S. aureus, including methicillin-resistant S. aureus, is common and requires
prompt institution of systemic antibiotic therapy. (See "Methicillin-resistant Staphylococcus aureus
(MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Antibiotic selection'.)
Cutaneous infection with herpes simplex virus requires treatment with antiviral medications such as
acyclovir, valacyclovir, or famciclovir. (See "Treatment of herpes simplex virus type 1 infection in
immunocompetent patients", section on 'Oral antiviral therapy'.)
If eyes appear involved, ophthalmologic assessment is appropriate. If oral involvement precludes

eating and drinking, consideration can be given to placement of a nasogastric tube or intravenous
fluids. If genitourinary involvement is present, consideration can be given to placement of a urinary
catheter.
Treatment of underlying conditions — After the underlying

etiology of erythroderma has been determined, appropriate treatment of the underlying condition
should be added to the initial management measures. (See 'Initial management' above.)
If a drug hypersensitivity reaction is suspected, all medications that are not essential should be
withdrawn. For these patients, a short course of moderate/high-dose systemic corticosteroids (eg,
prednisone 1 to 2 mg/kg per day) may be beneficial. (See "Exanthematous (maculopapular) drug
eruption", section on 'Management' and "Drug reaction with eosinophilia and systemic symptoms
(DRESS)", section on 'Management'.)
If a patient has Stevens-Johnson syndrome/toxic epidermal necrolysis, consideration should be

given to moving the patient to an environment where expert skin care can be appropriately provided
(eg, burn unit, intensive care unit with expert nursing). (See "Stevens-Johnson syndrome and toxic
epidermal necrolysis: Management, prognosis, and long-term sequelae".)
Patients with erythrodermic psoriasis require systemic therapies including methotrexate,

cyclosporine, acitretin, or biologics (eg, infliximab, etanercept, adalimumab, ustekinumab) [34,35].
(See "Treatment of psoriasis in adults", section on 'Erythrodermic psoriasis'.)
Patients with erythrodermic atopic dermatitis may benefit from systemic corticosteroids or other
immunosuppressants such as cyclosporine, methotrexate, or azathioprine, although most patients
respond to intensive topical treatments alone. (See "Treatment of atopic dermatitis (eczema)".)
Patients with Sézary syndrome may require systemic and skin-directed therapies that target the
circulating Sézary cells and control the skin manifestations. These treatments, which include
extracorporeal photochemotherapy, systemic retinoids, methotrexate, interferon, and brentuximab
vedotin, are discussed separately. (See "Treatment of advanced stage (IIB to IV) mycosis
fungoides".)
For patients with pityriasis rubra pilaris, treatment options include systemic retinoids, methotrexate,
TNF-alpha inhibitors, cyclosporine, and azathioprine. (See "Pityriasis rubra pilaris".)
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Management of patients with idiopathic
erythroderma — There are no specific treatments for idiopathic erythroderma. Most
patients respond to skin care measures (eg, wet dressings) and symptomatic treatment of skin
inflammation with low- to mid-potency topical corticosteroids and oral antihistamines. (See 'Initial
management' above.)
Patients who fail to respond to topical treatments are often empirically treated with systemic
corticosteroids or other immunosuppressants (eg, methotrexate, cyclosporine). However, evidence
for efficacy of systemic corticosteroids or other immunosuppressant therapy for patients with
erythroderma is scant and limited to small case series and their use in the absence of a precise
diagnosis remains controversial [2,4,14,36]. (See 'Initial management' above.)
For patients with idiopathic erythroderma that does not respond to topical therapy, systemic agents
may be considered if symptoms are severe. We suggest initial treatment with systemic
corticosteroids rather than methotrexate or cyclosporine because they have a more rapid onset of
action (usually within days rather than weeks). We generally use prednisone 0.5 to 1 mg/kg per day
for 7 to 10 days up to a maximum dose of 60 mg per day; prednisone is then slowly tapered over
several weeks to minimize the chances of rebound. During this time other immunosuppressive
agents, such as methotrexate, azathioprine, or mycophenolate mofetil, can be introduced.
A frequent problem with this regimen is that patients have a great difficulty in weaning from
prednisone because of the high chance of rebound after the interruption of treatment. Patients
should be monitored for potential adverse effects from systemic corticosteroids (in particular, fluid
retention, hypertension, hyperglycemia, increased risk of infection). (See "Major side effects of
systemic glucocorticoids".)
Cyclosporine (4 to 5 mg/kg per day) or methotrexate (10 to 20 mg weekly) may be alternative

therapies for patients for whom systemic corticosteroids are contraindicated. However, these agents
have a slower onset of action and a less predictable antiinflammatory effect than systemic
corticosteroids. Cyclosporine or methotrexate may be continued until the erythroderma is under
control and then gradually weaned to the lowest dose that satisfactorily controls the skin
inflammation. It is generally recommended that cyclosporine be used for less than one year to avoid
renal damage. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Monitoring — It is important that patients with idiopathic erythroderma be reevaluated

periodically, at least every six months. Over time, repeated skin biopsies and other laboratory or
imaging studies may reveal the underlying cause of erythroderma.
PREVENTION Relapses of erythroderma may be prevented by controlling the

underlying cause and avoiding triggers. Known triggers of erythroderma in patients with psoriasis or
atopic dermatitis include the abrupt discontinuation of corticosteroids or other
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immunosuppressants; topical application of irritants; medications (eg, lithium salts and
antimalarials in patients with psoriasis); and phototherapy burns. Patients with a history of
erythrodermic drug eruption must avoid reexposure to the culprit drug.
PROGNOSIS Erythroderma is a serious disorder associated with both increased

morbidity and mortality. The mortality rate for erythroderma ranges from 4 to 64 percent, with higher
rates reported in older case series. Advanced age, comorbidities, and need for hospitalization are
associated with unfavorable prognosis. In a population-based cohort study from Denmark, 31 and
40 percent of patients with erythrodermic psoriasis and exfoliative erythroderma, respectively, died
within the first three years following hospital admission, compared with 14 percent of patients
hospitalized for severe psoriasis vulgaris [37].
The prognosis may vary depending upon the underlying condition:
●Erythroderma secondary to psoriasis or atopic dermatitis usually improves within several weeks to
several months after starting appropriate treatment. However, chronic or recurrent erythroderma is
not uncommon in these patients [38].
●Erythroderma due to drug reactions usually resolves in two to six weeks after stopping the culprit
drug but can last for longer.
●Erythroderma in Sézary syndrome and paraneoplastic erythroderma are often refractory to therapy
and have a poor prognosis [39,40].
●Most patients with idiopathic erythroderma have a favorable prognosis. However, they require
clinical monitoring because the underlying diagnosis may become apparent over months to years
(see 'Monitoring' above). In some of these patients, erythroderma may represent a prelymphomatous
condition. In a study of 28 patients with idiopathic erythroderma observed over a mean period of 33
months, 15 improved, 10 went into remission, and 2 patients developed a cutaneous T cell
lymphoma [13]. In another study, 4 of 38 patients with erythroderma of unknown etiology followed
up for a median of 30 months developed mycosis fungoides [14].
SUMMARY AND
RECOMMENDATIONS
●Erythroderma (exfoliative dermatitis) is a severe and potentially life-threatening condition that
presents with diffuse erythema and scaling involving ≥90 percent of the skin surface area. (See
●The most common causes of erythroderma include exacerbation of a preexisting inflammatory

dermatosis, hypersensitivity reactions to drugs, and cutaneous T cell lymphomas. Less common
causes of erythroderma are summarized in the table (table 1). In approximately one third of patients,
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the cause of erythroderma remains undetermined (idiopathic erythroderma); this group requires
repeated reassessment as the underlying diagnosis may become apparent over months to years.
(See 'Etiology' above.)
●Erythroderma may develop acutely over hours or days or evolve gradually over weeks to months.
Patients typically present with erythematous patches that increase in size and coalesce into a
generalized bright red erythema with occasional islands of sparing (picture 1A-B). The skin feels
warm to the touch and dry. Patients appear uncomfortable, shiver, and complain of feeling cold.
Scaling begins two to six days after the onset of erythema and may become prominent.
Extracutaneous symptoms include fever or hypothermia, peripheral edema, and tachycardia. (See
'Clinical manifestations' above and 'Clinical course' above.)
●Erythroderma is relatively well tolerated by many patients. However, patients at the extremes of age
and patients with comorbidities may experience complications, including high-output heart failure,
fluid and electrolytic imbalance, heat loss, hypothermia, compensatory hypermetabolism, protein
loss and negative nitrogen balance, hypoalbuminemia, edema, muscle wasting, and secondary skin
infection. (See 'Complications' above.)
●Determining the cause of erythroderma is often difficult and involves a detailed history, physical
examination, skin biopsy, and laboratory studies. In some cases histology reveals the underlying
etiology (table 3), but it is more often nonspecific, and repeated skin biopsies may be necessary.
(See 'Diagnosis' above.)
●Patients who are hemodynamically unstable or those with severe symptoms may require
hospitalization. Regardless of the specific etiology, the initial management involves:
•Replacement of fluid and electrolytes
•Monitoring of the hemodynamic status
•Monitoring of body temperature
•Nutritional support
•Symptomatic treatment of skin inflammation and pruritus
•Treatment of edema
•Treatment of cutaneous superinfections
●For the symptomatic treatment of skin inflammation and pruritus, we suggest topical
corticosteroids and oral antihistamines (Grade 2C). We generally use low-potency to mid-potency
topical corticosteroids (groups 4 to 7 (table 4)) two to three times per day until improvement. (See
'Initial management' above.)
●After the underlying etiology of erythroderma has been determined, appropriate treatment of the
underlying condition must be initiated promptly. (See 'Treatment of underlying conditions' above.)
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●For patients with idiopathic erythroderma that does not respond to topical therapy, we suggest
systemic corticosteroids rather than methotrexate or cyclosporine (Grade 2C). We generally use
prednisone 0.5 to 1 mg/kg per day for 7 to 10 days. Prednisone is then slowly tapered over several
weeks to avoid rebound while introducing other immunosuppressive treatments. (See 'Management
of patients with idiopathic erythroderma' above.)
●Patients with idiopathic erythroderma should be closely monitored with clinical, histologic,
laboratory, or imaging evaluation, since an underlying etiology may become apparent over time. (See
'Monitoring' above.)
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Acquired hyperpigmentation disorders - UpToDate
uptodate.com/contents/acquired-hyperpigmentation-disorders/print
Literature review current through: Apr 2020. | This topic last updated: Nov 21, 2019.
INTRODUCTION Disorders of cutaneous discoloration comprise a large

group of skin conditions characterized by an increase of chromophores of melanotic origin
(hyperpigmentation) and/or an increase of nonmelanotic chromophores (hyperchromias) [1,2].
Hyperpigmentation is the darkening or increase in the natural color of the skin, usually due to an
increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. Less frequently, it
may be caused by the deposition in the dermis of endogenous or exogenous pigments, such as
hemosiderin, iron, or heavy metals.
Hyperpigmentation is a feature of a multitude of clinical conditions, ranging from normal variations

of skin color to acquired and inherited syndromes, and is one of the most common reasons for
dermatologic consultation, particularly in patients with darker skin types [1,3,4]. Although
hyperpigmentation is not harmful, it can cause significant cosmetic disfigurement and become a
persistent psychosocial burden for the patient, due to the limited efficacy of the available treatments.
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This topic will review the approach to the patient with acquired hyperpigmentation disorders.
Melasma and postinflammatory hyperpigmentation are discussed separately. Congenital and
inherited hyperpigmentation disorders are also discussed separately.
●(See "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis".)
●(See "Melasma: Management".)
●(See "Postinflammatory hyperpigmentation".)
●(See "Congenital and inherited hyperpigmentation disorders".)
PATHOPHYSIOLOGY OF
HYPERPIGMENTATION
Determinants of skin color — The color of human skin is mainly
determined by the two types of melanin, the black-brown eumelanin and the yellow-red pheomelanin.
Other significant determinants are the capillary blood flow, chromophores such as carotene or
lycopene, and the collagen content of the dermis.
Eumelanin and pheomelanin are present in individuals of all skin colors, but their ratio is highly
variable and determines the hue of the skin [5]. Differences in the number, size, and aggregation of
melanosomes within the melanocytes and keratinocytes, but not in the overall number of
melanocytes, contribute to ethnic differences in skin color [6,7]. Darker skin types have a higher
content of melanin, higher eumelanin-to-pheomelanin ratio, nonaggregated and larger
melanosomes,and slower melanosome degradation within the keratinocytes [8].
Melanin — Melanin is produced by melanocytes, specialized cells of neural crest origin that
reside in the basal layer of the epidermis. The biosynthesis of melanin occurs in lysosome-like
organelles called melanosomes, which are transported to the cell periphery and transferred from the
dendritic tips of the melanocytes to the surrounding keratinocytes [9]. Each melanocyte is
associated with approximately 36 basal keratinocytes to form the so-called epidermal melanin unit.
Melanin synthesis is triggered by the hydroxylation of L-phenylalanine to L-tyrosine or directly from

L-tyrosine. Tyrosinase hydroxylates L-tyrosine to 3,4-L-dihydroxyphenylalanine (L-DOPA), which
further undergoes oxidation to dopaquinone. Thereafter, two main pathways diverge, leading to
production of black-brown eumelanin and yellow-red pheomelanin. Melanin synthesis is regulated by
multiple complex signaling pathways, including melanocyte-stimulating hormones (MSH)/cAMP and
KIT [9].
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Hypermelanosis — Skin hyperpigmentation is in most cases caused by increased
biosynthesis and deposition of melanin in the epidermis and/or dermis. Epidermal hypermelanosis
results from an excess of melanin in the basal and suprabasal layers of the skin due to increased
melanin production either by an abnormally high number of melanocytes or by a normal melanocyte
population. These abnormalities may be due to both acquired and genetic factors.
The normal dermis does not contain melanin. Dermal hypermelanosis may develop through several
mechanisms:
●Transfer of melanin from the epidermis to the dermis and accumulation within melanophages
("pigmentary incontinence"). This process is commonly observed in inflammatory skin diseases that
involve a damage of the basal layer and/or the dermoepidermal junction.
●Production of melanin by ectopic dermal melanocytes. Examples of dermal melanocytosis are the
nevus of Ota and nevus of Ito.
●Binding of melanin to exogenous pigments deposited in the dermis.
Other pigments — Cutaneous hyperpigmentation can be caused by the deposition

in the dermis of endogenous or exogenous pigments, such as hemosiderin, iron, or heavy metals.
Recurrent extravasation of red blood cells in the dermis leads to deposition of hemosiderin, resulting
in a red-brown discoloration of the skin. Dermal hyperpigmentation mimicking dermal
hypermelanosis can be caused by topical or systemic exposure to heavy metals (eg, silver, gold,
mercury). Some metals, such as iron, may also stimulate melanogenesis, as observed in patients
with hemochromatosis.
PATIENT EVALUATION AND

DIAGNOSIS The diagnosis of hyperpigmentation disorders may be challenging.
An algorithmic approach to the diagnosis based upon history and clinical parameters is shown in
the figure (algorithm 1). In most cases, the initial patient evaluation involves a detailed family and
personal medical history and a complete physical examination, which should include a careful
search for additional cutaneous and extracutaneous signs and symptoms.
Questions that may be useful for the evaluation of patients with hyperpigmentation disorders
include [10]:
●Is the disorder congenital or acquired?
●Is the pigmentation localized or diffuse?
●Is the pigmentation well circumscribed or ill defined?
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●Does the pigmentation have a pattern (eg, linear, reticular)?
●Is the pigmentation associated with inflammation and/or prior cutaneous injury?
●Is the pigmentation stable, progressing, or regressing?
●Does the patient have concomitant systemic diseases?
●Does the patient have a history of exposure to a new medication?
History — A detailed medical history should be obtained from the patient to determine if the
hyperpigmentation is related to an underlying disease. The possibility of drug-induced pigmentation
must be kept in mind. Patients should also be questioned about occupational and or hobby-related
exposure to chemicals that may cause hyperpigmentation.
The course of the disorder is also a useful parameter in the clinical diagnosis of hyperpigmentation
disorders. Inherited disorders of hyperpigmentation are often stable, whereas most acquired forms
show progression or regression.
Skin examination — In all patients with hyperpigmentation disorders, a complete

skin examination should be performed under visible light and Wood's light. Important clinical
parameters include:
●Extent of the pigmentary abnormality (localized versus diffuse)
●Color hue (shades of brown/black, slate-gray/blue)
●Morphology of individual lesions
●Distribution (eg, sun-exposed areas, areas previously involved by inflammatory processes)
●Pattern (eg, linear, reticular, nonfigurate)
A careful search for associated cutaneous and extracutaneous signs and symptoms may provide
important clues to the diagnosis, particularly in patients with hyperpigmentation disorders
associated with systemic diseases or genetic syndromes.
Wood's light examination — Wood's light, also known as "black light," is

ultraviolet A light with a peak emission at 365 nm [11]. The patient is examined in a darkened room
with the light source held at 10 to 15 cm from the skin. Wood's light can be helpful in determining
whether the pigment deposition is predominantly epidermal, dermal, or mixed; however, its
effectiveness is limited in patients with darker skin tones [12,13].
521
●Epidermal hypermelanosis – Under natural light, epidermal hypermelanosis appears light brown to
dark brown in color. The pigmentation, as well as the contrast between involved and uninvolved skin,
is enhanced when viewed under a Wood's lamp.
●Dermal hypermelanosis – Under natural light, dermal hypermelanosis has a bluish or ashen gray
hue with margins less defined than epidermal hypermelanosis. The pigmentation is not accentuated
by the Wood's light.
●Mixed hypermelanosis – Mixed hypermelanosis appears light to dark brown under natural light,
whereas Wood's light examination will show enhancement in some areas and none in others.
Reflectance confocal microscopy — In vivo reflectance

confocal microscopy is a technique that allows noninvasive imaging of the epidermis and papillary
dermis at histologic resolution [14]. The confocal microscope emits a near-infrared light from a
diode laser source focused on a microscopic skin target. As this light penetrates cellular structures
with different refraction indexes, it is naturally reflected and then captured and recomposed by
computer software into a two-dimensional grayscale image [15,16].
Reflectance confocal microscopy is not widely available and is mainly employed in research
settings. However, it is a promising technique to diagnose and/or monitor treatment of hypo- and
hyperpigmentation disorders without performing repeated biopsies [17,18].
Skin biopsy — A skin biopsy for histopathologic evaluation is not routinely performed
for the diagnosis of hyperpigmentation disorders. However, it may be necessary when the clinical
diagnosis is uncertain. Standard stains (eg, hematoxylin and eosin, Fontana-Masson silver stain)
and histochemical techniques (eg, Mart-1, Melan-A) are used to evaluate the number and localization
of melanocytes and melanin granules in the epidermis and dermis. The main histopathologic
findings in selected hyperpigmentation disorders are summarized in the table (table 1).
CIRCUMSCRIBED
HYPERPIGMENTATION
Ephelides — Ephelides or freckles are small, well-demarcated, hyperpigmented macules,
usually 2 to 4 mm in diameter, that occur most frequently in individuals with red or blond hair and
fair complexion (picture 1). They first appear during early childhood on sun-exposed skin and are
most numerous on the face, dorsal hands, and upper trunk. Ephelides increase in number, size, and
depth of pigmentation during the summer months and are smaller, lighter, and fewer in number in
the winter. Melanocortin-1 receptor gene variants play a role in the development of ephelides [19,20].
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Ephelides are benign lesions and have no propensity for malignant transformation[21].
Histologically, there is a normal epidermis and normal number of melanocytes with large
melanosomes, resembling those seen in dark-skinned individuals.
Treatment involves the use of sun-protective measures. Additional treatment is for cosmetic
purposes only. Topical retinoids and depigmenting agents may lighten lesions to a minimal extent.
Pigment-specific lasers and light-based therapy are additional therapeutic modalities [22]. (See
"Laser and light therapy for cutaneous hyperpigmentation".)
Lentigines
Simple lentigines — Lentigines are benign pigmented macules that result from
increased activity of epidermal melanocytes. Simple lentigines are usually small (<5 mm), darker
than ephelides, and appear during childhood. They have a scattered distribution and do not show a
predilection for sun-exposed areas. Multiple lentigines are a feature of numerous genetic disorders
(table 2). (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on
'Lentigo' and "Congenital and inherited hyperpigmentation disorders", section on 'Genetic syndromes
associated with lentiginosis'.)
Solar lentigines — Solar lentigines are tan to dark brown macules, 3 to 20 mm in size,
that occur on sun-exposed areas, such as the face (picture 2A-B), dorsal aspect of hands (picture 3)
and forearms, upper chest (picture 4), and upper back (picture 5), in response to excessive or chronic
sun exposure. In younger individuals, they often appear after an acute sunburn. The differential
diagnosis and management of lentigines is discussed elsewhere. (See "Benign pigmented skin
lesions other than melanocytic nevi (moles)", section on 'Lentigo'.)
Other than for cosmetic purposes, treatment of lentigines is unnecessary. Therapeutic options
include lightening agents, retinoic acid, cryotherapy, intense pulsed light therapy, and laser therapy
with quality-switched (Q-switched) lasers [23].
PUVA lentigines — Psoralen plus ultraviolet A (PUVA) lentigines are large, irregularly
shaped, darkly pigmented macules arising also in sun-protected areas in patients treated with long-
term PUVA phototherapy, particularly in those with light phototypes. Histologically, these macules
are characterized by a lentiginous proliferation of large melanocytes with mild atypia [24]. Similar
macules have been noted in patients with mycosis fungoides treated with narrowband ultraviolet B
(UVB) phototherapy [25].
Partial unilateral lentiginosis — Partial unilateral lentiginosis (PUL) is a

rare disorder characterized by the presence of multiple lentigines arising on normally pigmented
skin in a unilateral or segmental pattern [26]. PUL is in most cases an acquired disorder, with
lentigines first appearing during childhood or adolescence. The pigmented macules can occur
523
anywhere on one side of the body and may have a zosteriform distribution. Histologically, there is
increased pigmentation of the basal layer, with normal or slightly increased number of melanocytes
[27].
In a minority of cases, PUL may be a manifestation of segmental neurofibromatosis type 1 (NF1), a

noninherited mosaic form of NF1, characterized by unilateral neurofibromas and/or café-au-lait
macules [28]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis",
section on 'Segmental NF1'.)
Laugier-Hunziker syndrome — Laugier-Hunziker syndrome is an acquired,

benign disorder presenting in adults with lentigines on the lips and buccal mucosa (picture 6A-B).
Approximately one-half of the patients also have longitudinal melanonychia and macular
pigmentation of the genitals [29] (see "Longitudinal melanonychia"). Palms and soles are frequently
involved. There are no underlying systemic abnormalities and no malignant predisposition.
The diagnosis of Laugier-Hunziker syndrome is one of exclusion and is usually made after ruling out
other causes of oral and labial hyperpigmentation, including physiologic pigmentation seen in dark-
skinned individuals and inherited diseases associated with lentiginosis (eg, Peutz-Jeghers
syndrome, LEOPARD [lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic
stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness] syndrome). The
absence of systemic symptoms such as fatigue, weight loss, cardiovascular, or gastrointestinal
disorders and negative findings in upper gastrointestinal endoscopy and colonoscopy support the
diagnosis of Laugier-Hunziker syndrome. (See "Congenital and inherited hyperpigmentation
disorders", section on 'Genetic syndromes associated with lentiginosis'.)
No treatment is necessary. However, some patients may require the removal of pigmented lesions
for cosmetic reasons. Cryosurgery, neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers,
and the Q-switched alexandrite laser have been used in single case reports [30-32]. (See "Laser and
light therapy for cutaneous hyperpigmentation".)
Cronkhite-Canada syndrome — Cronkhite-Canada syndrome is a rare,

noninherited disorder characterized by polyposis of the digestive tract associated with variable
anomalies of ectodermal tissues, including diffuse, nonscarring alopecia, nail dystrophy (picture 7),
and lentigines of the buccal mucosa, face, hands, and feet [33]. Approximately two-thirds of the
patients are of Japanese descent [34].
The disease typically manifests in the sixth decade of life. Presenting symptoms include diarrhea,
weight loss, nausea, vomiting, hypogeusia, and anorexia. A diffuse polyposis is present throughout
the gastrointestinal tract. Complications include protein-losing enteropathy, gastrointestinal
bleeding, intussusception, and prolapse.
Cronkhite-Canada syndrome is a progressive disease with variable course and poor prognosis.
Regardless of therapy, the mortality rate exceeds 50 percent. (See "Overview of colon polyps",
section on 'Cronkhite-Canada syndrome'.)
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Oral melanotic macule — Oral melanotic macules are small, well-circumscribed,
brown-to-black macules commonly occurring on the vermilion border of the lower lip (picture 8) or
on the oral mucosa, more often on the gingiva (picture 9) and hard palate (picture 10). They range in
size from a few millimeters to more than one centimeter, are often solitary but can be multiple, and
are frequently seen in individuals with darker complexions.
A biopsy may be required to rule out mucosal melanoma. Histologically, melanotic macules show an
increased deposition of melanin without increase in the number of basal melanocytes. Melanin
pigment is also observed in melanophages in the upper portion of the lamina propria.
Dermatosis papulosa nigra — Dermatosis papulosa nigra (DPN) is a

common benign condition, which is considered to represent a variant of seborrheic keratosis.
Lesions present as multiple 1 to 5 mm dark brown to black papules most commonly on the face,
neck, and upper back. DPN affects 35 to 77 percent of individuals of African descent and can also
present in other ethnic groups with darker skin tones. DPN typically present at a younger age
compared with seborrheic keratoses and can uncommonly be found in children [35,36].
The pathogenesis of DPN is unknown. Studies have found mutations in fibroblast growth factor
receptor 3 and phosphatidylinositol 3-kinase genes [37]. Since many patients report a family history
of DPN, a genetic predisposition is most likely. Histopathologic features include acanthosis,
papillomatosis, and increased pigmentation of the epidermis.
The diagnosis is typically made clinically. However, if the diagnosis is uncertain, a biopsy can be
performed to differentiate this entity from viral warts, melanocytic and epidermal nevi, and
melanoma.
DPN is a benign condition requiring no therapy. However, some patients may desire treatment for
cosmetic reasons. Treatment modalities include electrodesiccation and curettage, cryotherapy, snip
removal, long-pulsed 1064 nm Nd:YAG laser, 532 nm diode laser, pulsed-dye laser, fractionated photo
thermolysis 1550 nm, potassium-titanyl-phosphate (KTP), and carbon dioxide ablative lasers [38-43].
Smoker's melanosis — Smoker's melanosis is characterized by irregular

macular hyperpigmentation of the oral mucosa secondary to tobacco smoking [44-46]. It may be due
to the stimulating effect of nicotine on the melanocytes located in the basal layer of the oral
mucosa.
Lesions consist of brown patches most commonly located on the mandibular anterior gingiva in
cigarette smokers and buccal mucosa in pipe smokers[45]. In those who engage in reverse smoking
(smoking from the lit end), pigmentation changes are most common on the hard palate.
The diagnosis is usually clinical. However, a biopsy for histopathologic examination may be
warranted if the diagnosis is unclear or the lesion is suspicious for malignancy. The differential
diagnosis includes physiologic pigmentation (mucosal melanosis) in dark-skinned individuals,
525
amalgam tattoo, drug-induced hyperpigmentation, Addison's disease, melanoacanthoma, and
mucosal melanoma.
There are no treatments for smoker's melanosis. Lesions tend to resolve spontaneously over a
period of several years of smoking discontinuation [47].
Becker's melanosis — Becker's melanosis, also called Becker's nevus, is a

benign cutaneous hamartoma usually presenting in adolescents as a unilateral, hyperpigmented
macule or slightly elevated plaque located on the shoulder or upper trunk (picture 11A-B). In one-half
of the cases, there is an associated hypertrichosis. Becker nevus is discussed in greater detail
elsewhere. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on
'Becker nevus'.)
Maturational hyperpigmentation — Darkening of facial skin

tone is frequently seen in older individuals with darker skin types. Maturational hyperpigmentation or
maturational dyschromia are controversial and uncommonly used terms that refer to a primary
darkening of both mature and sun-exposed skin [48]. The onset is in adulthood and is not associated
with prior inflammation or skin injury. The hyperpigmentation generally occurs on the lateral aspects
of the face and also dorsal hands and feet as a result of chronic sun exposure (picture 12). (See
"Photoaging".)
The etiopathogenesis of maturational hyperpigmentation remains unclear. Chronic sun exposure is

likely implicated; obesity and diabetes have been postulated as predisposing factors [48]. The
histologic evaluation of hyperpigmented skin reveals mild to moderate proliferation of melanocytes,
minimal to absent dermal inflammation, and some reports of papillomatous epidermal proliferation.
Maturational hyperpigmentation is a diagnosis of exclusion. It is most commonly confused with

melasma, postinflammatory hyperpigmentation, or acanthosis nigricans. The differential diagnosis
also includes photoallergic dermatitis and exogenous ochronosis. (See 'Exogenous ochronosis'
below.)
Treatment includes sun-protective measures and topical skin-lightening agents. (See "Melasma:
Management", section on 'Topical skin-lightening agents'.)
Periorbital hyperpigmentation — Periorbital hyperpigmentation,

also called idiopathic cutaneous hyperchromia of the orbital region, periorbital melanosis, dark
circles, or infraorbital pigmentation, is a common finding in otherwise healthy individuals [49]. The
dyspigmentation around the orbital skin is typically bilateral and of a medium to dark brown color,
sometimes extending to the upper nose and glabella regions. It may be present on the upper, lower,
or both eyelids. It affects men and women equally and is more common in individuals with dark
complexions [50]. A familial form has also been recognized, with variable clinical expression in
different members of the family [51]. In familial cases, the hyperpigmentation usually starts during
childhood in the lower eyelids and progresses with age to involve the entire periorbital area.
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The cause of periorbital hyperpigmentation is multifactorial. Contributing factorsinclude genetic or
constitutional pigmentation; dermal melanocytosis; postinflammatory hyperpigmentation; periorbital
edema; excessive subcutaneous vascularity; thin, translucent lower eyelid skin overlying the
orbicularis oculi muscle; or a shadow effect due to skin laxity and prominent tear trough [8,49,50].
Excessive sun exposure, drugs, hormonal causes, and extension of pigmentary demarcation lines
may be additional contributingfactors [52]. Histologically, there is an increase in dermal melanin and
hemoglobin [53,54].
There are no therapies of proven efficacy for periorbital hyperpigmentation. Treatment should be
directed to the most apparent etiologic factor (eg, topical lightening agents for postinflammatory
hyperpigmentation, soft tissue filler for prominent tear trough). However, topical skin-lightening
agents, chemical peels [55], lasers [56-58], autologous fat transplantation, fat grafting with and
without blepharoplasty [59,60], and dermal fillers [61] have all been tried, but none have provided
long-term satisfactory treatment. (See "Melasma: Management", section on 'Topical skin-lightening
agents' and "Injectable soft tissue fillers: Overview of clinical use".)
Melasma — Melasma is an acquired hyperpigmentation of the skin that typically affects

the sun-exposed areas of the face, including the centrofacial, malar, and mandibular regions. It is
most common in women with darker complexions who live in areas of intense ultraviolet (UV)
radiation exposure [62]. The clinical features, diagnosis, and management of melasma are
discussed in detail separately. (See "Melasma: Management".)
Poikiloderma of Civatte — Poikiloderma of Civatte (PC) is a common

disorder characterized by mottled pigmentation (hyper- and hypopigmentation), skin atrophy, and
telangiectasias involving the lateral aspect of the face, neck, and V of chest (picture 13) caused by
chronic exposure to UV radiation [63]. The submental area is typically spared. PC is usually seen in
individuals older than 40 years with a light phototype and is more common in females.
Histologically, PC is characterized by thinning of the spinous layer, hydropic degeneration of the

basal cell layer, solar elastosis in the papillary dermis, presence of melanophages in the papillary
dermis, and dilatation of the papillary dermal capillaries [64].
PC has a chronic, progressive, and irreversible course that continues with exposure to UV light.
Photoprotection is an essential part of management. Therapies directed at reducing the
hyperpigmentation and the telangiectatic component include intense pulsed light [65-68] and
nonablative fractional laser. (See "Laser and light therapy for cutaneous vascular lesions" and "Laser
and light therapy for cutaneous hyperpigmentation".)
Nevus of Hori — Acquired bilateral nevus of Ota-like macules (ABNOM) or nevus of

Hori is a common dermal melanocytic hyperpigmentation seen in Asian populations, primarily in
young and middle-aged Chinese and Japanese women [69-71]. It is characterized by blue-gray to
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gray-brown macules, primarily on the zygoma and less often on the forehead, temples, upper eyelids,
and root and alae of the nose.
Although nevus of Hori shares histologic similarities with nevus of Ota, it can be clinically
distinguished from nevus of Ota by late onset in adulthood, bilateral presentation, speckled or
confluent distribution, and lack of ocular and mucosal involvement. The differential diagnosis
includes melasma, lentigines, and ephelides. (See "Melasma: Management" and "Benign pigmented
skin lesions other than melanocytic nevi (moles)".)
Laser therapy alone or in combination with chemical peels is the major treatment modality for nevus
of Hori [70]. Pigment-selective lasers and their combinations (eg, 532 nm Q-switched Nd:YAG laser
[QSNY] followed by a 1064 nm QSNY, or scanned carbon dioxide laser or intense pulsed light with a
Q-switched ruby laser) have been successfully used in small series of patients [72-76]. Adverse
effects of treatment include postinflammatory hypo- and hyperpigmentation. (See "Laser and light
therapy for cutaneous hyperpigmentation".)
Postinflammatory
hyperpigmentation — Postinflammatory hyperpigmentation is a common
reactive hypermelanosis that develops as a sequela of a variety of insults to the skin, including
inflammatory diseases, chemical or physical injuries, or trauma [77-79]. It presents with
hyperpigmented macules and patches in the same area involved by the preceding inflammation
(picture 14A-B) or trauma (picture 15). The color varies from light brown to slate-gray or black,
depending upon the skin color and location of melanin deposition (epidermal or dermal). Patients
with darker skin types are particularly predisposed to postinflammatory hyperpigmentation.
The clinical presentation, diagnosis, and treatment of postinflammatory hyperpigmentation are

discussed in detail separately. (See "Postinflammatory hyperpigmentation".)
Riehl's melanosis — Riehl's melanosis or pigmented contact dermatitis is a

dermal melanosis involving the face and neck caused by repeated contact with cosmetic ingredients
[80]. A mild erythema and pruritus typically precede the development of a diffuse or reticulated
hyperpigmentation (picture 16). The involved skin appears brown, brown-gray, or blue-gray,
depending upon the causal agent, depth of pigment deposition, and background skin color.
Histologically, there is vacuolar degeneration of the basal layer of the epidermis resulting in pigment
incontinence in the dermis [81]. The papillary dermis contains an infiltrate of lymphocytes and
macrophages containing large amounts of melanin.
The diagnosis is based upon the clinical appearance and history of cosmetic use. Patch testing to
standard series, cosmetic series, fragrance series, and additional ingredients found in patients'
personal products may be helpful in identifying the offending agent. Photopatch testing may be
useful in some patients. When results are equivocal or negative, provocative use test or repeated
open application test (ROAT) can be administered[53]. (See "Patch testing".)
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The differential diagnosis includes melasma, nevus of Hori, photosensitivity reactions, and berloque
dermatitis (phytophotodermatitis). (See "Melasma: Management" and "Clinical features and
diagnosis of allergic contact dermatitis".)
Treatment involves complete avoidance of the suspected allergen. Sun-protective measures, skin-
lightening agents, and chemical peels can accelerate the resolution of pigmentation changes.
Erythrose péribuccale pigmentaire de Brocq — A

rare form of facial hyperpigmentation and probably a variant of Riehl's melanosis is the so-called
"erythrose péribuccale pigmentaire de Brocq" or "erythrosis pigmentosa mediofacialis." It is
characterized by diffuse, symmetric, red-brown pigmentation around the mouth with sparing of the
vermillion border [82]. It may extend to the forehead, temples, and angles of the jaw.
Histologic examination shows orthokeratotic hyperkeratosis, no specific inflammatory epidermal

reaction pattern, and pigment incontinence with melanophages in the upper dermis. Enlarged
follicular openings containing keratin plugs and often Demodex folliculorum have also been noted
[83,84].
The pigmentation tends to be persistent. Treatment is difficult and involves sun avoidance and the
use of skin-lightening agents [85].
Erythromelanosis follicularis faciei et

colli — Erythromelanosis follicularis faciei et colli is a rare clinical variant of keratosis pilaris
primarily seen in adolescents and young adults[86]. It presents with a gradually progressive, reddish-
brown pigmentation surmounted by small follicular papules (picture 17) [82]. The pigmentation
involves the preauricular areas and extends to the cheeks and sides of the neck. Classic keratosis
pilaris lesions are often present on the trunk. (See "Keratosis pilaris".)
There is no effective treatment for erythromelanosis follicularis faciei et colli. Topical retinoids,
topical tacalcitol, hydroquinone, and laser therapy have been used in a few patients with temporary
improvement [86-88]. Complete regression is difficult to achieve and relapse is common.
Erythema dyschromicum perstans — Erythema

dyschromicum perstans (EDP), also called ashy dermatosis or dermatosis cenicienta, is an
uncommon, slowly progressive dermatosis characterized by hyperpigmented macules of variable
size and shape of an ashen-gray color[89].The majority of patients with this disorder are from Latin
America. EDP is usually seen in young adults, but it may also occur in children [90].
The etiology of EDP is unknown. There are isolated reports of EDP associated with exposure to
medications (most commonly, benzodiazepines and penicillin), radiographic contrast media,
pesticides, endocrinopathies, Trichuris trichiura (whipworm) infestation, and human
529
immunodeficiency virus (HIV) infection[77,91,92]. However, in most cases, a cause or trigger cannot
be identified. HLA-DR4 allele may be a risk factor for EDP in Mexican patients [93].
Histologic examination of the active border of the lesions shows vacuolar alterations of the basal
layer with occasional necrotic keratinocytes and colloid bodies resembling lichen planus [94]. In the
papillary dermis, there is a mild to moderate perivascular infiltrate of lymphocytes and histiocytes
with melanophages. Based upon these findings, it has been hypothesized that EDP may represent a
cell-mediated immune reaction to an ingestant, contact allergen, or microorganism [89,95].
Regardless, a diagnosis of EDP cannot be made based on histologic findings alone.
EDP presents with slate-gray to blue-brown, oval, circular, or irregularly shaped macules and patches
that develop gradually in a symmetric distribution (picture 18A-B). The long axis of the lesions may
follow the skin cleavage lines. Early lesions may have a thin, raised, and erythematous border.
Lesions typically involve the trunk, but they may spread to the neck, upper extremities, and face. EDP
is usually asymptomatic, but mild pruritus may occur.
EDP is difficult to diagnose. It may share clinical and histologic features with other entities, including
lichen planus pigmentosus, lichenoid drug eruption (picture 19), infectious diseases (eg, leprosy,
pinta), and postinflammatory hyperpigmentation. (See "Lichen planus" and "Lichenoid drug eruption
(drug-induced lichen planus)".)
There are no effective therapies for EDP. Topical agents such as corticosteroids and hydroquinone
are usually of limited benefit. Oral corticosteroids, antibiotics (eg, doxycycline), antimalarials,
isoniazid, griseofulvin, and UV light therapy have been tried with variable results. Successful
treatment with topical tacrolimus [96], dapsone [97], and clofazimine [98,99] has been reported in a
small number of patients. Sustained resolution with narrowband UVB has been reported in one
patient [100].
The disease is slowly progressive and persistent. Spontaneous resolution over months to years has
been reported in children [101].
Atrophoderma of Pasini and Pierini — Atrophoderma of

Pasini and Pierini is a rare disorder of unknown etiology presenting with single or multiple oval-
shaped, well-demarcated areas of skin that appear depressed and hyperpigmented (picture 20A-B).
The diagnosis, differential diagnosis, and treatment of atrophoderma of Pasini and Pierini are
discussed separately. (See "Atrophoderma of Pasini and Pierini".)
Acquired brachial cutaneous

dyschromatosis — Acquired brachial cutaneous dyschromatosis (ABCD) has
been reported as a pigmentary disorder occurring on the dorsal aspect of the forearm of older
individuals, particularly in women [102]. It presents with large, geographic, gray-brown patches
localized to the forearms, usually in a bilateral distribution. The differential diagnosis includes
extrafacial melasma. The presence of hypopigmented macules and the absence of characteristic
530
facial melasma lesions and any relation to estrogens, pregnancy, or hormone replacement therapy
can help distinguish ABCD from melasma. On histology, the hyperpigmented patches are
characterized by poikilodermatous changes, including epidermal atrophy, increased basal layer
pigmentation, solar elastosis, and telangiectasias. Based upon the histologic similarity with
poikiloderma of Civatte, ABCD is thought to be a manifestation of chronic sun damage [103].
Fixed drug eruption — Fixed drug eruption (FDE) is a distinctive type of

cutaneous drug reaction that characteristically recurs in the same locations upon re-exposure to the
offending drug. When fixed drug eruptions are encountered in practice following the acute phase,
lesions often appear as hyperpigmented, round patches. Acute FDE usually presents with a single or
a small number of dusky red or violaceous plaques that resolve leaving postinflammatory
hyperpigmentation (picture 21A-C). The clinical features, diagnosis, and management of fixed drug
eruption are discussed separately. (See "Fixed drug eruption".)
Exogenous ochronosis — Exogenous ochronosis is a rare condition

resulting from the deposition of homogentisic acid in the dermis following a prolonged exposure to a
variety of topical products used in skin-lightening agents, such as hydroquinone, resorcinol, phenol,
mercury, and picric acid [104,105]. The highest incidence is reported in African countries, due to the
widespread use of these agents [106,107].
Exogenous ochronosis presents as an asymptomatic, localized, symmetric, blue-gray discoloration

of the skin with characteristic hyperchromic, pinpoint, caviar-like papules in photo-exposed regions
(eg, face, sides and back of the neck, back, and extensor surfaces of limbs (picture 22)). There is
often an erythematous, pinkish hue of the skin underlying and surrounding the hyperchromic
papules.
The diagnosis is made by careful history-taking but often requires a skin biopsy, since exogenous
ochronosis can be easily confused with postinflammatory hyperpigmentation, melasma, and
pigmented contact dermatitis (Riehl's melanosis). Histology shows a microscopic deposition of
ochre-colored pigment in the papillary dermis, resembling the endogenous ochronosis associated
with alkaptonuria [108]. (See "Topical skin-lightening agents: Complications associated with misuse",
section on 'Exogenous ochronosis'.)
There is no effective treatment for exogenous ochronosis. Foremost, the offending medication
should be stopped. Topical agents, dermabrasion, carbon dioxide laser, chemical peels, Q-switched
Nd:YAG laser, and fractional carbon dioxide laser have been used in a small number of patients with
inconsistent results[104,109-113].
DIFFUSE HYPERPIGMENTATION
Linear pattern
531
Phytophotodermatitis — Phytophotodermatitis is a phototoxic reaction to
contact with plants containing furocoumarins (table 3). Patients with phytophotodermatitis typically
present with erythema, edema, and bullae in linear or bizarre configurations on sun-exposed skin
that reflect the manner in which they have come in contact with the causal furocoumarin. Some
patients do not experience the acute inflammatory phase and only present with bizarre, unexplained
pigmentation patterns in areas of exposed skin. The acute lesions typically heal leaving linear
hyperpigmented lesions (picture 23A-B). (See "Photosensitivity disorders (photodermatoses):
Clinical manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)
Drug-induced linear hyperpigmentation

Serpentine hyperpigmentation — Serpentine persistent supravenous
hyperpigmentation describes a pigmentary pattern that follows the course of an underlying vein
proximal to an infusion site (picture 24). This phenomenon can be caused by a variety of
chemotherapy agents, such as vinorelbine, daunorubicin, and topical fluorouracil, but is most
commonly associated with topical fluorouracil infusions (table 4) [114].
Flagellate hyperpigmentation — Flagellate hyperpigmentation, also called

flagellate erythema, is a characteristic cutaneous reaction to treatment with bleomycin [115,116].
Patients present with multiple linear, erythematous or hyperpigmented streaks arising at sites of
scratching or other minor traumas to the skin (picture 25). Generalized pruritus is common and may
precede the eruption. Histology shows hyperkeratosis, epidermal spongiosis, lymphocyte
exocytosis, increased melanin in the basal layer, dermal edema, and perivascular lymphocytic
infiltrate.
Reticulate pattern
Drug-induced reticulate hyperpigmentation — A reticulate
hyperpigmentation is an uncommon side effect of several drugs, most often chemotherapy agents
such as paclitaxel, cytarabine, topical fluorouracil, and idarubicin [117,118]. Diltiazem and topical
benzoyl peroxide have also been reported as a cause. Patients present with a diffuse reticulate
hyperpigmentation predominantly located on the trunk and lower extremities. Pruritus is often an
accompanying symptom. Histologically, lesions show increased melanin in the basal layer of the
epidermis and presence of melanophages in the dermis. The pigmentation tends to slowly resolve
after discontinuation of the offending drug.
Erythema ab igne — Erythema ab igne is a reticular, erythematous, pigmented

dermatosis resulting from repeated exposures to moderate heat or infrared radiation. Once common
among people who sat near open fires or stoves, it is infrequently seen after the introduction of
532
central heating. However, it is still seen in relation to occupational exposure to heat sources (foundry
workers, bakers), use of hot water bottles, heating pads or blankets (picture 26A-C), heated car seats,
and among laptop users who hold computers on their thighs [119-121].
Erythema ab igne can occur at any site, more often in an asymmetrical distribution, and is usually
asymptomatic. The early skin changes usually clear spontaneously in several weeks to months, after
the removal of the heat source from the skin. However, longstanding lesions may be associated with
permanent hyperpigmentation (picture 26A-C).
Confluent and reticulated papillomatosis — Confluent and

reticulated papillomatosis (CARP) of Gougerot and Carteaud is an uncommon dermatosis
characterized by hyperpigmented, scaly macules or papillomatous papules coalescing into
confluent patches or plaques centrally and exhibiting a reticular pattern peripherally (picture 27A-B).
It occurs in young adults and is usually persistent if left untreated. The pathogenesis, clinical
presentation, diagnosis, and treatment of CARP are discussed separately. (See "Confluent and
reticulated papillomatosis".)
Nonpatterned
Drug-induced — A wide variety of drugs and chemicals can lead to diffuse cutaneous
hyperpigmentation [122-124]. An increased production of melanin and/or the deposition of drug
complexes or metals in the dermis are responsible for the skin discoloration.
The drugs most often causing hyperpigmentation and associated clinical features are summarized
in the table (table 4). The hyperpigmentation usually resolves with discontinuation of the offending
agent, but the course may be prolonged over months to years.
Idiopathic eruptive macular pigmentation — Idiopathic eruptive

macular pigmentation is an exceedingly rare condition of unknown etiology that presents in both
children and adults with the eruption of asymptomatic, brown macules on the face, neck, proximal
extremities, and trunk [125-127]. Histologically, there is a basal layer hyperpigmentation with
occasional dermal melanophages; some specimens may show papillomatosis [125,128].
The diagnosis is based upon history and clinical and histopathologic findings. Proposed diagnostic
criteria include eruption of brown, nonconfluent, asymptomatic macules involving the trunk, neck,
and proximal extremities in children or adolescents; no preceding inflammatory lesions; no recent
drug exposure; and histopathologic findings of basal cell layer hyperpigmentation, prominent dermal
melanophages without visible basal layer damage or lichenoid inflammatory infiltrate, and normal
mast cell count [125,126].
Most patients will undergo spontaneous clearance in months to years [125].
533
Associated with endocrine, metabolic, and
autoimmune diseases
Addison's disease — Addison's disease or primary adrenal insufficiency is a clinical
syndrome caused by glucocorticoid, mineralocorticoid, and in women, androgen deficiency [129].
Signs and symptoms of chronic adrenal insufficiency include malaise, fatigue, hypotension,
anorexia, weight loss, and hyperpigmentation. (See "Clinical manifestations of adrenal insufficiency
in adults".)
The diffuse hyperpigmentation of Addison's disease is caused by the melanocyte stimulating

hormone (MSH)-like effect of elevated plasma levels of adrenocorticotropic hormone (ACTH). The
pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures, palmar and
plantar creases, and areas of pressure or friction (picture 28).
Normally hyperpigmented skin areas, such as the nipples and genitals, become darker. The buccal,
conjunctival, and genital mucosa may also be involved (picture 29). The nails and hair may also
darken (picture 30). (See "Clinical manifestations of adrenal insufficiency in adults", section on
'Hyperpigmentation'.)
The evaluation of the patient with suspected Addison's disease involves the measurement of basal
serum cortisol and plasma ACTH. The finding of low basal cortisol and elevated plasma ACTH is
diagnostic of primary adrenocortical insufficiency. (See "Diagnosis of adrenal insufficiency in
adults".)
The hyperpigmentation usually fades after a few months of adequate glucocorticoid therapy, due to
cornification and desquamation of hyperpigmented basal keratinocytes. Fading of hair and nails
takes longer because the pigmented part of the hair shaft and nail grows out slowly.
Diabetic dermopathy — Diabetic dermopathy, also called shin spots or pigmented

pretibial patches, occurs in approximately one-half of diabetic patients, most often in patients with
microangiopathic complications [130,131].
It presents with multiple asymptomatic, round, dull red to pink papules or plaques predominantly
located on the pretibial skin. Lesions evolve in one to two weeks to well-circumscribed, atrophic,
brown macules and patches, often with fine scale (picture 31).
The diagnosis of diabetic dermopathy is clinical. A skin biopsy is not routinely done. If performed, it
shows nonspecific findings, including edema of the epidermis and papillary dermis, red blood cell
extravasation, and a mild perivascular lymphohistiocytic infiltrate [130]. Older lesions show
epidermal atrophy and scattered hemosiderin deposits.
There is no treatment for diabetic dermopathy. The lesions may resolve spontaneously over time or
persist indefinitely.
534
Acanthosis nigricans — Acanthosis nigricans is a common disorder characterized by
hyperchromic, velvety plaques located in intertriginous areas such as the axillae, groin, and posterior
neck (picture 32). Histologically, it is characterized by hyperkeratosis, epidermal papillomatosis, and
slight, variable acanthosis, with normal melanocyte density [130]. There is no melanin deposition,
and the darkening is mainly due to hyperkeratosis.
Acanthosis nigricans occurs in approximately 40 percent of patients with diabetes mellitus type 2.
However, it may also occur in other endocrine and metabolic disorders, most of which are
associated with insulin resistance. Rarely, acanthosis nigricans may be a paraneoplastic syndrome.
The etiology, clinical manifestations, diagnosis, and treatment of acanthosis nigricans are discussed
in detail separately. (See "Acanthosis nigricans".)
Hyperthyroidism — Cutaneous changes associated with thyrotoxicosis include a localized

or generalized hyperpigmentation with a distribution similar to that seen in Addison's disease (eg,
creases of palms and soles, buccal mucosa). The hyperpigmentation is thought to be caused by
increased release of pituitary ACTH in response to increased cortisol degradation [132]. (See
"Overview of the clinical manifestations of hyperthyroidism in adults", section on
'Metabolic/Endocrine'.)
Hereditary hemochromatosis — Hereditary hemochromatosis is an autosomal

recessive disorder in which mutations in the HFE gene cause increased intestinal iron absorption
and abnormal accumulation of iron in the liver, pancreas, and other organs [133-135]. Clinical
manifestations include liver disease, skin pigmentation, diabetes mellitus, arthropathy, and cardiac
enlargement. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
A generalized darkening of the skin is seen in approximately 70 percent of patients. The

hyperpigmentation is due to a combination of hemosiderin deposition, which causes a diffuse, slate-
gray discoloration of the skin and increased melanin production.
In patients with suspected hemochromatosis, screening tests include the measurement of serum
transferrin saturation and ferritin. Genetic testing for HFE mutations (C282Y, H63D) should be
performed in patients with elevated transferrin saturation and/or elevated ferritin to confirm the
diagnosis. (See "Approach to the patient with suspected iron overload".)
Diffuse melanosis cutis — Diffuse melanosis cutis (DMC) is a rare presentation

of metastatic melanoma characterized by a diffuse, blue-gray discoloration of the skin and mucosae
(picture 33) [136,137]. Darkening of the urine (melanuria) is often associated with DMC.
Histologic examination reveals intracellular and extracellular melanin deposition in the dermis, with
a pronounced perivascular distribution. It is thought that melanin and melanosome released in the
circulation by cytolysis of metastatic melanoma cells are phagocytosed by dermal histiocytes,
resulting in skin and mucosal discoloration.
535
DMC and melanuria portend a very poor prognosis. They have also been reported in patients with
advanced metastatic melanoma treated with molecularly targeted therapies and checkpoint inhibitor
immunotherapy [137,138].
Post-chikungunya fever pigmentation — Chikungunya fever is a

mosquito-borne viral illness endemic to West Africa, Southeast Asia, and the Indian subcontinent
that causes acute febrile polyarthralgia and arthritis [82,139]. Other mucocutaneous manifestations
are common, including a patchy or diffuse maculopapular rash that may involve the face, intertrigo-
like lesions, vesicobullous lesions, and aphthous ulcerations and gingivitis [140,141]. (See
"Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
Histologic examination of hyperpigmented lesions shows increased basal pigmentation, pigmentary

incontinence, and melanophages (picture 34) [82,139,141]. These findings support the hypothesis
that the hypermelanosis associated with chikungunya fever is a form of postinflammatory
hyperpigmentation. (See 'Postinflammatory hyperpigmentation' above.)
Post-chikungunya fever facial pigmentation occurs in all age groups and presents as asymptomatic,
brownish-black, freckle-like macules involving the centrofacial area or diffuse pigmentation of the
face (picture 35A-B) [142]. Other patterns of pigmentation include a melasma-like pigmentation of
the face, exacerbation of a pre-existent melasma, periorbital melanosis, a flagellate pattern on the
trunk and extremities, and generalized hyperpigmentation [143].
Lesions may persist for three to six months after the infection [139]. Treatment involves sun
avoidance and the use of topical corticosteroids [139].
Lichen planus pigmentosus — Lichen planus pigmentosus (LPP) is a rare

variant of lichen planus that occurs predominantly in individuals with darker skin phototypes (III to
V) [144]. It generally affects young to middle-aged adults, especially those from India, Latin America,
and the Middle East. (See "Lichen planus".)
The etiology is unknown. Photodistribution suggests that ultraviolet (UV) light may play a role in the
pathogenesis of LPP. Mustard oil (which contains allyl isothiocyanate, a potential photosensitizer)
and amla oil have been suggested as possible inciting agents[145]. There are multiple reports of the
coexistence of LPP and frontal fibrosing alopecia, illustrating that LPP may be the herald sign of this
scarring type of hair loss and that both entities may have a pathogenic link [146,147]. (See "Lichen
planopilaris", section on 'Frontal fibrosing alopecia'.)
LPP typically presents with oval or irregularly shaped, brown to gray-brown macules and patches in
sun-exposed areas, including the forehead, temples, and neck (picture 36). It may also occur on the
trunk and in intertriginous areas (lichen planus pigmentosus inversus). Lesions are usually
symmetric but can present in a unilateral, linear fashion. In contrast with erythema dyschromicum
perstans, early LPP lesions lack an erythematous border. (See 'Erythema dyschromicum perstans'
above.)
536
In some patients, typical lesions of lichen planus may also be present[145]. LPP is usually
asymptomatic, but some patients report mild pruritus or burning.
The diagnosis of LPP is based upon clinical and histologic findings. Histology shows hyperkeratosis,
vacuolar cell degeneration in the basal layer with apoptotic keratinocytes, a band-like dermal
lymphocytic infiltrate with pigment incontinence, and melanophages. The differential diagnosis
includes lichen planus, erythema dyschromicum perstans, melasma, lichenoid drug eruptions, and
postinflammatory hyperpigmentation.
LPP is a chronic, relapsing disorder with exacerbations and remissions. First-line treatment involves
the use of sun-protective measures to prevent further darkening. Other treatment options include
topical corticosteroids, topical calcineurin inhibitors, skin-lightening agents, oral retinoids, UV light
therapy, antimalarials, and laser therapy [148-151]. (See "Lichen planus", section on 'Treatment'.)
Actinic lichen planus — Actinic lichen planus (ALP), also known as lichen planus
tropicus, is a rare photodistributed variant of lichen planus [152]. (See "Lichen planus".)
ALP is most commonly seen in children and young adults from the Middle East, East Africa, or India
[153,154]. Its pathogenesis is unknown, but exposure to UV radiation appears to have a precipitating
effect.
ALP usually presents as red-brown plaques with an annular configuration, but melasma-like,
hyperpigmented patches have also been observed[95].Lesions are typically photodistributed,
involving the forehead, face, neck, and dorsal aspect of upper extremities. Lesions typically appear
and are exacerbated during the summer months and may improve spontaneously in winter.
The diagnosis of ALP is based upon clinical and histologic features. On histology, lesions show the
typical findings of lichen planus (eg, vacuolar degeneration of the basal cell layer, dyskeratotic cells,
band-like lymphocytic dermal infiltrate) with marked pigmentary incontinence.
The differential diagnosis of ALP includes discoid lupus erythematosus, polymorphous light
eruption, melasma, and granuloma annulare. (See "Overview of cutaneous lupus erythematosus",
section on 'Discoid lupus erythematosus' and "Photosensitivity disorders (photodermatoses):
Clinical manifestations, diagnosis, and treatment", section on 'Polymorphous light eruption' and
"Melasma: Management" and "Granuloma annulare".)
Multiple therapies in combination with sunscreens have been tried in individual patients with ALP
with varying outcomes. Therapies include photoprotection, topical and intralesional corticosteroids,
antimalarials, acitretin, and cyclosporin [153,155-157]. There is a single case report of successful
treatment of ALP with intense pulsed light [158].
Primary cutaneous amyloidosis — Amyloidosis encompasses a

spectrum of disorders characterized by the deposition of amyloid fibrils (insoluble aggregates of
misfolded proteins, some of which are constituents of plasma) within the skin and other tissues.
537
Primary cutaneous amyloidosis is a form of localized, organ-specific amyloidosis in which the
amyloid deposition is limited to the skin. It may be a feature of multiple endocrine neoplasia type 2A
and pachyonychia congenita [159,160]. (See "Cutaneous manifestations of amyloidosis".)
The pathogenesis of primary cutaneous amyloidosis is not fully understood. Prolonged friction,
genetic predisposition, Epstein-Barr virus infection, and sun exposure have been proposed as
possible etiologic factors, but their role remains inconclusive [161-163]. The origin of the precursor
protein in primary cutaneous amyloidosis is also unclear. One hypothesis is that focal epidermal
damage and filamentous degeneration of keratinocytes is followed by apoptosis and conversion of
filamentous masses into amyloid in the papillary dermis [164].
The most common types of primary cutaneous amyloidosis are macular amyloidosis, lichen
amyloidosis, and biphasic amyloidosis [165].
●Macular amyloidosis – Macular amyloidosis presents with hyperpigmented, pruritic patches,

exhibiting either a confluent configuration or a characteristic ripple pattern with parallel bands or
ridges of hyperpigmentation (picture 37A-B). The rippled pattern can be best appreciated by
stretching the skin. The most common site of involvement is the upper back, especially over the
scapular area, followed by the extensor surfaces of the extremities.
●Lichen amyloidosis – Lichen amyloidosis usually presents with persistent, pruritic papules and
plaques on the shins or other extensor surfaces of the extremities (picture 38A-D). The initial lesions
are discrete, firm, scaly, skin-colored, or hyperpigmented papules, which later coalesce into plaques,
often with a rippled pattern. Lesions are usually unilateral at onset but can develop into a bilateral,
symmetrical distribution.
●Biphasic amyloidosis – In some patients, both macular and lichen amyloidosis can be present,
suggesting that the two forms may represent ends of a clinical spectrum.
●Amyloidosis cutis dyschromica – Amyloidosis cutis dyschromica is an exceedingly rare type of

primary cutaneous amyloidosis [166]. It is characterized by reticular hyperpigmentation with
hypopigmented macules distributed over nearly all of the body (picture 39).
The diagnosis of cutaneous amyloidosis is based upon the clinical presentation and histopathologic
examination of a skin biopsy. Histology shows hyperkeratosis, necrotic keratinocytes in the basal
layer, and melanophages as well as amorphous eosinophilic material (amyloid) deposits in the upper
dermis (picture 40).
There is no effective treatment for cutaneous amyloidosis. Several topical and systemic therapies
have been tried with inconsistent results, including topical and intralesional corticosteroids, topical
calcineurin inhibitors [167], systemic retinoids [168], thalidomide [169], cyclosporine [170], low-dose
cyclophosphamide, and narrowband ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA)
phototherapy [171].
538
Terra firma-forme dermatosis — Terra firma-forme dermatosis is an
acquired, idiopathic condition characterized by retention hyperkeratosis, which results in the
formation of dirt-like plaques despite normal hygiene. It is relatively common and most often occurs
in children[172,173].
Lesions typically involve the neck, ankle (posterior to the medial or lateral malleolus), and face but
may also occur on other body areas (picture 41A-B). Diagnosis and treatment can be achieved by
removing lesions with gentle isopropyl alcohol swabbing, with once a week application as
prophylaxis.
GENERAL PRINCIPLES OF
TREATMENT Treatment of cutaneous hyperpigmentation is challenging
because of its chronic, persistent, and relapsing nature. The approach to treatment involves the
removal of provoking factors, photoprotection, cosmetic camouflage, and a variety of pigment-
reduction modalities, including topical skin-lightening agents and laser therapy [174]. However, the
various treatment modalities for hyperpigmentation disorders have not been evaluated in high-
quality studies. In most cases, evidence for efficacy of topical or physical therapies is based upon
small series of patients or single-case reports and clinical experience.
Disorders associated with deposition of melanin in the epidermis (eg, melasma, postinflammatory
hyperpigmentation) usually respond to topical skin-lightening agents. In contrast, disorders
associated with deposition of melanin in the dermis do not respond to topical therapies and may be
successfully treated with lasers. (See 'Topical therapies' below and "Laser and light therapy for
cutaneous hyperpigmentation".)
Because sunlight is a major trigger of melanin synthesis, patients with hyperpigmentation should
adopt strict photoprotection measures. Cosmetic camouflage may be an option for the management
of facial hyperpigmentation.
Sun protection — All patients with hyperpigmentation disorders associated with

increased melanin production and deposition will benefit from sun avoidance and photoprotection,
which involves avoiding the peak hours of sunlight (between 11:00 AM and 4:00 PM), seeking shade,
wearing protective clothing (eg, broad-brimmed hats and long-sleeved shirts), and using a broad-
spectrum sunscreen with sun protection factor (SPF) of at least 30. (See "Selection of sunscreen
and sun-protective measures".)
Cosmetic camouflage — Physical-blocking opaque sunscreens, and in

particular those containing iron oxide, have the dual benefit of camouflaging hyperpigmentation and
preventing photo-induced darkening. Many of these physical blockers now come in tinted blends to
539
assist with camouflaging. In addition, many find that the use of make-up helps to even out skin tone.
Several available brands that provide heavy coverage include Dermablend, Cover FX, and
Covermark/CM Beauty[175]. (See "Melasma: Management", section on 'Cosmetic camouflage'.)
Topical therapies — Disorders associated with deposition of melanin in the

epidermis (eg, melasma, postinflammatory hyperpigmentation) can be often successfully treated
with topical skin-lightening agents. These include hydroquinone, azelaic acid, mequinol, Kojic acid,
tretinoin, and several combinations of topical agents. Topical skin-lightening agents are discussed in
detail elsewhere. (See "Melasma: Management", section on 'Topical skin-lightening agents'.)
Chemical peels — Chemical peels are an increasingly popular method for removal
of hyperpigmentation. Common peeling agents include alpha-hydroxy acids (eg, glycolic acid), beta-
hydroxy acids (eg, salicylic acid), trichloroacetic acid, Jessner's solution, and retinoids. In skin of
color, superficial to medium-depth peels are most typically used to reduce the risk of scarring and
dyspigmentation. (See "Chemical peels: Principles, peeling agents, and pretreatment assessment"
and "Chemical peels: Procedures and complications".)
Laser therapy — Hyperpigmentation disorders associated with melanin deposition in

the dermis (eg, nevus of Ota, nevus of Hori) do not respond to topical therapies but can be often
successfully treated with laser therapy [22]. In particular, Q-switched lasers (eg, 1064 nm Q-switched
neodymium:yttrium aluminum garnet) and picosecond lasers are widely used in darker skin types
because of longer wavelengths and short pulse durations, which allow for safe treatment.
The use of lasers for the treatment of specific hyperpigmentation disorders is discussed separately.
(See "Laser and light therapy for cutaneous hyperpigmentation".)
SUMMARY AND
RECOMMENDATIONS
●Hyperpigmentation is the darkening or increase in the natural color of the skin, usually due to an
increased deposition of melanin (hypermelanosis) in the epidermis and/or dermis. It is a feature of a
multitude of clinical conditions, ranging from normal variations of skin color to acquired and
inherited syndromes, and is one of the most common reasons for dermatologic consultation,
particularly in patients with darker skin types. (See 'Introduction' above.)
●The diagnosis of most hyperpigmentation disorders is made on clinical grounds. The initial patient
evaluation involves a detailed medical history and a complete skin examination. Investigation of
family history may be helpful to determine whether the disorder is acquired or inherited. (See 'Patient
evaluation and diagnosis' above and "Congenital and inherited hyperpigmentation disorders", section
on 'Patient evaluation and diagnosis'.)
540
●Skin examination should be performed under visible light and Wood's light. Important clinical
parameters include the extent of the pigmentary abnormality, color hue and morphology of individual
lesions, distribution, and pattern. An algorithmic approach to the diagnosis, based upon history and
clinical parameters, is shown in the figure (algorithm 1). (See 'Skin examination' above and
"Congenital and inherited hyperpigmentation disorders", section on 'Skin examination'.)
●Acquired disorders may present with circumscribed or diffuse hyperpigmentation. The latter may
show a linear or reticular pattern or no pattern. (See 'Circumscribed hyperpigmentation' above and
'Linear pattern' above and 'Reticulate pattern' above and 'Nonpatterned' above.)
●Treatment of cutaneous hyperpigmentation is challenging because of its chronic, persistent, and

relapsing nature. The approach to management involves the removal of provoking factors,
photoprotection, cosmetic camouflage, and a variety of pigment-reduction modalities, including
topical skin-lightening agents and laser therapy. (See 'General principles of treatment' above.)
541
Overview of nail disorders - UpToDate
uptodate.com/contents/overview-of-nail-disorders/print
INTRODUCTION The human nail shields the distal digit from harm,
assists in the picking up of small objects, improves fine touch, and enhances the aesthetic
appearance of the hand [1]. Aesthetically displeasing nails and nail-associated symptoms, such as
pain or throbbing, are common factors that contribute to a patient's decision to seek medical
attention.
This topic will discuss the clinical features, diagnosis, and treatment of common acquired nail
disorders. Nail dermoscopy, nail surgery, nail biopsy techniques, and hereditary nail disorders are
discussed separately.
●(See "Nail avulsion and chemical matricectomy".)
●(See "Principles and overview of nail surgery".)
●(See "Nail biopsy: Indications and techniques".)
542
●(See "Nail-patella syndrome".)
●(See "The genodermatoses: An overview", section on 'Pachyonychia congenita'.)
ANATOMY AND PHYSIOLOGY OF

THE NAIL UNIT The nail unit is composed of the nail matrix, the nail bed,
the proximal and lateral nail folds, and the hyponychium (picture 1 and figure 1) [2,3].
The nail matrix is the germinative epithelium from which nail matrix keratinocytes differentiate to
ultimately form the nail plate [2-4]. Most of the nail matrix is hidden beneath the proximal nail fold,
but the distal third is sometimes visible through the proximal portion of the nail plate as a half-moon-
shaped structure called the lunula (picture 1) [2-4]. Maturation and differentiation of the nail matrix
occurs along a diagonal axis oriented distally (figure 2). Thus, the keratinization of the distal matrix
cells forms the ventral portion of the nail plate, whereas the keratinization of the proximal matrix
cells forms the dorsal portion of the nail plate [2-5].Nail plate abnormalities typically result from
pathologic processes involving the nail matrix or space-occupying lesions involving the overlying
nail fold.
On average, fingernail regrowth takes approximately 6 months, and toenail regrowth takes
approximately 12 months (up to 18 months for the great toenail) [6]. Nail growth slows with
advancing age and vascular disease and can be partially or completely interrupted by systemic
illness, trauma, or medications (eg, antimitotic drugs) [6].
The nail bed dermis lies directly beneath the nail plate and is believed to contribute some epithelial
cells to the ventral surface of the nail, allowing the nail to grow continuously while adhering to the
nail bed [2]. For this reason, nail bed surgery may be complicated by mild onycholysis and, rarely, by
permanent nail dystrophy [2]. (See 'Onycholysis' below.)
The dermoepithelial interface of the nail bed is composed of longitudinal rete ridges and papillary
body ridges. Each papillary body ridge contains three to five longitudinally oriented capillaries,
explaining the longitudinal orientation of splinter hemorrhages [2-4]. (See 'Splinter hemorrhages'
below.)
The proximal and lateral nail folds are collectively known as the perionychium (picture 1) [2,3]. The
nail folds serve to protect the nail plate and direct nail plate growth in the correct orientation. The
hyponychium, located at the distal free edge of the nail plate just proximal to the distal groove, is
contiguous with the volar skin. The hyponychium functions to seal and protect the distal nail unit
from the environment. Disruption of the hyponychium may result in onycholysis and allow the
penetration of pathogens that are unable to digest keratin. The paronychium plus the hyponychium
and nail bed is called the perionychium.
The surgical anatomy and blood and nerve supply of the nail apparatus are discussed separately.
(See "Principles and overview of nail surgery", section on 'Surgical anatomy of the nail unit'.)
543
NAIL EVALUATION
Patient instructions — Before the visit, patients should be instructed to bring
all nail care products, including cosmetics and instruments, to the appointment. Nail polish, lacquer,
or other topical substances should be removed before the appointment to allow for the examination
of all nails.
History — Important aspects of the history in a patient with a complaint of nail problems
include the time of onset of the disease, occupation, hobbies, nail care habits, topical substance
exposure, medical history, medication history, and family history of nail disorders [7,8]. Some
clinicians ask their patients to complete a detailed nail questionnaire before the visit (table 1) [7].
(See 'Skin diseases with nail involvement' below.)
Nail examination — All nails should be examined under adequate lighting

without glare and with magnification [7,8]. Natural sunlight is preferred over artificial light.
Transillumination of the distal phalanx by using a penlight may help in localizing an abnormality. To
detect subtle changes of the nail plate surface, alcohol or acetone can be used to cleanse the
surface, remove any adherent substances, and reduce glare.
Digits should be relaxed and not pressed against a surface during the examination, since any
alteration in the hemodynamics of the nail bed can change the nail appearance. Each component of
the nail apparatus, including the nail plate, nail bed, proximal and lateral nail folds, and hyponychium,
should be evaluated for any abnormalities.
The nail plate is assessed for discoloration, detachment from the nail bed, and changes in thickness
and surface texture, including pitting, ridging, and longitudinal and transverse grooving. (See
'Surface texture abnormalities' below and 'Nail color changes' below and 'Defects of nail plate
attachment/nail shedding' below and 'Nail thickening' below.)
The nail bed, nail folds, and hyponychium should be assessed for discoloration, erythema, growths,
scale, cuticle attachment, and vascular abnormalities. If a subtle change in pigmentation is found,
squeezing the tip of the digit may be helpful in identifying vascular lesions, which become less
visible with the application of pressure.
The pattern of nail involvement must be identified. In cases where only one or a few nails are
affected, infection, trauma, tumor, or circulation disturbances are possible etiologic factors.
However, dermatoses such as lichen planus or psoriasis may affect only one nail.
The skin should also be examined for any concurrent findings [7,8]. Appropriate referral is indicated
for patients with nail signs associated with systemic diseases. (See 'Nail signs of systemic diseases'
below.)
544
SURFACE TEXTURE
ABNORMALITIES
Brittle nails — Brittle nails are characterized by roughness and dullness of the surface
of the nail plate. A lamellar exfoliation (onychoschizia) or splitting (onychorrhexis) may be present at
the distal margin of the nail plate.
Overview — Brittle nails are a common nail disorder that predominantly affect women over
the age of 50 years, with an estimated prevalence rate of approximately 20 percent in the general
population [9-11]. It presents with roughness of the surface of the nail plate, fragility, and peeling.
Ultrastructurally, brittle nails show a disorganized protein and lipid structure with a dishomogeneous
orientation of keratin filaments.
Causes of nail brittleness include [12]:
●Aging
●Pregnancy
●Associated dermatoses (eg, eczema, lichen planus, alopecia areata)
●Systemic disorders (eg, peripheral arterial disease, iron deficiency anemia, endocrine disorders)
●Environmental exposures (eg, wet work occupational exposure to chemicals [solvents, alkalis,
acids], use of nail cosmetics [nail polish, nail polish removers, nail sculpturing, application of acrylic
gels])
●Repeated microtrauma (occupational, onychotillomania, onychophagia)
●Drugs (eg, retinoids, chemotherapeutic agents)
●Idiopathic
The treatment of brittle nails involves uncovering and treating the underlying condition; avoiding
contact with detergents, solvents, external irritants, and trauma (eg, using gloves for wet work and
chores); avoiding aggressive manicures with excessive buffing and filing; and moisturizing the nails
with emollients. Although biotin supplementation is often used for the treatment of brittle nails,
evidence for its efficacy is lacking.
Onychoschizia — Onychoschizia, also called lamellar dystrophy, is characterized by

lamellar splitting of the free edge of the nail due to impairment of intercellular adhesive factors of
the nail plate (picture 2). It is often caused by exposure to external factors that alter the intercellular
545
adhesive factors of the nail plate (wet work, chemicals, trauma).
Onychorrhexis — Onychorrhexis occurs when superficial grooves in the nail plate lead
to a distal split (picture 3).
Transverse grooves (Beau lines) — Beau lines result from a

temporary arrest of proximal nail matrix proliferation and appear as transverse grooves that move
distally with nail growth (picture 4A-B). The time of the insult leading to transverse grooving can be
dated by measuring the distance of the groove from the proximal nail fold (approximately one month
for every millimeter from the proximal nail fold).
Causes of transverse grooving include [13-16]:
●Local trauma (eg, manicure, onychotillomania [habit tic deformity], ill-fitting footwear)
●Local cutaneous disease (eg, dermatitis, paronychia)
●Drugs (eg, retinoids, chemotherapy agents)
●Viral infections (eg, hand, foot, and mouth disease) (see "Hand, foot, and mouth disease and
herpangina", section on 'Coxsackievirus A6 HFMD' and "Hand, foot, and mouth disease and
herpangina")
●Pemphigus
●Kawasaki disease (see "Kawasaki disease: Clinical features and diagnosis", section on 'Extremity
changes')
Longitudinal grooves — Focal compression of the nail matrix from tumors

located in the proximal nail fold or nail bed may produce a longitudinal groove (picture 47D). Median
nail dystrophy, also called median canaliform dystrophy of Heller, is a distinctive form of longitudinal
groove characterized by a paramedian canal or split in the nail plate of one or more nails (picture 4C)
[17]. Small cracks or fissures that extend laterally from the central canal or split toward the nail edge
give the appearance of an inverted fir tree. The condition is usually symmetric and most often
affects the thumbs. The condition results from a temporary defect of matrix function of unknown
etiology. Trauma, including habitual nail picking, has been implicated as a causative factor in some
cases.
Longitudinal grooves must be distinguished from physiologic furrows and ridges, which are
accentuated in lichen planus, rheumatoid arthritis, peripheral vascular disease, older age, and Darier
disease. (See 'Darier disease' below.)
546
Pitting — Nail pitting results from focal areas of abnormal keratinization of the nail matrix
that produce foci of parakeratotic cells in the dorsal nail plate as it grows beyond the cuticle (picture
5A-B). Nail pitting is seen in patients with psoriasis, alopecia areata, and eczema. (See "Nail
psoriasis", section on 'Clinical manifestations' and "Alopecia areata: Clinical manifestations and
diagnosis", section on 'Nail abnormalities'.)
Trachyonychia — Trachyonychia is a nail plate abnormality characterized by

roughness, excessive longitudinal ridging, pitting, thickening of the cuticle, and distal brittleness
(picture 5C). Trachyonychia results from multiple foci of defective keratinization of the proximal nail
matrix.
Trachyonychia involving most or all nails is also called "twenty nail dystrophy" (picture 6). It occurs
predominantly in children and may be idiopathic or associated with other skin diseases, most
commonly psoriasis, lichen planus, alopecia areata, or atopic eczema [18]. Histology shows a
psoriasiform/lichenoid infiltrate or a spongiotic infiltrate [19]. In approximately 50 to 80 percent of
children, the disease resolves spontaneously over several years [20,21].
NAIL COLOR CHANGES

Leukonychia — "True leukonychia" results from defective keratinization of the distal
matrix with persistence of parakeratotic cells in the ventral nail plate. The nail has opaque, white
patches or striae that do not change upon applying pressure on the nail plate and move distally as
the nail grows (picture 7) [22].
In contrast, "apparent leukonychia" is due to abnormal vasculature of the nail bed, disappears with
pressure, and does not disappear as the nail grows.
Leukonychia punctata — Leukonychia punctata is the most common type of

leukonychia. It occurs most often in children and presents as small, 1 to 3 mm, white spots in the
nail plate that move distally as the nail grows. It is most frequently caused by trauma.
Transverse leukonychia (Mees' lines) — Transverse leukonychia,

also called leukonychia striata or Mees' lines (picture 8), is characterized by a white discoloration of
the nail plate in bands or striae 1 to 2 mm wide that run parallel to the nail base. They are caused by
abnormal keratinization of the nail matrix due to repeated trauma, infections, drugs (systemic
retinoids, taxanes), systemic disease, or exposure to arsenic and thallium [23-30].
Muehrcke's lines — Muehrcke's lines typically appear as a couple of transverse, white

bands that run parallel to the lunula across the entire width of the nail. First described in patients
with hypoalbuminemia and nephrotic syndrome, Muehrcke's lines are reported in association with
547
systemic diseases (eg, liver disease, malnutrition, organ transplant, HIV infection) and chemotherapy
[31]. They are a type of "apparent leukonychia," likely due to vascular changes in the nail bed.
Longitudinal white lines — Longitudinal white lines can be seen in most

patients with two rare inherited disorders: Darier disease (picture 9) and Hailey-Hailey disease. (See
"Darier disease" and "Hailey-Hailey disease (benign familial pemphigus)".)
Half-and-half nails — Half-and-half nails (also termed "apparent leukonychia" or

"Lindsay nails") present with a dull, white, ground-glass appearance involving the proximal portion of
the nail due to underlying nail bed changes (picture 10). They are predominantly seen in patients
with chronic renal insufficiency and uremia [32,33]. (See 'Nail signs of systemic diseases' below.)
Terry's nails — Terry's nails are characterized by leukonychia that involves more than the
proximal two-thirds of the nail plate, whereas the distal third appears red (picture 11A-B). They are
seen in patients with liver cirrhosis and other systemic diseases. (See 'Nail signs of systemic
diseases' below.)
Total leukonychia — In the rare inherited total leukonychia (MIM #151600), a

nonsyndromic, isolated nail disorder due to a mutation in the phospholipase C, delta-1 (PLCD1) gene,
all nails are milky and porcelain white (picture 12) [34].
Longitudinal melanonychia — Longitudinal melanonychia is a

banded, brown to black pigmentation of the nail due to the presence of melanin in the nail plate.
Longitudinal melanonychia may appear as a single band involving one nail or as multiple bands
affecting several nails. The latter form is most commonly seen in dark-skinned individuals (picture
13). Longitudinal melanonychia is discussed separately. (See "Longitudinal melanonychia".)
Longitudinal erythronychia — Longitudinal erythronychia is a pink to

red, longitudinal streak in the nail plate that corresponds to a band of thinned, more transparent nail
plate [35,36]. Longitudinal erythronychia is caused by a focal reduction of function in the distal
matrix. The nail bed underlying the band is less compressed than the adjacent portions so that blood
pools and the engorged tissue swells and fills the ventral groove of the nail plate.
Splinter hemorrhages are commonly found in longitudinal erythronychia. The thinned portion of the
nail plate extends to the distal free margin and is easily traumatized during daily activities, resulting
in splitting and V-shaped chipping. Reactive hyperkeratosis of the underlying hyponychium may also
occur.
Localized (monodactylous) longitudinal erythronychia involves one nail and may be associated with
benign or malignant nail tumors, including (picture 14A-B) [35-39]:
●Onychopapilloma (picture 15A-D) (see 'Onychopapilloma' below)
548
●Warty dyskeratoma
●Glomus tumor (see 'Glomus tumor' below)
●Squamous cell carcinoma (SCC), including SCC in situ (Bowen disease) (see 'Squamous cell
carcinoma' below)
●Amelanotic melanoma (see "Longitudinal melanonychia")
Longitudinal erythronychia involving multiple nails (polydactylous longitudinal erythronychia)

(picture 16) is most often associated with lichen planus or Darier disease, but systemic amyloidosis,
sarcoidosis, hemiplegia, graft-versus-host disease, acantholytic epidermolysis bullosa, and
idiopathic cases have also been reported [39-44]. (See "Darier disease", section on 'Nail changes'.)
The necessity of biopsy depends upon the number of involved digits and associated conditions or
symptoms. Biopsy is necessary for the diagnosis of monodactylous longitudinal erythronychia. For
patients with polydactylous longitudinal erythronychia and a known associated condition, biopsy is
not generally required for diagnosis. Patients with polydactylous longitudinal erythronychia without
associated cutaneous or systemic symptoms are generally observed over time for development of
cutaneous or systemic symptoms of associated conditions [36].
Biopsy indications and techniques for longitudinal erythronychia are discussed separately. (See
"Principles and overview of nail surgery", section on 'Longitudinal erythronychia'.)
Splinter hemorrhages — Splinter hemorrhages appear as red to black,

small, thin, longitudinal lines under the nail plate. In general, they are more commonly located in the
distal nail plate and represent rupture of the longitudinally oriented nail bed capillaries (picture 17A-
B). The most common causes of splinter hemorrhages are trauma (eg, nail biting) and nail psoriasis
(picture 17B and picture 18) [45].
However, splinter hemorrhages may be associated with other chronic dermatoses involving the nail
(eg, lichen planus, Darier disease (picture 19)) and, rarely, with systemic illness, such as infective
endocarditis (picture 20), connective tissue disease, antiphospholipid syndrome, chronic renal
failure, and trichinellosis [45-50]. (See "Lichen planus", section on 'Nail lichen planus' and "Darier
disease", section on 'Nail changes' and "Clinical manifestations and evaluation of adults with
suspected left-sided native valve endocarditis".)
Splinter hemorrhages associated with systemic diseases are often proximal in the nail, whereas
those due to trauma are usually distal. However, all splinter hemorrhages grow out distally (picture
19).
Color changes of the lunula — Erythema of the lunula ("red lunula")

has been described in patients with psoriasis, alopecia areata, and connective tissue diseases
[49,51-53]. A blue discoloration of the lunula has been reported in patients treated with
549
chemotherapy agents [54-56].
DEFECTS OF NAIL PLATE

ATTACHMENT/NAIL SHEDDING
Onycholysis — Onycholysis is defined as distal or distal-lateral separation of the nail
plate from the underlying nail bed and/or lateral supporting structures, such as the hyponychium
and lateral nail folds (picture 17B) [57,58]. The onycholytic portion of the nail plate appears white
due to air beneath the nail plate.
Onycholysis may be associated with many conditions, including trauma, wet work, psoriasis, lichen
planus, medications, onychomycosis, allergic or irritant contact dermatitis, or yellow nail syndrome.
For cases of chronic unexplained onycholysis, subungual squamous cell carcinoma should be
included in the differential diagnosis [58].
Onycholysis is a predisposing condition for secondary subungual infections from dermatophytes

(eg, Trichophyton rubrum), yeasts (eg, Candida albicans), or bacteria (including Pseudomonas
aeruginosa and Staphylococcus aureus). If infection is suspected, cultures should be obtained and
appropriate antifungal or antibacterial treatment started.
The management of onycholysis involves the identification and treatment of the underlying
condition. General nail care measures for onycholysis include [57,58]:
●Keeping nails trimmed short
●Avoiding trauma
●Avoiding contact irritants
●Keeping nails dry (avoiding wet work)
●Avoiding all nail cosmetics
●Protecting hands from cold or windy weather
Photo-onycholysis — Photo-onycholysis is a rare photosensitivity reaction

resulting in the separation of the nail plate from the nail bed, most often following the intake of
photosensitizing medications or in the setting of photosensitive blistering disorders, such as the
porphyrias or pseudoporphyria [59]. A few spontaneous cases of photo-onycholysis have also been
reported. (See "Porphyrias: An overview", section on 'Blistering cutaneous porphyrias' and
"Pseudoporphyria".)
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Drugs most frequently involved in photo-onycholysis include [59]:
●Tetracyclines
●Fluoroquinolones
●Antifungal agents (griseofulvin, voriconazole)
●Nonsteroidal anti-inflammatory drugs (diclofenac)
●Psoralens (psoralen plus ultraviolet A [PUVA] therapy)
●Targeted anticancer agents
●Topical aminolevulinic acid (photodynamic therapy)
●Antipsychotic drugs
Drug-induced photo-onycholysis typically manifests more than two weeks after the exposure to the
photosensitizing drug and may follow a cutaneous photosensitivity reaction or be an isolated
reaction. The onycholysis may involve one or more fingers and appears as a semilunar or oval area
of detachment of the nail plate with variable brownish pigmentation (picture 21).
Retronychia — Retronychia is a form of incomplete nail shedding that leads to the

embedding of the proximal nail plate into the proximal nail fold with subsequent inflammation
(picture 22) [60-62]. It predominantly occurs in young adults with a female predominance but has
also been reported in children [63,64]. In most cases, the great toes are affected, likely due to
repetitive minor trauma to the free nail margin that leads to incomplete separation of the proximal
nail plate from the matrix. The new nail growing from the matrix pushes the old one upward, causing
inflammation of the proximal nail fold and interrupting the longitudinal growth of the nail plate.
Simple avulsion is usually helpful, but the condition can recur in the setting of chronic distal
onycholysis and continued minor trauma/pressure on the distal nail plate.
Onychomadesis — The detachment of the nail plate from the proximal nail fold by
a full-thickness sulcus is called "onychomadesis" and results from a more severe or prolonged insult
to the nail matrix (picture 23A-B). Rare idiopathic or familial cases of onychomadesis have also been
reported [65,66].
NAIL THICKENING
Subungual hyperkeratosis — Subungual hyperkeratosis is due to an
abnormal keratinization of the distal nail bed and hyponychium, with accumulation of scales under
the distal nail plate. The most common causes include psoriasis (picture 17D), onychomycosis
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(picture 24A), trauma, and eczema. (See 'Psoriasis' below and "Nail psoriasis" and "Onychomycosis:
Epidemiology, clinical features, and diagnosis" and "Onychomycosis: Management".)
Onychogryphosis — Onychogryphosis, also called "ram's horn nail," is an

acquired nail disorder usually affecting the great toenail, which appears thickened, yellow-brown in
color, increased in length, and distorted (picture 25). It is common in older adults and neglected
individuals [67-70]. The cause of onychogryphosis is incompletely understood and may involve
peripheral vascular disease, repeated trauma from poor-fitting footwear, and self-neglect.
Onychogryphosis is a feature of some rare inherited disorders, including Papillon-Lefèvre syndrome,

Haim-Munk syndrome, ichthyosis hystrix, and junctional epidermolysis bullosa (picture 26). (See
"Hereditary palmoplantar keratodermas", section on 'Haim-Munk syndrome' and "Hereditary
palmoplantar keratodermas", section on 'Papillon-Lefèvre syndrome' and "Keratinopathic
ichthyoses", section on 'Ichthyosis hystrix Curth-Macklin and ichthyosis Lambert type' and
"Epidemiology, pathogenesis, classification, and clinical features of epidermolysis bullosa", section
on 'Junctional epidermolysis bullosa'.)
Complications include ingrown toenails, paronychia, and secondary onychomycosis. Treatment

involves conservative measures (eg, nail trimming/filing/grinding with nail clippers and electric burs,
use of appropriate footwear). The definitive treatment is nail avulsion followed by surgical or
chemical matricectomy using phenol.
Pachyonychia congenita — Pachyonychia congenita is a rare

autosomal dominant disorder characterized by the triad of hypertrophic nail dystrophy, plantar
keratoderma with underlying blisters, and severe plantar pain (picture 27 and picture 28).
Pachyonychia congenita is discussed separately. (See "Pachyonychia congenita".)
INFECTIONS OF NAILS AND

PERIUNGUAL TISSUES
Fungal infection — Onychomycosis, a fungal infection of the nail unit, is
characterized by nail discoloration, thickening, and deformity (picture 24A-E) [71]. The clinical
presentation, diagnosis, and treatment of onychomycosis are discussed separately. (See
"Onychomycosis: Epidemiology, clinical features, and diagnosis".)
Bacterial infections
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Green nail syndrome — P. aeruginosa, a water-borne bacterium, may secondarily
infect injured or onycholytic nails [72]. The infection is characterized by a blue-greenish color of the
nail plate due to the deposition of pyocyanin, a blue-green pigment produced by this bacterium
(picture 29). The pyocyanin pigmentation can persist for months despite adequate treatment. (See
"Pseudomonas aeruginosa skin and soft tissue infections", section on 'Green nail syndrome'.)
Acute paronychia — Acute paronychia is the most common infection of the hand
and typically results from local injuries to the nail fold (picture 30A-B) [73]. Most acute nail unit
infections are caused by S. aureus. Other bacteria, including Streptococcus or P. aeruginosa, may
cause acute paronychia.
Acute paronychia typically involves a single digit and is characterized by the rapid onset of painful
erythema and swelling of the proximal and lateral nail folds. A superficial abscess is frequently
present (picture 30A and picture 31).
The management of acute paronychia is discussed separately. (See "Paronychia".)
Blistering distal dactylitis — Blistering distal dactylitis is a localized infection

involving the volar pad of the distal phalanx of the digits. It occurs in children and adults. Tense,
nontender, oval bullae filled with thin, seropurulent fluid usually lie over the anterior fat pad and may
extend dorsally to involve the proximal or lateral nail fold (picture 32A-C). Cultures from the blister
fluid most commonly grow group A beta-hemolytic Streptococcus and, less often, S. aureus [74,75].
Felon (pulp space infection) — Felon is an acute infection of the fingertip

pulp space usually involving the thumb and index finger (picture 33). Abscess forms in the small
compartments of the fingertip pulp separated by vertical, fibrous septa (figure 3). Penetrating trauma
is the most common cause of felon, but it can also be a complication of untreated paronychia. (See
"Overview of hand infections", section on 'Pulp space infections'.)
Viral infection
Warts — Human papilloma virus infection is the most common viral infection of the nail. Warts
usually occur in the nail fold and, less frequently, in the nail bed (picture 34). Warts involving the
proximal nail fold result in longitudinal ridging and nail plate dystrophy. Nail bed warts may cause
onycholysis. Periungual and subungual warts are especially resistant to treatment, and overzealous
treatment in the area of the nail matrix can cause permanent nail dystrophy [72]. (See "Cutaneous
warts (common, plantar, and flat warts)".)
Herpetic whitlow — Herpetic whitlow is a herpes simplex virus infection of the hand
that involves the skin or the periungual area of a finger (picture 35). The infection is acquired by
direct inoculation of the virus following a minor local trauma [73,76]. Herpetic whitlow typically
553
occurs in children who suck their finger during a primary herpetic gingivostomatitis, but it is also an
occupational hazard for medical and dental personnel. (See "Overview of hand infections", section
on 'Herpetic whitlow'.)
SKIN DISEASES WITH NAIL

INVOLVEMENT
Psoriasis — Psoriasis is the most common dermatosis involving the nails [77,78]. (See
"Nail psoriasis".)
Clinical features that suggest nail psoriasis include [77]:
●Nail plate pitting – Nail pitting is the most common sign of nail psoriasis. It results from focal
areas of abnormal keratinization of the nail matrix that produce foci of parakeratotic cells in the
dorsal nail plate as it grows beyond the cuticle. Psoriatic pits are typically irregular, deep, and
randomly distributed within the nail plate (picture 5A).
●Nail bed salmon patches – Nail bed salmon patches (also termed "oil drops") are irregular areas of
yellow or pink discoloration in the nail bed visible through the nail plate, resulting from psoriatic
inflammation of the nail bed (picture 17C).
●Onycholysis – Onycholysis results from the distal separation of the nail plate from the inflamed,
underlying nail bed. An erythematous border and splinter hemorrhages are often associated with
onycholysis (picture 17B). Onycholysis and subungual hyperkeratosis may be the only
manifestations of psoriasis of the toenails (picture 17D).
Other signs of nail psoriasis include paronychia, leukonychia (white nails), erythema of the lunula,
and trachyonychia (rough, lusterless nails) [77,78]. (See 'Leukonychia' above and 'Trachyonychia'
above.)
Psoriasis of the nail folds resembles chronic paronychia and is often precipitated by treatment with
systemic retinoids [79].
Mycology testing is indicated to differentiate psoriatic nail disease from onychomycosis, particularly
if the disease is limited to the toenails. However, onychomycosis and nail psoriasis may coexist in
approximately 20 percent of patients with psoriasis [80].
The treatment of nail psoriasis is discussed separately. (See "Nail psoriasis", section on 'Treatment'.)
Parakeratosis pustulosa — Parakeratosis pustulosa is a nail disorder

that occurs almost exclusively in children (picture 36) [81]. In most cases, the disease is limited to
one nail, usually the thumb or the index finger, and presents with distal onycholysis, fingertip
554
desquamation, and mild subungual hyperkeratosis. Parakeratosis pustulosa begins with an acute,
eczematous inflammation of the periungual skin, causing hyperkeratosis and thickening of the free
edges of the nail. Scaling is more marked than pustulation. The course is often protracted, and
recurrences are the rule. Spontaneous regression may occur after puberty.
Lichen planus — Lichen planus is an inflammatory condition of unknown etiology

that affects the skin, mucous membranes, hair follicles, and nails.
Approximately 10 to 25 percent of patients with lichen planus have nail involvement [77,78,82,83].
Lichen planus of the nails occurs more commonly in the adult population and typically affects
several or most nails.
The clinical features of lichen planus vary by site of involvement within the nail apparatus [77,78].
Lichen planus of the nail matrix results in longitudinal ridging, nail plate thinning, longitudinal
fissuring (picture 37A), trachyonychia (picture 37B), and erythema of the lunula [77].
Postinflammatory hyperpigmentation of the proximal nail fold and longitudinal melanonychia can
also occur with nail matrix involvement [84]. Nail bed lichen planus usually occurs in conjunction
with nail matrix involvement and is characterized by onycholysis, with or without subungual
hyperkeratosis, and a violaceous hue of the nail bed.
Lichen planus of the nails can be rapidly progressive. Permanent nail dystrophy in the forms of
anonychia and dorsal pterygium (the extension and adherence of the proximal nail fold to the nail
bed secondary to scarring of the nail matrix (picture 37C and picture 38)) may occur.
Lichen planus is usually diagnosed by clinical examination alone, but if the diagnosis is
questionable, a 3 mm punch biopsy of the nail matrix and/or nail bed is usually conclusive.
Histology reveals a band-like infiltrate of the nail matrix and nail bed dermis, with hyperkeratosis,
hypergranulosis, and acanthosis of the nail matrix epithelium [85].
Lichen planus of the nails is generally treated with systemic or intralesional corticosteroids.
Systemic corticosteroids are preferred in cases that are rapidly progressive or involve more than
three nails. Oral prednisone 0.5 to 1 mg/kg per day (maximum 60 mg per day) is given for four to six
weeks and then tapered over the next four to six weeks [86]. As an alternative, monthly
intramuscular injections of triamcinolone acetonide at a dose of 0.5 mg/kg may be given for three to
six months [77,78,87].
Intralesional corticosteroid therapy is an option when less than three nails are involved.
Triamcinolone acetonide diluted to 2.5 to 5 mg/mL can be injected into the proximal and lateral nail
folds at monthly intervals [87]. These injections are placed intradermally in the nail folds, from which
the solution can diffuse to the underlying matrix. Injection directly into the nail matrix is
uncomfortable and unnecessary. Treatment is generally continued at monthly intervals until the
proximal one-half of the nail appears normal, at which time injections can be tapered.
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In patients who do not respond to treatment, systemic or topical corticosteroids should be stopped
after five to six months. Acitretin at a dose of 0.35 mg/kg per day may be a treatment option in
recalcitrant cases [87].
The treatment of nail lichen planus with topical or systemic corticosteroids has not been evaluated
in randomized trials. Their use is based upon clinical experience and limited evidence from small
case series.
In a study of 27 patients with nail lichen planus treated with intramuscular or intralesional
corticosteroids who were followed for more than 5 years (mean follow-up 10 years), 9 patients did
not respond to treatment, 18 were cured, and 11 relapsed [87]. In another study, 67 patients with
histologically confirmed lichen planus of the nails were treated with systemic and/or intralesional
corticosteroids for six months [85]. Complete or substantial improvement was reported in 42
patients (63 percent).
Alopecia areata — Nail involvement occurs in approximately 50 percent of

children and 20 percent of adults with alopecia areata [88,89]. Nail changes may not occur at the
same time as hair loss and are more common in males and severe cases [77,78,88,90,91].
Abnormalities may involve one or more nails and include mottled erythema of the lunula ("spotted
lunula"), longitudinal ridging or trachyonychia (picture 5C), and geometric pitting (multiple small,
superficial pits regularly distributed along longitudinal and transverse lines on the nail plate (picture
5B)). (See "Alopecia areata: Clinical manifestations and diagnosis".)
The diagnosis is usually made clinically, but a nail matrix biopsy may be performed in questionable
cases. Pathology reveals a lymphocytic infiltrate with spongiosis in the proximal nail fold, nail matrix,
nail bed, and hyponychium [19].
Nail abnormalities are typically stable and improve spontaneously over a period of years. Topical
corticosteroids or monthly intralesional injections of 2.5 to 3 mg/mL of triamcinolone acetonide into
the proximal nail fold can be administered if spontaneous clearing of the nails does not occur [78].
Darier disease — Darier disease, also termed "keratosis follicularis," is an autosomal

dominant condition characterized by greasy, hyperkeratotic papules in seborrheic regions.
Approximately 90 percent of patients with Darier disease have nail involvement [78]. (See "Darier
disease".)
Fingernails are affected more often than toenails. Nail matrix involvement results in onychorrhexis
(nail fragility), splitting, fragility, and red and white, longitudinal streaks in the nail plate (picture 39
and picture 9). Nail bed involvement is characterized by subungual hyperkeratosis and V-shaped
notches in the distal nail plate at the free edge. Keratotic papules may be present over the proximal
nail fold.
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Sarcoidosis — Nail involvement is rare in patients with sarcoidosis. Nails appear
yellow and dystrophic, often with splinter hemorrhages, nail plate pitting and/or crumbling,
subungual hyperkeratosis, and painful paronychia (picture 40) [92,93]. (See "Cutaneous
manifestations of sarcoidosis", section on 'Nail sarcoidosis'.)
NAIL DISORDERS RELATED TO NAIL

COSMETICS A number of nail disorders can be induced by cosmetic
procedures or products. These include nail discoloration (picture 41), superficial damage of the nail
plate, traumatic onycholysis, and contact reactions (irritant or allergic) to acrylic-based gel polishes
or artificial nail application [94-96]. (See "Common allergens in allergic contact dermatitis", section
on 'Acrylates'.)
Contact allergic reactions may present with subungual hyperkeratosis and/or onycholysis
resembling nail psoriasis. Pterygium inversum unguis (abnormal adherence of the hyponychium to
the ventral surface of the nail plate) has also been described [97].
Thinning of the distal nail plate and onychoschizia ("worn down nail") may occur due to repeated
trauma from application and removal of acrylic nail gel [98,99].
BENIGN TUMORS
Fibroma — Nail fibromas are benign tumors of the connective tissue that most commonly
originate in the nail matrix. However, they can also arise in the nail bed or in the proximal nail fold
and extend to the nail plate surface [100-102]. There are several types of nail fibromas, including:
●Acquired periungual fibrokeratoma – Acquired periungual fibrokeratoma is an acquired tumor

presenting as a small, asymptomatic, fleshy growth with a keratotic distal tip (picture 42C) [103]. It
usually arises following local trauma.
●Dermatofibroma – A dermatofibroma is a flesh-colored, pea-shaped growth that usually develops

spontaneously (picture 42A-B).
●Koenen tumor (periungual fibroma) – Koenen tumors are periungual or subungual fibromas that
develop in approximately 50 percent of patients with tuberous sclerosis during childhood or
adolescence. Koenen tumors occur more commonly on the toenails than on the fingernails. They
present as erythematous, polypoid, digitated growths; are often multiple; and may produce a
longitudinal groove in the nail plate due to matrix compression (picture 42D). (See "Tuberous
sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Dermatologic features'.)
557
Onychomatricoma — Onychomatricoma is a rare benign fibroepithelial tumor
that originates from the nail matrix. Clinical manifestations of onychomatricoma include (picture 43)
[104,105]:
●Yellow, longitudinal bands of variable width
●Splinter hemorrhages of the proximal portion of the nail plate
●Prominent longitudinal ridging associated with woodworm-like cavities
●Increased transverse curvature of the nail plate
Less frequent presentations of onychomatricoma include pincer nail deformity (picture 44),
cutaneous horn, melanonychia, nail bleeding, or pterygium (the extension and adherence of the
proximal nail fold to the nail bed secondary to scarring of the nail matrix (picture 38)) [106-114]. Nail
plate avulsion in onychomatricoma reveals finger-like projections originating from a villous tumor of
the nail matrix.
It has been suggested that a diagnosis of onychomatricoma can be made by histologic examination
of a distal clipping of the free edge of the nail plate [115]. The specimen is submitted for routine
hematoxylin and eosin staining and sectioned in the transverse plane. The finding of increased nail
thickness with cavitations filled with serous material and surrounded by a layer of
epithelium suggests the diagnosis of onychomatricoma.
Onychomatricoma may mimic subungual fibroma, fibrokeratoma, or squamous cell carcinoma

(including squamous cell carcinoma in situ [Bowen disease]) [111,112].
The surgical removal of onychomatricoma is discussed separately. (See "Principles and overview of
nail surgery", section on 'Onychomatricoma'.)
Digital myxoid cyst or myxoid pseudocyst — A

digital myxoid cyst (DMC) or myxoid pseudocyst typically presents as a translucent nodule on the
dorsum of the digit between the distal interphalangeal joint and the proximal nail fold (picture 45A)
[116]. DMCs are most frequently located on the radial fingers [100].
DMCs result from mucoid degeneration of the connective tissue and/or joint fluid leaking from an
osteoarthritic distal interphalangeal joint by way of a communicating canal. Although DMC is
commonly referred to as a cyst, on histologic examination, the collection of mucinous fluid is not
surrounded by an epithelial lining. Thus, a more appropriate term is "myxoid pseudocyst."
A DMC located distally in the proximal nail fold may exert pressure on the underlying nail matrix,
resulting in a longitudinally oriented, depressed groove in the nail plate (picture 45B) (see
'Longitudinal grooves' above). Occasionally, a DMC may discharge its mucinous content and reduce
558
the pressure on the nail matrix, resulting in an irregular, longitudinal depression in the nail plate
[116]. Subungual DMC variants may present as subungual tumors associated with a red lunula,
transverse nail plate over-curvature, and ingrowing nail plate [100,117].
High-resolution ultrasonography or magnetic resonance imaging (MRI) may confirm the diagnosis in
cases that are clinically ambiguous [100]. The communicating canal between the DMC and the distal
interphalangeal joint are visible on MRI in over 80 percent of cases [118].
A wide range of therapies are used to treat DMCs, including digital compression, cryotherapy,
sclerosant injection, or surgical excision. Spontaneous discharge of a DMC is a risk factor for septic
osteoarthritis of the distal interphalangeal joint and is an indication for DMC removal [100]. The
surgical treatment of DMCs is discussed separately. (See "Principles and overview of nail surgery",
section on 'Digital myxoid cyst'.)
Pyogenic granuloma — A pyogenic granuloma is a benign vascular tumor

presenting as a rapidly evolving, sessile or polypoid nodule composed of red, friable granulation
tissue that bleeds easily (picture 46) [119]. Pyogenic granuloma may involve the nail fold or be
subungual and penetrate the nail plate. Subungual pyogenic granulomas arise from the nail matrix
and produce a localized deformity of the nail plate. Local trauma or medications have been
associated with the development of periungual or subungual pyogenic granuloma. (See "Pyogenic
granuloma (lobular capillary hemangioma)".)
Glomus tumor — Glomus tumor is a rare, benign tumor composed of cells

resembling the smooth cells of the normal glomus body [120]. It presents as a red to purple or blue
lesion under the nail plate (picture 47A-D) [120-122]. Symptoms include paroxysmal pain, cold
sensitivity, and tenderness. The diagnosis is suspected based upon clinical appearance and history
of paroxysmal pain and cold sensitivity [122,123]. (See "Overview of benign lesions of the skin",
section on 'Glomus tumor'.)
Imaging studies with MRI or high-variable frequency ultrasonography may be helpful for confirming
the clinical suspicion and assessing the size and location of the tumor preoperatively [124-126]. The
treatment of glomus tumors is surgical. Histologic examination of the excised tumor is necessary to
confirm the diagnosis.
The surgical treatment of glomus tumors is discussed separately. (See "Principles and overview of
nail surgery", section on 'Glomus tumors'.)
Subungual exostosis — Subungual exostosis is a benign,

osteocartilaginous tumor that most commonly occurs on the dorsomedial aspect of the tip of the
great toe in adolescents or young adults [127]. In its early stage, the tumor typically presents as a
firm, porcelain-white, telangiectatic nodule with an overlying collarette of scale that extends from
559
beneath the distal nail, causing reddish onycholysis. With time, the tumor becomes hyperkeratotic
(picture 48A-B). Pain is variable and can be absent in some patients. Plain radiographs may confirm
the clinical diagnosis [127]. Treatment is surgical excision.
The surgical treatment of subungual exostosis is discussed separately. (See "Principles and
overview of nail surgery", section on 'Subungual exostosis'.)
Onychopapilloma — Onychopapilloma is a rare, benign tumor of the nail bed or

distal part of the nail matrix that most commonly presents as a longitudinal erythronychia (picture
15A-D) [128,129] (see 'Longitudinal erythronychia' above). Less common presentations include
leukonychia, melanonychia, or splinter hemorrhages (picture 15D) [129-132]. A fissure of the distal
nail plate associated with a V-shaped notch can be seen in some patients. The lesion is usually
asymptomatic.
On dermoscopic examination, onychopapilloma shows a homogeneous, brown or gray band in the

nail plate originating in the lunula, with splinter hemorrhages and a characteristic gray, keratotic
mass at the free distal edge (picture 49). (See "Dermoscopy of nonpigmented nail lesions", section
on 'Onychopapilloma'.)
A biopsy is necessary to confirm the diagnosis. Characteristic histopathologic features include

papillomatous acanthosis of the distal matrix and nail bed; in the distal portion of the nail bed, there
are layers of hyperkeratosis containing fusiform cells with eosinophilic cytoplasm resembling those
of the keratogenous zone of the matrix (matrix metaplasia of the nail bed) [128].
The differential diagnosis of onychopapilloma includes other causes of localized (monodactylous)

longitudinal erythronychia, such as glomus tumor, squamous cell carcinoma, or amelanotic
melanoma. (See 'Malignant tumors' below.)
Treatment of onychopapilloma is surgical excision.
MALIGNANT TUMORS
Squamous cell carcinoma — Squamous cell carcinoma (SCC),
including SCC in situ (Bowen disease), is the most common malignant tumor of the nail occurring
most often on the fingernails, within the nail bed, or within lateral nail grooves. Nail SCC usually
affects older adults, predominantly males [133]. Trauma, radiation exposure, smoking, and infection
with human papilloma virus types 16 and 18 are predisposing factors for SCC development [134].
(See "Epidemiology and risk factors for cutaneous squamous cell carcinoma", section on 'Risk
factors'.)
The clinical features of periungual or subungual SCC are generally nonspecific, often causing
prolonged delay in the diagnosis. SCC of the nail bed or lateral nail groove or nail fold may present
as hyperkeratosis, persistent onycholysis, longitudinal erythronychia, verruca, paronychia, nail plate
560
dystrophy, or a subungual mass (picture 14B-E) [135,136]. SCC should be suspected when a
verrucous or keratotic lesion of the lateral nail groove or fold is persistent or recurs after cryotherapy
or other treatment for common warts.
Keratoacanthoma, a rare clinical variant of SCC, typically presents with painful onycholysis, digital
erythema and swelling, or painful paronychia [119]. Keratoacanthomas usually grow rapidly, and
osteolysis of the bone is commonly observed on radiography. Patients with incontinentia pigmenti
may develop multiple subungual keratoacanthomas at a young age [137,138].
A lesion suspicious for SCC or keratoacanthoma should be biopsied using the punch, excisional, or
tangential (shave) excision techniques. (See "Nail biopsy: Indications and techniques".)
Mohs micrographic surgery is the preferred treatment for SCC without bone involvement [139,140].
Alternative treatments include wide surgical excision or digit amputation if the bone is involved. The
recurrence rate is low after wide excision or amputation [141]. (See "Mohs surgery".)
Melanoma — Melanoma of the nail apparatus is a form of acral melanoma that arises
from the nail matrix. Nail melanoma is rare. It accounts for 1 to 3 percent of melanomas occurring in
white populations and 15 to 30 percent of melanomas occurring in dark-skinned populations [142].
In two-thirds of cases, nail melanoma presents as a brown to black, longitudinal stripe in the nail
plate, known as longitudinal melanonychia (picture 50A-B) [143]. In one-third of cases, nail
melanoma is amelanotic and presents as a nail bed mass or nail plate abnormality (picture 51A-B).
(See 'Longitudinal melanonychia' above.)
The clinical presentation, diagnosis, and treatment of melanoma of the nail unit are discussed
separately. (See "Longitudinal melanonychia".)
NAIL SIGNS OF SYSTEMIC

DISEASES Nail abnormalities associated with systemic diseases usually involve
most or all nails. Signs of temporary disturbance in nail growth, such as Beau lines and
onychomadesis, may occur in association with high fever, viral diseases (eg, hand, foot, and mouth
disease), or Kawasaki syndrome [13,14,144]. (See 'Transverse grooves (Beau lines)' above.)
Permanent or prolonged abnormalities of nail shape, thickness, and color associated with systemic
diseases include yellow nail syndrome, digital clubbing, half-and-half nails (apparent leukonychia),
and koilonychia.
Yellow nail syndrome — Yellow nail syndrome is an uncommon disorder

characterized by the triad of pulmonary disease, lymphedema, and slow-growing, yellow nails
without a cuticle or lunula (picture 52) [145-148]. Nails progressively thicken, becoming opaque and
curved with loss of the lunula and cuticle. Swelling of the periungual tissue and onycholysis can
561
occur. In most cases, yellow nail syndrome is sporadic, but it may be inherited in autosomal
dominant or recessive fashion [149]. A number of pulmonary diseases are associated with this
syndrome, including pleural effusion, bronchiectasis, and chronic sinusitis [150]. (See "Diagnostic
evaluation of pleural effusion in adults: Additional tests for undetermined etiology", section on
'History'.)
Terry's nails — Terry's nails are a type of apparent leukonychia that involves more than
the proximal two-thirds of the nail plate, whereas the distal third appears red (picture 11A-B) [151].
Initially described in patients with alcoholic liver cirrhosis, Terry's nails have been described in a
number of systemic diseases, including autoimmune hepatitis, diabetes mellitus type 2, rheumatoid
arthritis, Reiter syndrome, congestive heart failure, and other systemic diseases [151,152]. (See
"Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Extremity
findings'.)
The pathogenesis is incompletely understood. Changes in nail bed vascularity may be involved
[153].
Clubbing — Digital clubbing is the most common manifestation of hypertrophic

osteoarthropathy [154,155]. It is characterized by increased distal fingertip mass and increased
longitudinal and transverse nail plate curvature (picture 53A-C) [92,145,156,157]. The Lovibond
angle, the angle between the nail plate and the proximal nail fold when viewed from the side, is >180°
in clubbed nails and 160° in normal nails (figure 4). Clubbed fingers show the Schamroth sign, the
obliteration of the diamond-shaped window normally visible when the dorsal surfaces of the
terminal phalanges of corresponding fingers from opposite hands are placed together [158].
Digital clubbing can be acquired or hereditary:
●Acquired bilateral clubbing is the most common form. It usually begins in the thumb and index
fingers and is most often associated with pulmonary or cardiovascular diseases, including lung
cancer, interstitial pulmonary fibrosis, lung abscess, pulmonary tuberculosis, pulmonary lymphoma,
congestive heart failure, infective endocarditis, and cyanotic congenital heart disease [156]. Less
frequently, digital clubbing may occur in patients with extrathoracic disease, including inflammatory
bowel disease, liver cirrhosis, and gastrointestinal neoplasms. (See "Approach to the adult with
interstitial lung disease: Clinical evaluation", section on 'Clubbing' and "Clinical presentation and
diagnosis of inflammatory bowel disease in children", section on 'Extraintestinal manifestations' and
"Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)
●Acquired unilateral or single-digit clubbing is commonly related to nearby vascular lesions (such as
a peripheral shunt, arteriovenous fistula, or aneurysm) but Pancoast tumors, lymphadenitis, or
erythromelalgia can also cause unilateral clubbing [92,145]. Single nail involvement is typically
traumatic but may be congenital. (See "Superior pulmonary sulcus (Pancoast) tumors".)
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●Isolated congenital digital clubbing (MIM #119900) is considered an incomplete form of primary
hypertrophic osteoarthropathy (PHO) [159]. PHO is an autosomal recessive disorder due to
mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene [160]. It presents in
otherwise healthy children with clubbing, periostosis, and skin manifestations, including thickening
of the skin of the face and scalp, coarsening of facial features, hyperhidrosis, and seborrhea.
Thyroid acropachy — Thyroid acropachy is a rare manifestation of Graves'

disease characterized by digital clubbing, soft-tissue swelling of the hands and feet, and periosteal
reaction with new bone formation (picture 54). It is almost always associated with thyroid
dermopathy and exophthalmos and usually becomes apparent after the diagnosis and treatment of
hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
Half-and-half nails — Half-and-half nails (also termed "apparent leukonychia" or

"Lindsay nails") are a manifestation of chronic renal insufficiency and uremia [32,33]. A half-and-half
nail typically exhibits a red, pink, or brown; horizontal; distal band that occupies 20 to 60 percent of
the total length of the nail [92,145,161]. The proximal portion of a half-and-half nail usually has a dull,
white, ground-glass appearance due to underlying nail bed changes (picture 10). The nails may
revert to normal following renal transplantation [162].
Half-and-half nails have also been reported in association with other systemic diseases (including
Kawasaki disease, cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and
pellagra) and drugs [22].
Koilonychia — Koilonychia, also called spoon nail, is the upward curving of the distal
nail plate that results in a spoon-shaped nail that could hold a drop of water on the surface (picture
55A-B). Koilonychia has been associated with iron deficiency and other systemic conditions in rare
case reports; however, it is more commonly seen as an occupational change in nails and may be
idiopathic. Ruling out iron deficiency anemia in someone with koilonychia is the only work-up
necessary in this condition. (See "Iron deficiency in infants and children <12 years: Screening,
prevention, clinical manifestations, and diagnosis".)
SUMMARY
●The nail unit is composed of the nail matrix, nail bed, proximal and lateral nail folds, and
hyponychium (picture 1 and figure 1). Acquired nail disorders may involve all the components of the
nail unit. They include infections, tumors, disorders associated with skin or systemic diseases, and
abnormal pigmentation. (See 'Anatomy and physiology of the nail unit' above.)
●The nail plate is assessed for changes in surface texture, discoloration, detachment from the nail
bed, and changes in thickness, including pitting, ridging, and longitudinal and transverse grooving.
(See 'Nail evaluation' above.)
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●Common surface texture abnormalities include brittle nails, onychoschizia (picture 2),
onychorrhexis (picture 3), transverse and longitudinal grooves (picture 4A-C, 23A-B, 47D), pitting
(picture 5A-B), and trachyonychia (picture 5C). (See 'Surface texture abnormalities' above.)
●Color changes include leukonychia (picture 7), longitudinal erythronychia (picture 14A-B),
longitudinal melanonychia, and splinter hemorrhages. Longitudinal melanonychia is reviewed
separately. (See 'Nail color changes' above and "Longitudinal melanonychia".)
●Defects of nail plate attachment to the nail bed often present with onycholysis, distal or distal-
lateral separation of the nail plate from the underlying nail bed and/or lateral supporting structures
(picture 17B). Retronychia is a form of incomplete nail shedding that leads to the embedding of the
proximal nail plate into the proximal nail fold with subsequent inflammation (picture 22). The
detachment of the nail plate from the proximal nail fold by a full-thickness sulcus is called
onychomadesis (picture 23A-B). (See 'Defects of nail plate attachment/nail shedding' above.)
●Common nail infections include onychomycosis (picture 24A-E); bacterial infections, including
acute paronychia (picture 30A-B), blistering distal dactylitis (picture 32A-C), pulp space infection
(felon) (picture 33), and green nail syndrome (picture 29); and viral infections, such as warts (picture
34) and herpetic whitlow (picture 35). (See 'Infections of nails and periungual tissues' above.)
●The nails may be involved in numerous skin diseases, including psoriasis (picture 5A, 17B-D),
parakeratosis pustulosa (picture 36), lichen planus (picture 37A-C), alopecia areata (picture 5B-C),
Darier disease (picture 39), and sarcoidosis (picture 40).
●Benign nail tumors include fibromas (picture 42A-D), onychomatricoma (picture 43), digital myxoid
cyst (picture 45A-B), pyogenic granuloma (picture 46), glomus tumor (picture 47A-D), and subungual
exostosis (picture 48B). (See 'Benign tumors' above.)
●Squamous cell carcinoma (SCC), including SCC in situ, is the most common malignant tumor of the
nail. It presents with nonspecific symptoms, such as hyperkeratosis, persistent onycholysis,
longitudinal erythronychia, verruca, paronychia, nail plate dystrophy, or a subungual mass (picture
14B-E). (See 'Squamous cell carcinoma' above.)
●Nail abnormalities associated with systemic diseases usually involve most or all nails. Signs of
temporary disturbance in nail growth, such as Beau lines and onychomadesis, may occur in
association with high fever, viral diseases (eg, hand, foot, and mouth disease), or Kawasaki
syndrome. Permanent or prolonged abnormalities of nail shape, thickness, and color associated with
systemic diseases include yellow nail syndrome (picture 52), clubbing (picture 53A-C), half-and-half
nails (picture 10), and Terry's nail (apparent leukonychia (picture 11A-B)). (See 'Nail signs of
systemic diseases' above.)

to acknowledge Julie A Jefferson, MD, who contributed to an earlier version of this topic review.
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Atopic dermatitis (eczema): Pathogenesis, clinical
manifestations, and diagnosis
uptodate.com/contents/atopic-dermatitis-eczema-pathogenesis-clinical-manifestations-and-diagnosis/print
Literature review current through: Apr 2020. | This topic last updated: Jun 18, 2019.
INTRODUCTION Atopic dermatitis is a chronic pruritic inflammatory skin

disease that occurs most frequently in children, but also affects adults. Atopic dermatitis is often
associated with elevated serum level of immunoglobulin E and a personal or family history of atopy,
which describes a group of disorders that includes eczema, asthma, and allergic rhinitis [1,2].
Although sensitization to environmental or food allergens is clearly associated with the atopic
dermatitis phenotype, it does not seem to be a causative factor but may be a contributory factor in a
subgroup of patients with severe disease [3]. (See "Role of allergy in atopic dermatitis (eczema)".)
The terms "dermatitis" and "eczema" are frequently used interchangeably. When the term "eczema" is
used alone, it often refers to atopic dermatitis (atopic eczema). The term "eczematous" also
connotes some crusting, serous oozing, or blister formation as opposed to mere erythema and
scale.
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The epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis are
reviewed here. The treatment of atopic dermatitis, the role of allergy in atopic dermatitis, and other
types of eczematous dermatitis are discussed separately.
●(See "Treatment of atopic dermatitis (eczema)".)
●(See "Management of severe atopic dermatitis (eczema) in children".)
●(See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)
●(See "Role of allergy in atopic dermatitis (eczema)".)
●(See "Clinical features and diagnosis of allergic contact dermatitis".)
●(See "Cradle cap and seborrheic dermatitis in infants".)
●(See "Seborrheic dermatitis in adolescents and adults".)
EPIDEMIOLOGY Atopic dermatitis affects approximately 5 to 20 percent

of children worldwide [4]. In the United States, the prevalence is approximately 11 to 15 percent [5,6].
Data on the prevalence of atopic dermatitis in adults are limited and in most cases based upon self-
administered questionnaire information. In a Danish population-based study including
approximately 16,500 adults aged 30 to 89 years, the one-year prevalence of atopic eczema was 14
percent [7]. In a West Sweden study of approximately 30,000 individuals aged 16 to 75 years, the
current eczema prevalence was 11 percent [8]. In a Danish cohort study including approximately
1300 individuals aged 28 to 30 years who had been followed-up for 15 years, 10 percent reported
atopic dermatitis, but 6 percent were found to have atopic dermatitis at clinical examination [9]. In a
United States cross-sectional study including nearly 1300 adults, the prevalence of atopic dermatitis
was 7.3 percent (95% CI 5.9-8.8) [10].
The incidence of atopic dermatitis appears to be increasing. It may occur in any race or geographic
location, although there appears to be a higher incidence in urban areas and developed countries,
especially Western societies. A systematic review of epidemiologic studies performed between 1990
and 2010 found an increasing trend in incidence and prevalence of atopic eczema in Africa, eastern
Asia, western Europe, and parts of northern Europe [11].
In the vast majority of cases, atopic dermatitis has an onset before age five years, and prevalence
data in children show a slight female to male preponderance (1.3 to 1) [12]. Persistent atopic
dermatitis may be present in approximately 50 percent of patients diagnosed with atopic dermatitis
during childhood [9,13].
RISK FACTORS A family history of atopy (eczema, asthma, or allergic

rhinitis) and the loss-of-function mutations in the filaggrin (FLG) gene, involved in the skin barrier
function, are major risk factors for atopic dermatitis [14]. (See 'FLG mutations' below.)
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Approximately 70 percent of patients have a positive family history of atopic diseases. Children with
one atopic parent have a two- to threefold increased risk of developing atopic dermatitis, and the risk
increases to three- to fivefold if both parents are atopic [2].
Although 30 to 80 percent of patients with atopic dermatitis are sensitized to certain foods, the
timing of solid food introduction or food avoidance strategies in pregnant or nursing women does
not appear to influence the risk of atopic dermatitis [15]. There is no evidence of an association
between proinflammatory dietary patterns and risk of atopic dermatitis [16]. (See "Role of allergy in
atopic dermatitis (eczema)", section on 'Food allergies'.)
There is evidence from a 2011 systematic review to support an inverse relationship between atopic
dermatitis and exposure to endotoxin, early day care, farm animal, and dog pets in early life (the
"hygiene hypothesis") [17].
Epidemiologic evidence from ecologic studies linked high hardness (high levels of calcium
carbonate) of domestic water with increased prevalence of atopic dermatitis in children [18-21]. A
United Kingdom population-based cross-sectional study including 1303 three-month-old infants
suggests that hard water may increase the risk of developing atopic dermatitis early in life [22]. In
this study, a high water level of calcium carbonate, but not of chlorine, in the household water was
associated with a nearly doubled risk of visible atopic dermatitis compared with low calcium
carbonate water, after adjusting for potential confounders (presence of filaggrin mutation, sex,
ethnicity, and maternal age). However, residual confounding from unmeasured factors, such as
changes in skin care practices associated with presence of eczema or dry skin, cannot be excluded.
Further studies are needed to evaluate whether the installation of water softening devices is helpful
for the prevention of atopic dermatitis in high-risk infants.
PATHOGENESIS A multiplicity of factors, including skin barrier

abnormalities, defects in innate immunity response, Th2-skewed adaptive immune response, and
altered skin resident microbial flora are involved in the pathogenesis of atopic dermatitis [23,24].
Whether skin inflammation is initiated by skin barrier dysfunction ("outside-in" hypothesis) or by
immune dysregulation ("inside-out" hypothesis) is still in debate.
Epidermal barrier — The epidermis is the first line of defense between the body
and the environment. The skin barrier keeps environmental irritants, allergens, and microbes from
entering the body and prevents excessive water loss. The barrier function of the skin is primarily
located in the stratum corneum, which consists of vertical stacks of anucleate corneocytes packed
with keratin filaments embedded in a matrix of filaggrin breakdown products [25]. The corneocyte
layers are embedded in an extracellular matrix replete with multiple lamellar bilayers enriched in
ceramides, cholesterol, and free fatty acids derived from secreted lamellar body precursor lipids [26].
The permeability of the epidermis is determined by complex interactions between terminal

differentiated keratinocytes on the surface of the skin and groups of structural proteins, such as
filaggrin, regulatory enzymes, and lipids. Filaggrin deficiency is a major determinant of defective
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barrier function [14]. Other factors that can result in skin barrier breakdown include imbalance
between stratum corneum protease (eg, kallikrein, stratum corneum chymotryptic enzyme) and
antiprotease activity (eg, LEKTI), tight junction abnormalities, microbial colonization, and release of
proinflammatory cytokines [27]. The tight junctions are located in the stratum granulosum below the
stratum corneum and are thought to seal the intercellular space to prevent the free diffusion of
macromolecules [28].
The epidermis of patients with atopic dermatitis is characterized by a genetically impaired skin
barrier function with increased transepidermal water loss [29]. These abnormalities may be present
at birth and predict the development of atopic dermatitis in the first year of life [30]. Higher levels of
transepidermal water loss in patients with atopic dermatitis have been associated with greater
disease severity [31,32].
Filaggrin — Filaggrin is a protein produced by differentiating keratinocytes encoded by the

FLG gene on the 1q21 epidermal differentiation complex, a cluster of more than 70 genes encoding
proteins involved in skin barrier formation and differentiation of stratified epithelia [33,34]. The cells
of the granular layer contain dense cytoplasmic granules primarily composed of profilaggrin, with
other protein components required for the formation of the corneocytes that are responsible for the
barrier function of the skin.
Following its synthesis, profilaggrin undergoes extensive phosphorylation, is stored in keratohyalin

granules, and subsequently dephosphorylated, resulting in the formation of filaggrin monomers that
have keratin-filament-aggregating properties. The hygroscopic free amino acids and their
derivatives, such as pyrrolidone carboxylic acid and trans-urocanic acid, resulting from the
breakdown of filaggrin, are major components of the natural moisturizer factor (NMF) [34]. NMF
maintains skin hydration and water retention within the stratum corneum in conditions of low
environmental humidity.
Other proteins in the stratum corneum — In addition to filaggrin,

other skin barrier-related proteins may be defective in atopic dermatitis skin. In one study, proteomic
profiling of patients with atopic dermatitis revealed that filaggrin-2, corneodesmosin, desmoglein-1,
desmocollin-1, transglutaminase-3, and enzymes involved in the production of natural moisturizing
factor (eg, arginase-1, caspase-14, and gamma-glutamyl cyclotransferase) were expressed at lower
levels in lesional sites than in normal skin [35].
Tight junction-related proteins — Abnormalities of the tight junction

function located in the granular layer of the epidermis may contribute to the decreased skin barrier
function observed in atopic dermatitis. Tight junctions are composed of a number of
transmembrane proteins, such as proteins of the claudin family, junctional adhesion molecule
(JAM)-A, occludin, and tricellulin. A reduced expression of the tight junction protein claudin-1 has
been demonstrated in nonlesional skin of individuals with atopic dermatitis [36].
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Genetics — A genetic basis for atopic dermatitis is suggested by twin studies that have
found concordance rates of 80 percent for monozygotic twins compared with 20 percent for
dizygotic twins [37-39]. Linkage studies and meta-analyses have implicated loci associated with skin
barrier abnormalities, in particular those located in the epidermal differentiation complex on
chromosome 1q21, which include the filaggrin gene (FLG) [40,41]. Subsequent genome-wide studies
(GWAS) and meta-analyses performed in European and Asian populations have confirmed this
association and identified additional susceptibility loci for atopic dermatitis [42-45].
FLG mutations — Loss-of-function mutations in the filaggrin gene FLG, including the
two initially reported (R501X and 2282del4) cause ichthyosis vulgaris, the most common inherited
disorder of keratinization, and are associated with a more severe phenotype of X-linked recessive
ichthyosis and pachyonychia congenita [14,46,47] (see "Overview and classification of the inherited
ichthyoses"). The same FLG mutations are major risk factors for atopic dermatitis and other skin and
allergic diseases including irritant contact dermatitis, asthma, and food allergy [14,40,48].
Two meta-analyses have confirmed the association of FLG mutations with atopic dermatitis [40,48].
In both studies, the risk of atopic dermatitis was more than fourfold higher in individuals carrying
either one or both R501X and 2282del4 mutations, compared with noncarriers. A subsequent case-
control study found that FLG mutations were associated with atopic dermatitis occurring at an early
age (≤8 years), but not with atopic dermatitis developing in late childhood or adulthood [49]. In
addition, in patients with a history of atopic dermatitis, homozygous FLG mutations appear to be
associated with increased prevalence and persistence of hand and foot dermatitis during adulthood
[50]. The FLG genotype may also influence the response to treatment. In a cohort study of 842
children enrolled in the Pediatric Eczema Elective Registry and followed-up for an average of 7.6
years, patients with homozygous loss-of-function FLG mutations were less likely to report any period
of skin clearance and more likely to report frequent steroid use than patients with wild-type FLG or
heterozygous FLG mutations [51].
SPINK5 — The SPINK5 gene encodes the protease inhibitor lymphoepithelial Kazal-type 5
serine protease inhibitor LEKTI that is involved in profilaggrin into filaggrin processing. LEKTI1 is
deficient in Netherton syndrome, a rare autosomal recessive disorder characterized by severe atopic
dermatitis and a specific hair shaft abnormality [52]. LEKTI inhibits a well-characterized protease
stratum corneum chymotryptic enzyme (SCCE) that is involved in cleaving the intercellular
attachments between corneocytes in normal desquamation process. LEKTI deficiency results in
upregulated SCCE function, increased cleavage of intercellular attachments, reduced corneocyte
cohesion, and compromised barrier function [53]. Several genetic association studies suggest a
contribution of LEKTI deficiency to the pathogenesis of atopic dermatitis [54-57].
Other genes — In addition to FLG and SPINK5, many other genes have been proposed as
potential contributors to atopic dermatitis, including genes involved in the formation of the skin
barrier or in immune regulation [58,59].
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A meta-analysis of genome-wide association study (GWAS) including approximately 11,000 atopic
dermatitis cases and 40,000 controls from 30 population-based cohorts of European descent
confirmed the association of atopic dermatitis with genes identified in previous GWAS (FLG on 1q21
and TNFRSF6B on 20q13) and identified three new susceptibility loci for atopic dermatitis: 5q31
(KIF3A), 11q13 (OVOL1), 19p13 (ADAMTS10/ACTL9) [42-44].
KIF3A encodes a component of the kinesin complex involved in assembly of cilia; OVOL1 belongs to
a highly conserved family of genes involved in the regulation of the development and differentiation
of epithelial tissues and germ cells; and ADAMTS are a group of complex secreted zinc-dependent
metalloproteinases, which bind to and cleave extracellular matrix components and are involved in
connective tissue remodeling and extracellular matrix turnover and inhibiting T cell chemotaxis [60].
Mutations in the gene TMEM79, encoding the protein mattrin, involved in the regulation of lamellar
body assembly, have been found in patients with atopic dermatitis who lack FLG mutations [61]. This
finding suggests that not only inherited deficiencies in structural proteins, but also mutations that
impair the delivery of lamellar body contents may be a predisposing factor for atopic dermatitis [25].
Immune dysregulation
Innate immune response — The innate immune system is the first-line rapid-
response mechanism to prevent microbial invasions. It consists of four major components: the
physical barrier (stratum corneum and intercellular junctions); antimicrobial peptides (AMPs),
cytokines, and chemokines; antigen-presenting cells, keratinocytes, mast cells, and PMNs; and the
skin-resident normal microbial flora [23]. The exposure to microorganisms through a defective or
injured physical barrier initiates a rapid, innate immune response that prevents further microbial
invasion and replication.
Keratinocytes and antigen-presenting cells in the skin express a number of innate immune receptors
called pattern recognition receptors, which include toll-like receptors (TLRs). Stimulation of TLRs by
tissue damage or microorganisms leads to the release of a wide range of inflammatory mediators,
including AMPs, cytokines, and chemokines, and enhances the strength of tight junctions to further
limit the penetration of allergens and microorganisms [62]. An additional function of TLRs is to
induce dendritic cell maturation, which determines the character and magnitude of the adaptive
immune response [63]. (See "An overview of the innate immune system".)
Patients with atopic dermatitis have been found to have reduced TLR2 and TLR9 function [23,63]. A
defect in this innate immune-mediated epidermal barrier repair process may lead to alteration in the
skin microbiome and more severe inflammation, as seen in patients with atopic dermatitis who are
colonized with Staphylococcus aureus [64]. While in normal skin AMPs production is upregulated by
two cytokines, IL-17 and IL-22, secreted by Th17 T and Th22 cells, this effect is abrogated in atopic
skin by the presence of Th2 cytokines [65].
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Adaptive immune response — The enhanced allergen penetration through
an impaired skin barrier resulting in a Th2-type milieu has been proposed as the critical link between
the primary barrier defect in patients with atopic dermatitis and Th2 polarization [24]. This
hypothesis is supported by the observation that in filaggrin-null mouse models with phenotypic and
histologic features of ichthyosis vulgaris, the topical application of allergens or protein antigens
resulted in IgE-mediated allergic sensitization and characteristic skin changes of atopic dermatitis
[66].
The acute initiation of atopic dermatitis lesions is characterized by increased expression of Th2,
Th22, and Th17 cytokines [67]. Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) appear to
modulate the epidermal barrier function by suppressing the expression of terminal keratinocyte
differentiation genes (eg, FLG, loricrin, involucrin), inhibiting the production of AMPs, and promoting
epidermal hyperplasia [67]. (See "The adaptive cellular immune response: T cells and cytokines".)
Thymic stromal lymphopoietin — Thymic stromal lymphopoietin (TSLP)

is an IL-7-like cytokine highly expressed in the epithelial cells at barrier surfaces (eg, skin, gut,
lung). TSLP promotes the development of naïve T helper cells into inflammatory Th2 cells and may
be a critical factor linking defective barrier function to Th2 responses to epicutaneous allergen
exposure [68-71]. TSLP polymorphisms have been proposed as markers of disease severity. A
multicenter case-control study demonstrated an association between variants of the TSLP gene and
risk of atopic dermatitis and eczema herpeticum (EH) [72]. Moreover, genetic variants of TSLP have
been associated with a decreased likelihood of having persistent atopic dermatitis, even in
individuals with FLG loss-of-function mutations [73].
PATHOLOGY Histologically, atopic dermatitis is characterized by epidermal

changes, including spongiosis (epidermal edema), with varying degrees of acanthosis and
hyperkeratosis, accompanied by a lymphohistiocytic infiltrate in the dermis. In the acute phase, the
histological picture is dominated by spongiosis, an intercellular epidermal edema that leads to
stretching and eventual rupture of the intercellular attachments, with the formation of vesicles.
Common features — Dry skin and severe pruritus are the cardinal signs of
atopic dermatitis. However, the clinical presentation is highly variable, depending upon the patient's
age and disease activity.
Acute eczema is characterized by intensely pruritic erythematous papules and vesicles with
exudation and crusting, whereas subacute or chronic lesions present as dry, scaly, or excoriated
erythematous papules. Skin thickening from chronic scratching (lichenification) and fissuring may
develop over time. In many patients, lesions in different stages may be present at the same time.
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Most patients with atopic dermatitis have a cutaneous hyperreactivity to various environmental
stimuli, including exposure to food and inhalant allergens, irritants, changes in physical environment
(including pollution, humidity, etc), microbial infection, and stress [27].
Atopic dermatitis occurs in the first year of life in 60 percent of cases and by the age of five years in
nearly 85 percent of cases. The clinical presentation at various ages is outlined below [74]:
●In infants and young children (zero to two years), atopic dermatitis typically presents with pruritic,
red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp (picture 1A-C). There is
usually sparing of the diaper area (picture 2) [74]. Acute lesions can include vesicles, and there can
be serous exudates and crusting in severe cases.
●In older children and adolescents (2 to 16 years), atopic dermatitis is characterized by less
exudation and often demonstrates lichenified plaques in a flexural distribution, especially of the
antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck (picture 3A-D) [74]. The
sides of the neck may show a reticulate pigmentation, the so-called "atopic dirty neck" (picture 4).
●In adults, atopic dermatitis is considerably more localized and lichenified. The areas involved are in
most cases the skin flexures (picture 5A-B). Less frequently, the dermatitis may involve the face,
neck (picture 4), or hands [74,75].
In all age groups, any area of the body can be involved in severe cases, although it is uncommon to
see lesions in the axillary, gluteal, or groin area; lesions in these locations should prompt
consideration of other diagnoses such as psoriasis, allergic contact dermatitis, or seborrheic
dermatitis. (See 'Differential diagnosis' below.)
Up to 80 percent of patients with atopic dermatitis have increased serum immunoglobulin E (IgE)
levels, often with increased eosinophilia. The IgE level tends to vary with disease severity, although
some patients with severe disease have normal IgE values.
Associated features — Patients with atopic dermatitis may present a variety

of cutaneous findings, so-called atopic stigmata, which include centrofacial pallor, white
dermographism, keratosis pilaris (picture 6A-B), palmar hyperlinearity, pityriasis alba (picture 7),
periorbital darkening and Dennie-Morgan infraorbital folds (picture 8), thinning or absence of the
lateral portion of the eyebrows (Hertoghe's sign), infra-auricular and retroauricular fissuring, and
nipple eczema [76]. Although considered minor diagnostic criteria, these findings are frequently seen
and may be supportive of the diagnosis of atopic dermatitis in some patients.
Clinical variants — Regional and morphologic variants of atopic dermatitis have

been described in both children and adults [76,77]. They may be the only manifestation of atopic
dermatitis or occur in association with the classic age-related manifestations. Regional variants
include:
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●Atopic hand eczema – Atopic hand eczema typically involves the volar wrists and dorsum of the
hands. It is most common in adults with a history of atopic dermatitis who no longer have dermatitis
in typical areas (eg, flexural), especially in those who are exposed to "wet-work" environments [78].
Concurrent foot eczema has been reported in approximately one-third of patients with atopic hand
eczema [79]. (See "Chronic hand eczema".)
●Eyelid eczema – Eyelid dermatitis is a common feature of atopic dermatitis and, in some patients,
may be the only manifestation [80]. It is often associated with lichenification and presence of
Dennie-Morgan lines.
●Atopic cheilitis – Lip eczema or "cheilitis sicca" is a common manifestation of atopic dermatitis,
characterized by dryness, peeling, and fissuring of the lips (picture 9). The clinical appearance may
be indistinguishable from irritant or allergic cheilitis. (See "Cheilitis".)
Morphologic variants include nummular, prurigo nodularis-type, and follicular type atopic dermatitis
[77,81]. (See "Nummular eczema" and "Prurigo nodularis".)
Clinical course and complications — Atopic dermatitis

follows a chronic relapsing course over months to years. Patients with mild disease may experience
intermittent flares with spontaneous remission, but patients with moderate to severe dermatitis
rarely clear without treatment.
The majority of patients are clear of eczema by late childhood, but the disease may persist into
adolescence and adulthood in a variable proportion of cases [7,9,82-85]. A pooled analysis of 45
studies including over 110,000 subjects found that 20 percent of cases of childhood atopic
dermatitis had persistent disease eight years after the diagnosis and less than 5 percent 20 years
after the diagnosis [86]. The age of onset was the main factor associated with persistence of atopic
dermatitis. The hazard ratio was 2.65 (95% CI 2.54-2.75) for onset at age two to five years, 4.22 (95%
CI 3.86-4.61) for onset at age 6 to 11 years, and 2.04 (95% CI 1.66-2.49) for age of onset at 12 to 17
years, compared with age of onset <2 years. Other risk factors for persistence were disease severity
and duration and female sex. Hypersensitivity to one or more allergens did not seem to influence the
persistence of atopic dermatitis.
Patients with atopic dermatitis are predisposed to the development of bacterial and viral skin
infections. Because Staphylococcus aureus colonizes nearly 100 percent of patients, impetiginization
of lesions of atopic dermatitis is frequent and is associated with disease exacerbation. However,
infection from community-acquired methicillin-resistant Staphylococcus aureus is uncommon among
children with atopic dermatitis [87-89].
Eczema herpeticum, also called Kaposi's varicelliform eruption, is the rapid dissemination of a
herpes simplex viral infection on the affected skin of patients with atopic dermatitis (picture 10A-C).
Eczema herpeticum is a rare complication, occurring in less than 3 percent of patients with atopic
dermatitis. Severe eczema, high levels of serum IgE, and history of food allergy or asthma appear to
be predisposing factors [90].
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COMORBIDITIES
Allergic rhinitis, asthma, and food allergy — Patients
with atopic dermatitis and genetic predisposition to produce IgE following exposure to allergens may
develop a typical sequence of atopic dermatitis, allergic rhinitis, and asthma at certain ages (the
"atopic march") [1,91,92]. Multiple studies indicated that the risk of progression to atopic march is
inversely associated with the age of onset of atopic dermatitis.
●A cohort study including nearly 4000 children with at least three years of follow-up found that the
cumulative incidence of seasonal allergies and asthma during the follow-up was higher among
children with atopic dermatitis onset before age 2 than among those with onset at ages 3 to 7 or 8 to
17 (39, 32, and 30 percent, respectively) [93]. However, since the age at onset was self-reported, a
misclassification bias cannot be excluded.
●In a Canadian cohort of 2311 children with atopic dermatitis, allergic sensitization detected by skin
prick testing at age one year was associated with a seven-fold increased risk of asthma at age three,
compared with absence of allergic sensitization (relative risk [RR] 7.04, 95% CI 4.13-11.99) [94].
Whether there is a cause-effect relationship between atopic dermatitis and subsequent development
of respiratory allergy is still debated. It has been hypothesized that epicutaneous sensitization to
allergens can occur in early life in children with atopic dermatitis due to the defective skin barrier,
therefore increasing the risk of other forms of allergic disease during childhood [95,96]. Several trials
are underway to evaluate whether the enhancement of a defective skin barrier with daily application
of emollients during the first months of life, which has been shown to halve the incidence of atopic
dermatitis in infants, also reduces the risk of early allergic sensitization and, therefore, the incidence
of respiratory allergy later in life [97-99]. (See "Treatment of atopic dermatitis (eczema)", section on
'Skin barrier enhancement'.)
Patients with atopic dermatitis also have an increased risk of food-induced urticaria/anaphylaxis
[100,101]. Studies suggest that environmental exposure to food allergens through an impaired skin
barrier is a plausible route for food sensitization and allergy [102,103]. In one study of 512 children
younger than 15 months with a history of atopic dermatitis, exposure to peanut antigen in household
dust was associated with a twofold increased risk of peanut sensitization and peanut allergy [104].
However, although in infants and young children the rate of food sensitization is high, ranging from
approximately 30 to 60 percent, depending upon the population and diagnostic test, the actual rate
of confirmed food allergy is much lower [100,105-109]. Thus, serum immunoglobulin E (IgE) should
not be used for the diagnosis of food allergy in the absence of clinical reactions to the ingestion of a
certain food. (See "Food allergy in children: Prevalence, natural history, and monitoring for
resolution".)
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Ichthyosis vulgaris — Approximately 10 to 30 percent of patients with atopic
dermatitis have ichthyosis vulgaris [110,111]. Hyperlinear palms (picture 11) and keratosis pilaris are
usually present in patients with atopic dermatitis and ichthyosis vulgaris. (See "Overview and
classification of the inherited ichthyoses", section on 'Ichthyosis vulgaris' and "Keratosis pilaris".)
Eye diseases — Ocular comorbidities occurring in patients with atopic dermatitis

include atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). AKC is a chronic
allergic ocular disease that occurs most often in adults with a history of atopic dermatitis [112]. VKC
most commonly occurs in children living in warm, dry subtropical climates [113]. Ocular itching,
burning, tearing, and mucus discharge are common symptoms. Complications include keratoconus,
infectious keratitis, and blepharitis. (See "Atopic keratoconjunctivitis" and "Vernal
keratoconjunctivitis".)
Obesity and metabolic syndrome — The association between

atopic dermatitis and obesity in children and adults is controversial [114-118].
●In a multicenter case-control study, 132 children aged 4 to 17 years with moderate to severe atopic
dermatitis were compared with 143 children with other skin problems [114]. Children with atopic
dermatitis were more likely than controls to have a body mass index (BMI) in the 97th percentile or
higher and a waist circumference in the 85th percentile or higher (odds ratio [OR] 2.64, 95% CI 1.15-
6.06, and OR 3.92, 95% CI 1.50-10.26, respectively). In addition, atopic dermatitis was associated
with a higher percentile of systolic and diastolic blood pressure after controlling for age, sex, and
family history of hypertension.
●A cross-sectional analysis of data from the Canadian Partnership for Tomorrow Project, including
nearly 260,000 Canadian residents aged 30 to 74 years, of whom approximately 21,000 had a history
of atopic dermatitis, found that atopic dermatitis was associated with a mild reduction in the risk of
hypertension (OR 0.87, 95% CI 0.83-0.90), type 2 diabetes (OR 0.78, 95% CI 0.71-0.84), myocardial
infarction (OR 0.87, 95% CI 0.75-1.00), and stroke (OR 0.79, 95% CI 0.66-0.95), after adjusting for age,
sex, ethnic background, BMI, smoking 100 cigarettes, weekly alcohol intake, average daily sleep, and
weekly physical activity [119].
●A 2015 systematic review and meta-analysis of 30 observational studies found that being
overweight and obese were associated with increased prevalence of atopic dermatitis in Asian and
North American populations (OR 1.23, 95% CI 1.11-1.41, and OR 1.47, 95% CI 1.21-1.79, respectively)
[120].
However, the mechanisms underlying this association are largely unknown.
Cardiovascular disease — Previous studies evaluating the association

between atopic dermatitis and cardiovascular (CV) disease provided conflicting evidence. A 2017
meta-analysis using adjusted data from 13 studies did not find an association between atopic
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dermatitis and myocardial infarction (pooled OR 1.03, 95% CI 0.88-1.21), stroke (OR 1.12, 95% CI
0.95-1.32), or hypertension (OR 1.10, 95% CI 0.97-1.24) but found a nearly 50 percent increased risk
of angina pectoris (OR 1.48, 95% CI 1.23-1.79) [121].
A subsequent large population-based study using 1998 to 2015 data from the United Kingdom
Clinical Practice Research Datalink compared the data from nearly 400,000 adult patients with
atopic dermatitis and 1.5 million controls matched by age, sex, calendar time, and age and date at
cohort entry [122]. This study found that patients with atopic dermatitis, and in particular those with
severe disease (as defined by treatment with systemic immunosuppressants, phototherapy, or
specialist referral), had an increased risk of CV disease, including myocardial infarction (hazard ratio
[HR] 1.37, 95% CI 1.12-1.68), unstable angina (HR 1.41, 95% CI 1.02-1.95), heart failure (HR 1.67, 95%
CI 1.36-2.05), atrial fibrillation (HR 1.35, 95% CI 1.14-1.59), and CV death (HR 1.30, 95% CI 1.10-1.53).
Although known confounding factors (eg, BMI, smoking, hypertension, hyperlipidemia, diabetes) had
been adjusted for, the possibility that the results were driven by residual confounding cannot be
excluded. In addition, this study could not determine whether atopic dermatitis per se or treatments
for atopic dermatitis confer an increased risk of CV disease.
Despite these caveats, this study indicates that in adults presenting with severe atopic dermatitis,
screening for CV disease and known risk factors for CV disease may be appropriate.
Anemia — An analysis of caregiver-reported and self-reported data on over 200,000 children

and adolescents from the United States National Health Interview Survey 1997 to 2013 found that
children with a history of atopic disorders, including eczema, asthma, hay fever, or food allergy, have
an increased risk of anemia (for eczema, OR 1.83, 95% CI 1.58-2.13) [123]. The risk was much higher
in children with all four disorders (adjusted OR 7.87, 95% CI 5.17-12). Using laboratory data from the
National Health and Nutrition Examination Survey 2014 to 2015 on over 30,000 children, the authors
found that children with a current history of atopic eczema had a twofold increased risk of anemia,
particularly microcytic anemia (OR 2.03, 95% CI 1.20-3.46).
Whether anemia in atopic children is related to chronic inflammation or malnutrition secondary to

dietary restrictions in patients suspected to have food allergies is unknown. Further ad hoc designed
studies are needed to confirm this association and clarify the underlying mechanisms.
Psychiatric disorders — There is a growing body of evidence that a number

of psychiatric disorders and symptoms, including impaired psychosocial functioning, attention
deficit hyperactivity disorder, depression, and anxiety disorders are more common among adults and
children with atopic dermatitis than in the general population [124-126]. The association of atopic
dermatitis with psychosocial distress and other psychiatric disorders may be influenced by the
perceived disease severity and other factors that affect negatively the quality of life, such as the loss
of sleep, disabling pruritus, and social embarrassment [125].
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Attention deficit hyperactivity disorder — The results of a 2010
systematic review of 20 studies including over 170,000 individuals and several subsequent
observational studies suggest an association between atopic dermatitis and attention deficit
hyperactivity disorder (ADHD) [124,127-130]. The mechanisms underlying ADHD and atopic
dermatitis are unknown. Sleep disturbance secondary to nocturnal pruritus, elevated levels of
psychological stress, and the effects of proinflammatory cytokines on brain development are the
leading hypotheses to explain this association [130-132]. (See "Attention deficit hyperactivity
disorder in children and adolescents: Clinical features and diagnosis" and "Attention deficit
hyperactivity disorder in adults: Epidemiology, pathogenesis, clinical features, course, assessment,
and diagnosis" and "Attention deficit hyperactivity disorder in children and adolescents:
Epidemiology and pathogenesis".)
Depression and anxiety disorder — Several cohort studies and meta-

analyses have found an association between atopic dermatitis and anxiety disorder, depression,
suicidal ideation, and attempted suicide in adults and children [124,133-137].
●An analysis of data on over 90,000 children from the 2007 National Survey of Children's Health in
the United States found that among children with atopic dermatitis the prevalence of depression and
anxiety disorders was significantly higher than among their peers without atopic dermatitis (6.5
versus 3.4 percent and 7.3 versus 4.1 percent, respectively) and showed an increasing trend with
increasing parent-reported severity of dermatitis [124].
●A large longitudinal cohort study using data from the Taiwan National Health Insurance Research
Database from 1998 to 2008 assessed the risk of developing major depression or anxiety disorders
later in life among more than 8000 adolescents and adults with atopic dermatitis and age- and sex-
matched controls [133]. This study found that patients with atopic dermatitis had an increased risk
of developing major depression (HR 6.56, 95% CI 3.64-11.84), any depressive disorder (HR 5.44, 95%
CI 3.99-7.44), and anxiety disorders (HR 3.57, 95% CI 2.55-4.98).
●A 2019 meta-analysis of 37 observational studies found a nearly twofold increased risk of

depression in patients with atopic dermatitis compared with individuals without atopic dermatitis
(OR 1.71, 95% CI 1.48-1.98); based on data from 14 studies, patients with atopic dermatitis were also
more likely to have suicidal ideation (OR 1.97, 95% CI 1.19-3.25) [137].
●The association between atopic dermatitis and suicidality was examined in another meta-analysis
of 15 observational studies including over 310,000 patients with atopic dermatitis and nearly 4.5
million controls [136]. Compared with persons without atopic dermatitis, patients with atopic
dermatitis were found to have an increased risk of suicidal ideation (pooled OR 1.44, 95% CI 1.25-
1.65) and suicide attempts (pooled OR 1.36, 95% CI 1.09-1.70). Two of the included studies reporting
on the risk of completed suicide among patients with atopic dermatitis provided conflicting results
[138,139].
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The results of these studies emphasize the need for a multidisciplinary approach to the
management of atopic dermatitis that includes patient/parent education and psychologic and
behavioral support (see "Treatment of atopic dermatitis (eczema)"). Clinicians treating atopic
dermatitis should be vigilant for depressive symptoms, especially in patients with severe disease
who may need psychiatric referral.
RISK OF LYMPHOMA The association between atopic dermatitis

and lymphoma is controversial [140,141]. A 2015 systematic review and meta-analysis of 4 cohort
studies and 18 case-control studies found a modest increase in the risk of lymphoma in patients
with atopic dermatitis compared with the general population [142]. The risk increase was significant
in the meta-analysis of the cohort studies (relative risk [RR] 1.43, 95% CI 1.12-1.81) but not in the
case-control studies (odds ratio [OR] 1.18, 95% CI 0.94-1.47). However, the large heterogeneity of
case-control studies in study design and diagnostic criteria does not allow any definite conclusion.
Three of the studies included in this meta-analysis reported a significant association between
severity of atopic dermatitis and cutaneous T cell lymphoma (CTCL) [143-145]. However, this finding
must be interpreted with caution because a misclassification bias cannot be excluded. Due to
overlapping clinical features, CTCL cases may have been initially misdiagnosed and treated as
severe atopic dermatitis.
Finally, this meta-analysis did not find a significant association between the use of topical
calcineurin inhibitors and risk of lymphoma in patients with atopic dermatitis, although one included
cohort study reported a significant fivefold increased risk of lymphoma associated with the use of
topical tacrolimus (RR 5.44, 95% CI 2.51-11.79) [146]. The use of high-potency topical
corticosteroids was also associated with increased risk of lymphoma (OR 1.73, 95% CI 1.52-1.97)
[142].
DIAGNOSIS The diagnosis of atopic dermatitis is clinical, based upon history,

morphology and distribution of skin lesions, and associated clinical signs [2]. The United Kingdom
working group on atopic dermatitis published criteria for diagnosing atopic dermatitis that include
one mandatory and five major criteria [147,148]:
●Evidence of pruritic skin, including the report by a parent of a child rubbing or scratching.
In addition to itchy skin, three or more of the following are needed to make the diagnosis:
●History of skin creases being involved. These include: antecubital fossae, popliteal fossae, neck,
areas around eyes, fronts of ankles.
●History of asthma or hay fever (or history of atopic disease in a first-degree relative for children <4
years of age).
●The presence of generally dry skin within the past year.
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●Symptoms beginning in a child before the age of two years. This criterion is not used to make the
diagnosis in a child who is under four years old.
●Visible dermatitis involving flexural surfaces. For children under four years of age, this criterion is
met by dermatitis affecting the cheeks or forehead and outer aspects of the extremities.
The UK working group's analysis excluded allergy criteria as originally proposed by Hanifin and
Rajka. The UK working group data have been validated by investigators from the Netherlands [149].
Skin biopsy and laboratory testing, including IgE levels, are not used routinely in the evaluation of
patients with suspected atopic dermatitis and are not recommended. However, in selected patients,
histologic examination of a skin biopsy or other laboratory tests (eg, serum immunoglobulin E,
potassium hydroxide preparation, patch testing, genetic testing) may be helpful to rule out other skin
conditions [2]. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS The differential diagnosis

of atopic dermatitis includes:
●Allergic or irritant contact dermatitis – Allergic or irritant contact dermatitis may be difficult to
differentiate from atopic dermatitis (picture 12). Moreover, allergic contact dermatitis may coexist
with atopic dermatitis [150]. The localization of dermatitis to a specific skin area, history of exposure
to irritants or potential sensitizers, and a relevant patch test positivity suggest the diagnosis of
contact dermatitis. (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Seborrheic dermatitis – Seborrheic dermatitis is the most common differential diagnosis in infants
(picture 13A-C). The two conditions may also coexist. The presence of salmon-red erythematous
skin patches with greasy scale, involvement of the scalp, and little or no pruritus support the
diagnosis of seborrheic dermatitis. (See "Seborrheic dermatitis in adolescents and adults" and
"Cradle cap and seborrheic dermatitis in infants".)
●Psoriasis –In contrast with atopic dermatitis, in infants and young children, psoriasis often
involves the diaper area, with well-demarcated erythematous patches with little scale (picture 14A-
B). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
●Scabies – Scabies may present as a diffuse eruption mimicking atopic dermatitis (picture 15). The
involvement of the skin folds (and, in infants, of the diaper area) and the presence of vesicopustules
on the palms and sole suggest the diagnosis of scabies. The demonstration of mites or eggs by skin
scraping, dermoscopy, or adhesive tape test can confirm the diagnosis. (See "Scabies: Epidemiology,
clinical features, and diagnosis".)
●Less common conditions that may be confused with atopic dermatitis include:
•Drug reactions (picture 16) (see "Exanthematous (maculopapular) drug eruption")
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•Primary immunodeficiencies, including Wiskott-Aldrich syndrome (picture 17) and
hyperimmunoglobulin E syndrome (picture 18) (see "Wiskott-Aldrich syndrome" and "Autosomal
dominant hyperimmunoglobulin E syndrome")
•Nutritional deficiencies, acrodermatitis enteropathica (picture 19) (see "Zinc deficiency and
supplementation in children")
•Netherton syndrome (picture 20A-B) (see "Overview and classification of the inherited ichthyoses",
section on 'Netherton syndrome')
•Cutaneous T cell lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of
mycosis fungoides")

provided separately. (See "Society guideline links: Atopic dermatitis".)

●Basics topics (see "Patient education: Eczema (atopic dermatitis) (The Basics)")
●Beyond the Basics topics (see "Patient education: Eczema (atopic dermatitis) (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Atopic dermatitis is a chronic pruritic inflammatory skin disease that occurs most frequently in
children, but also affects adults. A family history of atopy (eczema, asthma, or allergic rhinitis) and
the loss-of-function mutations in the filaggrin (FLG) gene, involved in the skin barrier function, are
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major risk factors for atopic dermatitis. (See 'Introduction' above and 'Epidemiology' above and 'Risk
factors' above.)
●The cardinal features of atopic dermatitis are dry skin and severe pruritus that is associated with
cutaneous hyperreactivity to various environmental stimuli, including exposure to food and inhalant
allergens, irritants, and infection. Erythema, papulation, oozing and crusting, excoriation, and
lichenification vary with the patient's age and stage of lesions. (See 'Clinical manifestations' above.)
●The diagnosis of atopic dermatitis is clinical, based upon history, morphology, and distribution of
skin lesions and associated clinical signs. Diagnostic criteria for the clinical diagnosis include:
•Evidence of pruritic skin (mandatory), plus three or more of the following major criteria
•History of dermatitis involving the skin creases
•Visible dermatitis involving flexural surfaces
•Personal or family history of asthma or hay fever
•Presence of generally dry skin within the past year
•Symptoms beginning in a child before the age of 2 years or, in children <4 years, dermatitis affecting
the cheeks or dorsal aspect of extremities
●Skin biopsy and laboratory testing, including immunoglobulin E (IgE) levels, are usually not
necessary in patients felt clinically to have atopic dermatitis. (See 'Diagnosis' above.)
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Role of allergy in atopic dermatitis (eczema)
uptodate.com/contents/role-of-allergy-in-atopic-dermatitis-eczema/print
INTRODUCTION There is some controversy with regard to the role of

allergy in atopic dermatitis (AD; eczema). Some clinicians believe that allergic responses to
aeroallergens are a rare cause of exacerbations of AD and that food allergy is generally not a factor.
Other clinicians believe that allergy plays a strong role in exacerbating AD in some patients [1]. They
believe that food allergies trigger symptoms primarily in young children and environmental allergens
play a greater role in older children and adults.
Despite its name, AD itself is not a type I allergy, nor is it necessarily associated with allergic
sensitization. However, overall, the data indicate that allergy plays a role in selected patients with AD.
The epidemiology, clinical manifestations, diagnosis, and treatment of AD, as well as the role of
delayed-type hypersensitivity to chemicals in topical medications and skin care products in
exacerbating AD, are discussed separately. (See "Atopic dermatitis (eczema): Pathogenesis, clinical
manifestations, and diagnosis" and "Treatment of atopic dermatitis (eczema)".)
ATOPIC ASSOCIATIONS Patients with AD have higher rates

of allergic diseases than the general population. Up to 80 percent of children with AD develop
asthma and/or allergic rhinitis later in childhood [2]. This progression from AD in infancy to allergic
rhinitis and asthma in childhood and young adulthood is referred to as the "allergic march" or "atopic
march" [3-6].
The converse is true as well. A higher rate of AD is seen in teenagers with asthma than those
without asthma (risk ratio [RR] 4.5, 95% CI 3.1-6.5) [7]. Ten to 20 percent of patients with AD have
food-induced urticaria/anaphylaxis [8,9] compared with 1 to 3 percent of the general population
[10,11]. In infants with eczema, the prevalence of immunoglobulin E (IgE)-mediated food allergy
confirmed by double-blind, placebo-controlled food challenge (DBPCFC), except in patients with a
history of anaphylaxis and positive specific IgE, ranges from 33 to 63 percent [8,12-16]. Earlier onset
(<3 months of age) and more severe AD is associated with high egg, milk, and/or peanut-specific IgE
[17]. Patients with AD and concomitant egg, peanut, or dust mite allergy are more likely to have AD
that persists beyond five years of age [18].
AD is also associated with elevated serum IgE. A high total serum IgE level is a strong risk factor for
AD in children from birth to six years of age [19]. Interleukin (IL) 13 variants are associated with
slightly higher total IgE levels and sensitization to food allergens, most commonly hen's egg, in
young children with AD [20]. In adults, elevated total IgE is associated with persistent eczema with a
wide distribution after 10 years of follow-up [21].
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AD is considered the major risk factor for development of food allergies. The current hypothesis is
that cutaneous sensitization through disrupted skin barrier leads to food sensitization and food
allergies. In particular, defects in serine peptidase inhibitor, Kazal type 5 (SPINK5) are associated with
food challenge-proven food allergy [22,23]. In addition, skin barrier impairment at birth predicts food
allergy at two years of age [24]. Thus, the concept of skin barrier for the prevention of food allergy is
under study in multiple clinical trials.
ALLERGEN SENSITIZATION Numerous studies have

demonstrated an increased rate of sensitization to both food and aeroallergens in patients with AD
[25]. On average, 50 percent of children and 35 percent of adults with AD are sensitized to common
allergens. However, these proportions vary widely (7 to 78 percent) [26,27].
Evidence of allergen sensitization is not proof of clinically relevant allergy. Confirming clinical
reactivity is especially important when food allergies are suspected in young children since
avoidance of food allergens can put growing children at nutritional risk. (See "Management of food
allergy: Nutritional issues" and 'Food allergies' below.)
Infants and young children with AD are more commonly sensitized to foods (wheat and egg
sensitization are most prevalent) [27,28]. Children over five years and adults are more commonly
sensitized to aeroallergens (dust mite sensitization is most prevalent in both children and adults)
[29]. A higher rate of dust mite sensitization in patients with AD is also seen with atopy patch testing
(APT) [30].
Several studies have compared allergic sensitization patterns in patients with AD from different
countries. The findings demonstrate a wide variability in sensitization patterns between countries
and confirm that allergic sensitization is associated with higher socioeconomic status:
●In the International Study of Asthma and Allergies in Childhood (ISAAC), 28,591 children aged 8 to
12 years from 20 countries were examined for flexural eczema and skin tested to at least six
common aeroallergens [31]. The point prevalence of AD ranged from <1 to 14 percent. The
percentage of children who had at least one positive skin prick test ranged from 0 to 74 percent. The
association of AD and allergic sensitization was stronger in affluent versus nonaffluent countries
(odds ratio [OR] 2.69, 95% CI 2.31-3.12 versus 1.17, 0.81-1.70).
●Similar findings were seen in a study of five- to six-year-old children with AD and allergic
sensitization in East and West Germany [32]. Only 36 percent of children with AD in East Germany
were skin prick test positive to at least one food or inhalant allergen compared with 50 percent of
children with AD in West Germany.
●In a randomized early prevention trial for asthma, baseline evaluation of 2184 infants with AD from
atopic families included total serum IgE and specific IgE to eight food and inhalant allergens [33]. A
total of 53 percent of infants had IgE ≥30 kU/L, with the percentage ranging from 35 to 67 percent in
12 different countries. Ninety-six percent of the infants had complete specific IgE results. Over half
of these infants were sensitized (specific IgE ≥0.70 kU/L), 19 percent monosensitized, and 37
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percent polysensitized. Nearly one-half were sensitized to at least one food, and one-third were
sensitized to one or more inhalant allergens (egg white, 42 percent; cow's milk, 27 percent; peanut,
24 percent; house dust mite, 21 percent; cat dander, 13 percent; tree pollen, 8 percent; grass pollen, 8
percent; and Alternaria, 4 percent). Rates of specific allergen sensitization varied widely between
countries. As an example, the rate of egg white sensitization was 54 percent in Australia and 23
percent in Belgium.
FOOD ALLERGIES Two types of dermatologic manifestations are

believed to be associated with food allergies: urticaria/anaphylaxis and food-exacerbated AD. Only
the second type of reaction is examined here. (See "Food-induced anaphylaxis" and "New-onset
urticaria".)
In food-exacerbated AD reactions, ingestion of the food acutely is thought to cause a flare of the
patient's AD (increased erythema and pruritus of eczematous lesions) [34]. The flare occurs within
minutes to a few hours if the reaction is IgE mediated but may take hours to days if the reaction is
non-IgE mediated. The patient has persistent lesions if the food is eaten chronically. (See "Clinical
manifestations of food allergy: An overview".)
The diagnosis of food allergy involves two steps: identification of the food sensitization and
confirmation of clinical allergy [35]. Identification involves history taking and allergy testing. Patients
are unlikely to have food allergies as a trigger of their severe AD if they have periods of clear skin on
a regular diet without medication. Food allergy is a more likely trigger if the onset or worsening of AD
correlates with exposure to the food. Infants with AD and food allergy may have additional findings
that suggest the presence of food allergy, such as vomiting, diarrhea, and failure to thrive [36]. (See
"History and physical examination in the patient with possible food allergy".)
Food allergy can be evaluated by either prick skin testing or in vitro testing for food-specific IgE.
Eosinophilia may be a predictor of food allergy in patients with AD [37]. The diagnostic utility of
patch testing for foods in patients with AD is under investigation and is discussed in detail
separately. (See "Diagnostic evaluation of food allergy" and "Overview of skin testing for allergic
disease", section on 'Skin conditions' and "Future diagnostic tools for food allergy", section on 'Atopy
patch testing'.)
In patients with AD, the rate of sensitization to foods ranges from 30 to 80 percent, depending upon
the population, but the actual rate of confirmed food allergy is much lower [27,38-40]. As an example,
52 percent of children in a birth cohort who developed AD during the first six years of life were
sensitized to at least one food allergen, but only 15 percent had challenge-confirmed food allergy
[27]. Wheat was the most common food to which patients were sensitized, but egg was the most
common food to which patients were allergic, as confirmed by food challenge.
Most patients with food sensitization and AD fall into a gray area in which the test is neither negative
nor above the 95 percent positive predictive value (PPV). Other patients may have suspected non-
IgE-mediated food allergy, for which no standardized diagnostic tests are available. Food challenges
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need to be performed in these cases to confirm clinical reactivity to the food(s) in question and
prevent malnutrition from inappropriate food avoidance [36].
Clinical reactivity can be confirmed by double-blind, placebo-controlled food challenge (DBPCFC) for
suspected IgE-mediated allergy or reproducible findings upon elimination and reintroduction of the
food for suspected non-IgE-mediated allergy. There is a risk of a more severe reaction, including
anaphylaxis, when foods are reintroduced [41,42]. The rate of food-exacerbated AD varies with the
severity of the eczema. Approximately 1 to 3 percent of children with mild AD, 5 to 10 percent with
moderate AD, and 20 to 33 percent with severe AD have food-induced AD [43-46]. Food-exacerbated
AD is rare in adults. (See "Oral food challenges for diagnosis and management of food allergies" and
"Diagnostic evaluation of food allergy".)
The following studies are illustrative:
●A subset of patients with AD (22 percent) was identified in a birth cohort of 512 children followed
until two years of age [38]. The children with AD were evaluated for food allergy. Food allergy was
diagnosed based upon a history of an immediate reaction to a food allergen and a positive skin prick
test/specific serum IgE or a history of suspected food allergy with no immediate reaction and either
an open elimination/challenge test (performed twice, considered allergic if positive both times) or a
DBPCFC.
Thirty-two percent of children in the above study were sensitized to at least one allergen [38].
However, clinical reactivity was confirmed in only 18 percent. Two children developed AD after they
had developed tolerance to the food. The rest of the children (16 percent) developed AD and adverse
reactions to food simultaneously and were considered to have food-exacerbated AD. Six children
had non-IgE-mediated cow's milk allergy only. Eight children had IgE-mediated food allergy. The
mean SCORAD (SCORing Atopic Dermatitis) index, a measure of AD severity, was higher in children
with non-IgE- or IgE-mediated food allergy than children without food allergy (28 and 30 versus 20,
respectively).
●Other studies have reported similar findings with regard to the frequency of food-induced AD
reactions in relation to the severity of AD. Food allergies play a role in exacerbating AD in up to 33
percent of patients with severe AD, 10 to 20 percent with moderate AD, and 6 percent with mild AD
[8,12,47].
●In another birth cohort study, 22 percent (122 of 562) of children had AD. Fifteen percent (18 of
122) were confirmed to have food allergy (by skin prick test, specific IgE, and food challenge). Most
children were also sensitized to other foods that they tolerated. Self-reported food allergy was
confirmed in less than one-third of cases.
●In a study of 125 children with suspected food allergy and elevated specific IgE, 84 to 93 percent of
the individual foods were successfully added back into the diet despite a history of AD [48].
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●In a study of 1087 children with moderate-to-severe AD who were enrolled at 3 to 18 months of age,
16 percent developed food allergy by six years of age. However, 95 percent PPV for food-specific IgE
could not be determined for any foods [44]. In this study, severity of AD was associated with
increased risk for food allergy (8 percent in the mild group and 25 percent in the severe group).
●In a study of 3- to 15-year-old patients with AD and suspected food allergies, 75 percent (52 of 69)
had positive challenges (average two foods, range one to three), based upon comparing pre- and
post-challenge photographs of representative skin lesion sites [49]. Most patients had negative-
specific IgE to the challenge-positive foods. Exclusion of these foods from the diet for three months
led to significant clinical improvement.
●A meta-analysis showing lack of benefit of exclusion diets in patients with AD is held up by some
as evidence of lack of a role for food allergy in AD [50]. However, 9 out of 10 of the randomized trials
in this meta-analysis enrolled patients with AD who were not selected for a suspicion of food allergy
based upon clinical history and/or test results. The single trial that did select for patients with
suspected food allergy (positive specific IgE to egg and suspected egg allergy) demonstrated that an
egg elimination diet led to improvements in the extent and severity of AD in half of infants with AD.
Food elimination diets — The findings above highlight that foods should
not be eliminated from the diet randomly without firm clinical suspicion. Nor should foods be
excluded from the diet long term (as opposed to short term for diagnostic purposes) based upon
positive skin or in vitro tests or patient history alone.
Test results should be correlated with the clinical history and clinical reactivity confirmed when
necessary by DBPCFC or elimination/challenge test. Elimination of food allergens in patients with
AD and confirmed food allergy can lead to significant clinical improvement. Patients should be
evaluated at regular intervals to determine if the food allergy has resolved. (See "Food allergy in
children: Prevalence, natural history, and monitoring for resolution".)
ENVIRONMENTAL ALLERGIES There are less

data on the role of environmental allergies in AD compared with food allergies. The data available
suggest that environmental allergens are a trigger of AD in a small subset of children and adults.
Patients who have environmental allergies as a trigger of AD have persistent disease with chronic
exposure to an allergen in the environment.
Aeroallergens — Exposure to aeroallergens may occur by inhalation or by direct skin

contact.
There are several lines of evidence that support the concept that immune responses in AD skin can
be elicited by aeroallergens in sensitized patients:
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●In one study of schoolchildren, sensitization to aeroallergens, particularly cat and dust mite,
correlated with disease severity [51]. These children had persistent AD on areas of exposure (eg, on
areas of their arms not covered by a shirt).
●A small study of adults with AD demonstrated that exposure to grass pollen in an environmental
challenge chamber for two consecutive days resulted in a significant worsening of AD (increased
SCORAD [SCORing Atopic Dermatitis] scores and itch intensity) compared with exposure to clean air
(placebo) [52].
●Atopy patch tests (APT) to aeroallergens elicit delayed-type eczematous reactions on uninvolved
skin in 40 to 85 percent of patients with AD [29,53-57]. Rates of positive APT are generally lower in
young children with mild AD and higher in older children and adults with moderate to severe AD.
Positive APT reactions are also more frequent in patients that have AD in an air-exposed distribution
pattern. However, APT results do not always correlate with disease extent, severity, or localization
[57]. Dust mites are consistently the most common positive aeroallergen and also appear to be the
most clinically relevant [29]. (See "Future diagnostic tools for food allergy".)
●Intranasal and bronchial challenges with aeroallergens cause pruritus and flare up of AD lesions in
some patients with AD [58,59].
●Effective measures to reduce house dust mite allergen lead to modest improvement in AD in
patients with sensitization to one or more aeroallergens [35,60].
●T cells that selectively respond to Dermatophagoides pteronyssinus (Der p 1) and other aeroallergens
have been isolated from AD skin lesions and allergen patch test sites [61-63].
An additional line of evidence in support of the role of environmental allergies in AD is that therapies
used for other atopic diseases are also effective in AD. Dust mite subcutaneous immunotherapy in
adults with chronic moderate AD improved eczema severity scores and reduced use of topical
glucocorticoids [64,65]. Anti-IgE (omalizumab) therapy improved AD in patients with concomitant
asthma [66-68]. (See "Treatment of atopic dermatitis (eczema)", section on 'Immunotherapy' and
"Management of severe atopic dermatitis (eczema) in children".)
Malassezia — Malassezia yeast is part of the normal cutaneous microflora and is found
predominantly in lipid-rich areas, such as the head and neck. Immune reactions, both IgE and T cell
mediated, to Malassezia species can also worsen AD [69,70]. IgE specific to Malassezia has been
found in adolescent and adult patients with refractory head and neck AD. These patients may
respond to antifungal therapy (eg, a one- to two-month course of daily itraconazole or ketoconazole
followed by long-term weekly treatment). In addition, topical calcineurin inhibitors may inhibit the
growth of Malassezia.
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EFFICACY OF ANTI-IgE
THERAPY Immunoglobulin E (IgE) neutralization therapy with the anti-IgE
monoclonal antibody omalizumab has been shown to be effective for the treatment of AD in some
patients [71]. Limited data from case reports, case series, and small, randomized trials suggest that
certain subgroups of patients are most likely to respond, such as those without filaggrin mutations
or those with lower elevations of total IgE. (See "Anti-IgE therapy", section on 'Other allergic
disorders'.)

SUMMARY
●Although there has been some controversy with regard to the role of allergy in atopic dermatitis
(AD; eczema), the bulk of the data indicate that allergy plays a role in selected patients with AD. (See
●Infants and young children with AD are more commonly sensitized to foods, whereas children over
five years and adults are more commonly sensitized to aeroallergens. However, evidence of allergen
sensitization is not proof of clinically relevant allergy. (See 'Allergen sensitization' above.)
●In patients with AD, the rate of sensitization to foods (positive skin or in vitro test) ranges from 30
to 80 percent, depending upon the population. The rate of confirmed food allergy is much lower.
Food allergies play a role in exacerbating AD in up to 33 percent of patients with severe AD, 10 to 20
percent with moderate AD, and 6 percent with mild AD. Elimination of food allergens in patients with
AD and confirmed food allergy can lead to significant clinical improvement. (See 'Food allergies'
above.)
●Foods should not be eliminated from the diet randomly without any clinical suspicion. Nor should
foods be excluded from the diet long term (as opposed to short term for diagnostic purposes) based
upon positive skin or in vitro tests or patient history alone. Test results should be correlated with the
clinical history and clinical reactivity confirmed when necessary by double-blind, placebo-controlled
food challenge (DBPCFC) or elimination/challenge test. (See 'Food elimination diets' above.)
●The data on the role of aeroallergens in exacerbating AD are less extensive. Dust mites are
consistently the most common positive aeroallergen and also appear to be the most clinically
relevant. Immune reactions, both immunoglobulin E (IgE) and T cell mediated, to Malassezia species
can also worsen AD. (See 'Environmental allergies' above.)
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Treatment of atopic dermatitis (eczema)
uptodate.com/contents/treatment-of-atopic-dermatitis-eczema/print
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INTRODUCTION Atopic dermatitis is a chronic, pruritic, inflammatory skin

disease that occurs most frequently in children but also affects many adults [1]. Clinical features of
atopic dermatitis include skin dryness, erythema, oozing and crusting, and lichenification. Pruritus is
a hallmark of the condition and is responsible for much of the disease burden for patients and their
families.
The goals of treatment are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and
minimize therapeutic risks. Standard treatment modalities for the management of these patients are
centered around the use of topical anti-inflammatory preparations and moisturization of the skin, but
patients with severe disease may require phototherapy or systemic treatment [2,3].
Conventional therapy for atopic dermatitis is reviewed here. The management of severe, refractory
atopic dermatitis in children and adults and the epidemiology, pathogenesis, clinical manifestations,
and diagnosis of atopic dermatitis are discussed separately.
●(See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)
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ASSESSMENT OF SEVERITY For the management
of the individual patient, it is important that clinicians evaluate the extent and characteristics of the
rash (eg, presence of erythema, excoriations, oozing, lichenification, clinical signs of bacterial
superinfection) and ask general questions about itch, sleep, impact on daily activities, and
persistence of disease [4]. Several disease severity scales (eg, the Scoring of Atopic Dermatitis
[SCORAD] index, the Eczema Area and Severity Index [EASI], and the Patient-Oriented Eczema
Measure [POEM]) and patient quality-of-life measurement scales have been tested and validated for
use in clinical trials, but they are not commonly used in clinical practice [4]. However, POEM, which
asks about the frequency of seven symptoms (itch, sleep disturbance, dryness, flaking, weeping or
oozing, bleeding, and cracking) in the previous seven days, typically takes less than two minutes to
complete and is available from the Centre of Evidence Based Dermatology [5].
A practical guide to visual assessment of eczema severity that also includes the evaluation of
disease impact on quality of life and psychosocial well-being has been proposed by the United
Kingdom National Institute for Health and Care Excellence:
●Mild – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on
everyday activities, sleep, and psychosocial well-being
●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized
skin thickening); moderate impact on everyday activities and psychosocial well-being, frequently
disturbed sleep
●Severe – Widespread areas of dry skin, incessant itching, redness (with or without excoriation,
extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation); severe
limitation of everyday activities and psychosocial functioning, nightly loss of sleep
GENERAL APPROACH The optimal management of atopic

dermatitis requires a multipronged approach that involves the elimination of exacerbating factors,
restoration of the skin barrier function and hydration of the skin, patient education, and
pharmacologic treatment of skin inflammation (algorithm 1) [6].
Patient education — Patient education is an important component of the

management of atopic dermatitis. A systematic review of nine randomized trials (2003
participants) of educational interventions for atopic dermatitis suggests that children and their
parents or caregivers may benefit from structured education provided by nurses or multidisciplinary
teams [7]. In the largest of these trials including 992 children and adolescents with atopic dermatitis
and their families, a six-week education program was compared with no intervention [8]. The
program consisted of two-hour weekly sessions covering medical, nutritional, and psychologic
issues and were carried out by a multiprofessional team of dermatologists or pediatricians,
psychologists, and dietitians. After one year, the decrease in the total severity of the Scoring of
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Atopic Dermatitis (SCORAD) score was greater in the intervention group than in the control group.
There was also a significant improvement in subjective assessment of severity, itching behavior, and
emotional coping.
Elimination of exacerbating factors — Exacerbating factors

in atopic dermatitis that disrupt an already abnormal epidermal barrier include excessive bathing
without subsequent moisturization, low-humidity environments, emotional stress, xerosis (dry skin),
overheating of skin, and exposure to solvents and detergents [9,10]. Avoiding these situations is
helpful for acute flares as well as for long-term management. Since atopic individuals tend to
respond more readily to pruritic stimuli, anything that tends to induce itch in an individual should be
avoided.
Adjunctive measures that can be useful in all patients with dermatitis include [11]:
●Avoid trigger factors such as heat and low humidity
●Treat skin infections such as Staphylococcus aureus and herpes simplex (see 'Management of
infection' below)
●Use antihistamines for sedation and control of itching (see 'Controlling pruritus' below)
●Manage stress and anxiety
Aeroallergens and food allergens — There is controversy regarding

whether environmental or food allergies are exacerbating factors in patients with atopic dermatitis.
(See "Role of allergy in atopic dermatitis (eczema)".)
Hypersensitivity to house dust mites (eg, Dermatophagoides pteronyssinus, Dermatophagoides farinae),

animal danders, molds, and pollens is thought to be associated with flares of atopic dermatitis
[12,13]. However, although many atopic dermatitis patients are sensitized to house dust mites,
reduction of house dust mite antigens in the atopic dermatitis patient's environment does not seem
to be useful for disease control [14,15].
There is a lack of evidence that dietary interventions are helpful in reducing the severity or
preventing flares of atopic dermatitis in unselected patients. Although approximately 50 percent of
children with atopic dermatitis may have positive skin prick tests or specific immunoglobulin E (IgE)
to one or more food allergens (in particular, cow's milk, egg, wheat, and peanut), food sensitization is
clinically irrelevant in most cases [16]. A systematic review of nine randomized trials including 421
children and adults with atopic eczema indicates that either milk and egg exclusion, a few-foods diet,
or an elemental diet are not beneficial in unselected patients with atopic dermatitis [17]. Moreover,
food restriction in toddlers may result in lower Z-scores of weight, height, head circumference, and
body mass index for age [18]. One trial suggests that an egg-free diet may be helpful for infants with
proven sensitivity to eggs [19].
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Contact allergens — Atopic individuals are at an increased risk for developing
allergic contact dermatitis (ACD) to nickel as well as to many components of topical treatments (eg,
fragrances, preservatives, neomycin) [20,21]. ACD should be suspected when patients do not
respond to appropriate topical therapy or when affected areas continue to spread beyond the usual
flexural locations.
Maintaining skin hydration

Emollients and moisturizers — Skin hydration is a key component of the
overall management of patients with atopic dermatitis. To maintain skin hydration, emollients should
be applied at least two times per day and immediately after bathing or hand washing.
Lotions, which have a high water and low oil content, can worsen xerosis via evaporation and trigger
a flare of the disease. In contrast, thick creams, which have a low water content, or ointments (eg,
petroleum jelly), which have zero water content, better protect against xerosis, but some patients
may complain that they are greasy.
Since atopic skin is deficient in stratum corneum lipids (especially ceramide) and "natural
moisturizing factor" (a mixture of hygroscopic amino acids resulting from filaggrin breakdown),
moisturizers that contain those ingredients may be beneficial. There are a number of topical
moisturizers available in the United States by prescription. These agents contain a variety of
components intended to improve skin barrier function but are expensive. There are few data
demonstrating their efficacy, but one randomized trial suggests that they are no more effective than
over-the-counter emollients [22].
A 2017 systematic review of 77 studies including 6603 participants (mean age 19 years) with mostly
mild to moderate eczema evaluated the efficacy of emollients and moisturizers in reducing the signs
and symptoms of eczema and the frequency of flares [23,24]:
●Based on both physician and patient assessment, the use of any moisturizers reduced eczema
severity and itch compared with no use, resulted in fewer flares, and reduced the need for topical
corticosteroids.
●In three studies, patients found that a moisturizer containing glycyrrhetinic acid (a natural anti-
inflammatory agent) was four times more effective than vehicle in reducing eczema severity.
●In four studies, patients using a cream containing urea (a humectant agent) reported improvement
more often than those using a control cream without urea.
●Three studies assessed a moisturizer containing glycerol (a humectant agent) versus control. More
patients in the glycerol group experienced skin improvement, both by physician and patient
assessment.
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●Four studies examined oat-containing moisturizers versus no treatment or control. No significant
difference in skin improvement was noted between groups, although patients using oat moisturizers
tended to have fewer flares and reduced need for topical corticosteroids.
Emollients are best applied immediately after bathing, when the skin is well hydrated.
Bathing practices
Frequency of bathing — Warm soaking baths or showers using mild or soap-free
cleansers should be part of the routine skin care for patients with atopic dermatitis. Some
controversy exists concerning the frequency of bathing and whether showering or bathing is
preferable in patients with atopic dermatitis [25-27]. Most experts recommend a hydrating bath
followed by immediate emollient application, but others recommend a shower of short duration. No
well-designed studies have been published to address this controversy. We feel that either option is
reasonable but suggest daily bathing to most patients. Whether bath or shower is preferred, rapid
application of emollients and/or prescribed topical preparations immediately after is important.
A small, randomized, single-blind, crossover trial examined the effect of frequent versus infrequent
bathing on atopic dermatitis. In this study, 42 children (median age 3.9 years, range 6 months to 11.5
years) with moderate to severe atopic dermatitis were randomized to two groups. Group 1 was
assigned to twice-weekly, soak-and-seal baths for 10 minutes or less for two weeks (infrequent
bathing) followed by twice-daily, soak-and-seal baths for 15 to 20 minutes for two weeks (frequent
bathing); group 2 did the inverse [28]. Frequent bathing was associated with a greater decrease of
SCORAD score from baseline compared with infrequent bathing (mean difference in SCORAD 21.2
[95% CI 4.9-27.6]).
Bath additives — We do not support the use of bath additives for atopic dermatitis.
However, despite a lack of high-quality studies providing evidence of benefit, bath emollient additives
(eg, liquid paraffin, oils with or without emulsifiers, colloidal oatmeal) are widely used to improve skin
hydration in children and adults with atopic dermatitis, especially in Europe, where their use is
supported by national and international guidelines [29,30]. In the United States, while the American
Academy of Allergy, Asthma, and Immunology's practice parameter for atopic dermatitis supports
the use of bath additives, the American Academy of Dermatology guidelines recommend against
them [2,31].
A large, well-designed, pragmatic, randomized trial demonstrated that emollient bath additives
provide no additional benefits beyond standard care in the management of atopic dermatitis [32,33].
In this study, 463 children aged 1 to 11 years with mild to moderate atopic dermatitis were assigned
to use bath emollient additives or no bath additives in addition to standard care (ie, leave-on
emollients and topical corticosteroids as needed) for 52 weeks. The primary outcome was eczema
severity assessed weekly by the Patient-Oriented Eczema Measure (POEM) over 16 weeks. At 16
weeks, there was no significant difference between the mean POEM score in the bath additives
group and that in the no bath additives group (7.5 versus 8.4). After adjusting for potential
confounders (eg, baseline severity, use of topical corticosteroids, use of soap substitutes), the POEM
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score in the no bath additives group was 0.41 (95% CI -0.27 to 1.10) points higher than in the bath
additives group, which is markedly lower than the accepted minimal clinically important difference
of three points [34,35]. Similar results were obtained at 52 weeks.
CONTROLLING PRURITUS The management of atopic

pruritus requires a multipronged approach that addresses the multiple factors involved in its
pathogenesis [36-40]. These include:
●Skin barrier disruption
●Aberrant type 2 immune response, with increased IgE production, eosinophilia, mast cell activation,
and overexpression of Th2 cytokines
●Itch mediators, such as histamine, nerve growth factor (NGF), substance P (SP), proteases, and
cytokines/chemokines (eg, thymic stromal lymphopoietin [TSLP], interleukin [IL] 2, IL-4, IL-13, and IL-
31)
●Hyperinnervation of skin and central sensitization of itch
Nonpharmacologic interventions — Optimal skin hydration

and moisturization and treatment with topical anti-inflammatory therapy are the cornerstone of
atopic itch management.
Tepid baths to hydrate and cool the skin, followed by application of emollients, can relieve itching. In
more severe cases, the use of wet dressings (wet wraps) helps soothe the skin, reduce pruritus, and
interrupts the itch-scratch cycle by limiting access to the skin. Emollients are applied to the skin, and
dampened cotton garments are worn over the affected area and covered with a dry garment [41].
The patient may use these dressings overnight if tolerated or change them every few hours during
the day. Antipruritic ingredients, such as phenol, menthol, and camphor, are found in some
moisturizers.
Psychologic interventions, including habit reversal training, relaxation training, and cognitive
behavioral therapy, have been reported as beneficial in patients with chronic pruritus [42-44].
Topical treatments — Topical anti-inflammatory therapy with topical

corticosteroids or topical calcineurin inhibitors is effective in controlling pruritus. In a meta-analysis
of 22 randomized trials including 481 adult patients, pimecrolimus 1% cream or tacrolimus 0.03 to
0.1% ointment were more effective than vehicle in reducing pruritus (odds ratio [OR] 0.64, 95% CI
0.61-0.68) [45].
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of mild to
moderate atopic dermatitis in patients aged ≥2 years, appears to be effective in reducing pruritus
[46]. Inhibition of PDE4 results in an increase in intracellular cyclic adenosine monophosphate,
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which causes a decrease in the production of pruritogenic cytokines [47].
Topical doxepin, a tricyclic antidepressant with potent H1- and H2-blocking properties, may be used
as a second-line treatment if others fail [48]. However, allergic contact dermatitis to this agent is
common [49].
Phototherapy — In patients with diffuse pruritus that is not controlled with topical
therapy alone, narrowband ultraviolet B (NBUVB) or ultraviolet A1 (UVA1) phototherapy are
therapeutic options [36,50,51]. The mechanism of action involves a reduced production of histamine
from mast cells and basophils. Moreover, as ultraviolet A (UVA) light penetrates deeper into the skin,
compared with ultraviolet B (UVB), it may also cause damage to Schwann and perineural cells,
resulting in decreased sensitivity to pruritus.
Both NBUVB and medium-dose UVA1 have been shown to be equally effective in reducing atopic
pruritus [52]. However, high-dose UVA1 may be more effective in reducing pruritus and other
symptoms of atopic dermatitis in individuals with darker skin types [50].
Oral antihistamines — Oral H1 antihistamines are widely used as a

therapeutic adjunct in patients with atopic dermatitis to alleviate pruritus [53]. The evidence
supporting their use is relatively weak since no large, randomized, placebo-controlled trials with
definitive conclusions have been performed. Nevertheless, first-generation, sedating antihistamines
(eg, diphenhydramine, hydroxyzine, and cyproheptadine) may be beneficial for patients with
disturbed sleep secondary to itch, although optimal doses and length of treatment have not been
determined [3].
The efficacy of second-generation, less-sedating H1 antihistamines, such as fexofenadine, cetirizine,

or loratadine, as an adjunct to topical treatment in adults and children with atopic dermatitis remains
uncertain, and their use should be limited to patients with concurrent symptoms of urticaria or
allergic rhinitis. A 2019 systematic review of 25 randomized trials, most of which were of low
methodologic quality, did not find evidence that these agents are effective in improving the
symptoms of atopic dermatitis [54]. In one of the trials including 795 children aged one to two years
with eczema, cetirizine 0.5 mg/kg per day for 18 months was no more effective than placebo in
reducing the Scoring of Atopic Dermatitis (SCORAD) score (from 24.9 to 15.2 in the cetirizine group
and from 25.1 to 15.7 in the placebo group) [55]. Another study including 400 adult patients with
atopic dermatitis found that fexofenadine 120 mg daily for one week reduced patient-assessed
pruritus more than placebo, although the reduction was probably not clinically significant (mean
change -0.75 in the fexofenadine group versus -0.5 in the placebo group on a pruritus scale of 0 to 8)
[56].
Oral immunosuppressants — The efficacy of oral cyclosporine in

improving pruritus and other symptoms of atopic dermatitis has been demonstrated in several
randomized trials [57,58]. Cyclosporine may be especially useful for the rapid control of pruritus
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associated with atopic dermatitis. However, recurrence is common upon discontinuation of
treatment.
Dupilumab — Dupilumab, a fully human monoclonal antibody inhibiting IL-4 and IL-13,
has been shown to rapidly and substantially improve atopic pruritus, even in patients with an
unsatisfactory cutaneous response. In an analysis of patients from two randomized trials who were
not clear or almost clear (Investigator's Global Assessment >1) after 16 weeks of treatment with
dupilumab or placebo [59], dupilumab was more effective than placebo in improving secondary
outcome measures, including pruritus (numerical rating scale -35 versus -9 percent) [60].
An analysis of data from 1505 adult and adolescent patients from four randomized trials showed
that the least-squares mean percent change from baseline of daily Peak Pruritus Numerical Rating
Scale scores was approximately -48 to -57 percent in the dupilumab groups compared with -19 to -31
percent in the placebo groups. The improvement in the dupilumab groups occurred by day 2 in
adults and day 5 in adolescents and was sustained through the end of treatment [61].
PATIENTS WITH MILD TO

MODERATE DISEASE
Initial treatment — Topically applied corticosteroids and emollients are the
mainstay of therapy for atopic dermatitis (algorithm 1) [2]. The choice of the corticosteroid potency
should be based upon the patient's age, body area involved, and degree of skin inflammation.
Topical calcineurin inhibitors may be an alternative to topical corticosteroids, in particular for the
treatment of the face, including the eyelids, neck, and skin folds.
Topical corticosteroids — For patients with mild atopic dermatitis, we suggest a

low-potency (groups 5 and 6 (table 1)) corticosteroid cream or ointment (eg, desonide 0.05%,
hydrocortisone 2.5%) (algorithm 1). Topical corticosteroids are applied one or two times per day for
two to four weeks. Emollients should be liberally used multiple times per day in conjunction with
topical corticosteroids. Emollients can be applied before or after topical corticosteroids [62]. (See
'Emollients and moisturizers' above.)
For patients with moderate disease, we suggest medium- to high-potency (groups 3 and 4 (table 1))
corticosteroids (eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate 0.05%). In
patients with acute flares, super high- or high-potency topical corticosteroids (groups 1 to 3 (table 1))
can be used for up to two weeks and then replaced with lower-potency preparations until the lesions
resolve.
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The face and skin folds are areas that are at high risk for atrophy with corticosteroids. Initial therapy
in these areas should start with a low-potency steroid (group 6 (table 1)), such as desonide 0.05%
ointment. High-potency topical corticosteroids are generally avoided in skin folds and on the face.
However, limited, brief use (five to seven days) of potent corticosteroids may produce a rapid
response, after which patients can be switched to lower-potency preparations.
Topical corticosteroid-based ophthalmic solutions can be used for the treatment of atopic dermatitis
involving the ear canal. (See "External otitis: Treatment", section on 'Glucocorticoids'.)
Maintenance therapy that includes intermittent use of a topical corticosteroid or a topical calcineurin
inhibitor may help prevent relapse. (See 'Maintenance and prevention of relapses' below.)
Efficacy and adverse effects — A systematic review of randomized trials identified

83 studies of topical corticosteroids for atopic dermatitis [63]. Although studies were of poor
methodologic quality and short duration (<4 weeks), all indicated a large therapeutic efficacy of
topical corticosteroids compared with placebo. No clear benefit has been demonstrated with more
than once-daily application [64-66].
Long-term use of topical corticosteroids, especially high- or super high-potency preparations, on

large body areas may lead to adrenal suppression. Other adverse effects include skin thinning,
telangiectasias, folliculitis, and contact dermatitis. (See "Topical corticosteroids: Use and adverse
effects", section on 'Adverse effects'.)
Topical calcineurin inhibitors — Topical calcineurin inhibitors are

nonsteroidal immunomodulating agents that, unlike topical corticosteroids, do not cause skin
atrophy or other corticosteroid adverse effects. They can be used as an alternative to topical
corticosteroids for the treatment of mild to moderate atopic dermatitis involving the face, including
the eyelids, neck, and skin folds [67,68].
Tacrolimus ointment and pimecrolimus cream are applied twice a day. Tacrolimus comes in two
strengths. The 0.1% formulation is appropriate initial therapy for adults (and those >15 years old),
and the 0.03% formulation is appropriate for children and for adults who do not tolerate the higher
dose. In patients who do not tolerate tacrolimus because of burning or stinging, pimecrolimus may
be better tolerated.
Both tacrolimus and pimecrolimus topical preparations are approved by the US Food and Drug
Administration (FDA) for use in children over the age of two years. However, concerns have been
raised by the FDA about a possible link to cancers, in particular lymphoma and skin cancer [69,70].
(See 'Long-term safety concerns' below.)
Efficacy and minor side effects — Topical calcineurin inhibitors are generally
recognized as being equal in strength to medium-potency (groups 4 and 5 (table 1)) topical steroids
and should be considered a second-line therapy [71]. In addition to its inhibitory effect on cytokine
production, topical tacrolimus causes alterations in epidermal antigen-presenting dendritic cells that
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may result in decreased immunologic response to antigens [72]. Pimecrolimus 1% cream is a
calcineurin inhibitor, like tacrolimus, that was developed specifically to treat inflammatory skin
conditions. Its mechanism of action is similar to topical tacrolimus, and it does not appear to have
systemic immune effects [73]. Transient burning, erythema, and pruritus are the most common
adverse effects [74].
The efficacy of tacrolimus has been demonstrated in several randomized trials and systematic
reviews [67,75,76]. Tacrolimus ointment, particularly the 0.1% preparation, may be more effective
than pimecrolimus cream, although it may also cause greater local irritation:
●A meta-analysis of 25 randomized trials including 6897 patients showed that tacrolimus 0.1% was
more effective than vehicle for the treatment of patients with moderate to severe atopic dermatitis
(44 percent of patients in the tacrolimus group improved by >90 percent versus 20 percent in the
vehicle group) [67]. Tacrolimus was more effective than hydrocortisone acetate and comparable in
efficacy to hydrocortisone butyrate. Pimecrolimus was more effective than vehicle in the treatment
of mild to moderate atopic dermatitis (33 percent of patients were clear or almost clear at three
weeks versus 10 percent of those who used the vehicle) and in preventing flares. Pimecrolimus was
less effective than betamethasone valerate, but its potency compared with hydrocortisone was not
evaluated in any of the included trials.
●A subsequent meta-analysis of four randomized trials comparing tacrolimus with pimecrolimus for
the treatment of atopic dermatitis including more than 1800 patients found that tacrolimus 0.1%
ointment was more effective than pimecrolimus 1% cream after six weeks of therapy in adult
patients (relative risk 0.58, 95% CI 0.46-0.72) [76]. In pediatric patients with moderate to severe
eczema, tacrolimus 0.03% was superior to pimecrolimus 1% (relative risk 0.65, 95% CI 0.57-0.75).
However, in the group of pediatric patients with mild to moderate eczema, there was no significant
difference between tacrolimus 0.03% and 1% pimecrolimus.
●In a systematic review of 31 randomized trials, pimecrolimus was significantly better than vehicle
in preventing flares at six months [77]. However, pimecrolimus was less effective than medium-
potency topical corticosteroids (triamcinolone acetonide 0.1% and betamethasone valerate 0.1%)
and tacrolimus 0.1%.
Long-term safety concerns — Although the topical calcineurin inhibitors in

controlled trials have appeared to be safe in adults and children [74,78-81], in 2005, based upon case
reports, animal studies, and the known risks with systemic calcineurin inhibitors, the FDA issued
warnings about a possible link between the topical calcineurin inhibitors and cancer [82] and, in
2006, placed a boxed warning on the prescribing information for these medications [83].
Issues of concern include:
●Animal studies in mice, rats, and monkeys have found an increased risk of lymphoma and skin
cancers with topical or oral exposure to calcineurin inhibitors.
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●As of December 2004, the FDA had received 29 reports of cancers in adults and children treated
with topical calcineurin inhibitors. Approximately half the cases were lymphomas, and the other half
were cutaneous tumors.
●Between January 2004 and January 2009, the FDA received 46 reports of new cancer cases among
children 0 to 16 years old who used topical pimecrolimus and/or topical tacrolimus (30
lymphomas/leukemias, 8 skin cancers, and 8 other cancers).
However, no definite causal relationship has been established [84], and two case-control studies did
not detect an increased risk of lymphoma among patients treated with topical calcineurin inhibitors
[85,86]. The Pediatric Eczema Elective Registry (PEER) is an industry-sponsored, ongoing cohort
study established in 2004, as part of the postmarketing commitments for the approval of
pimecrolimus, to evaluate the risk of malignancy in children. Among 7500 children enrolled between
2004 and 2014, five malignancies (two leukemias, one osteosarcoma, and two lymphomas) were
reported [87]. The standardized incidence ratio, based upon the age-standardized Surveillance,
Epidemiology, and End Results Program population, was 1.2 (95% CI 0.5-2.8) for all malignancies, 2.9
(95% CI 0.7-11.7) for lymphoma, and 2.0 (95% CI 0.5-8.2) for leukemia. Although the excess risk of
lymphoma and leukemia is not statistically significant, the authors acknowledge that the small
sample size and the resulting wide confidence interval may not allow the exclusion of all risk.
A subsequent meta-analysis did not find a statistically significant association between the use of
topical calcineurin inhibitors and risk of lymphoma [88], although an included cohort study reported
a fivefold increased risk of T cell lymphoma in patients exposed to topical tacrolimus (relative risk
5.44, 95% CI 2.51-11.79) [89].
Waiting for more reassuring data from larger studies, the following FDA recommendations seem
reasonable precautions [90,91]:
●Use these agents only as second-line therapy in patients unresponsive to or intolerant of other
treatments.
●Avoid the use of these agents in children younger than two years of age; clinical studies have
found higher rates of upper respiratory infections in children younger than two years who were
treated with pimecrolimus.
●Use these agents only for short periods of time and use the minimum amount necessary to control
symptoms; avoid continuous use.
●Avoid the use of these agents in patients with compromised immune systems.
Providers and patients will need to weigh the risks and benefits of topical calcineurin inhibitors in
comparison with those of other therapies. In particular, calcineurin inhibitors may continue to have
an important role in the management of atopic dermatitis in areas at high risk for skin atrophy when
treated with corticosteroids (eg, face) [92].
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Off-label use in infants — Topical calcineurin inhibitors have been approved in the
United States as second-line therapies for the short and intermittent treatment of mild to moderate
atopic dermatitis in adults and children aged ≥2 years. However, they have been used off-label in
children as first-line treatment for atopic dermatitis and in children <2 years, in the absence of long-
term studies evaluating their efficacy and safety compared with low- or mid-potency topical
corticosteroids [93].
A five-year, industry-sponsored, randomized trial evaluated the safety and long-term efficacy of
pimecrolimus 1% cream compared with low-potency (1% hydrocortisone) or medium-potency (0.1%
hydrocortisone butyrate) topical corticosteroids in over 2400 infants 3 to 12 months of age with mild
to moderate atopic dermatitis [94]. After five years, overall treatment success, measured by an
investigator global assessment score, was achieved in approximately 89 percent of children in the
pimecrolimus group and 92 percent in the topical corticosteroid group. Vaccine responsiveness,
growth, immune function, and cancer rates were similar in the two groups. The overall rates of
adverse events were also similar in the two groups, although episodes of bronchitis, infected
eczema, impetigo, and nasopharyngitis were slightly more frequent in the pimecrolimus group than
in the topical corticosteroid group.
Since the rates of cutaneous adverse events (eg, skin irritation, atrophy, telangiectasias) were not
reported in this trial, the advantage of using pimecrolimus rather than low- to mid-potency topical
corticosteroids for infants with mild to moderate atopic dermatitis remains unclear.
Crisaborole — Crisaborole is a boron-based, small molecule, topical phosphodiesterase 4

(PDE4) inhibitor approved by the FDA for the treatment of mild to moderate atopic dermatitis in
adults and children three months of age and older [95]. Preliminary studies in adolescents and
adults indicated that crisaborole 2% ointment may improve the clinical signs of atopic dermatitis,
including erythema, excoriation, exudation, lichenification, and, in particular, pruritus [46,96-98].
Adverse effects of topical crisaborole were mild and mainly limited to application site reactions
(pain, paresthesia). Systemic exposure to crisaborole has been shown to be limited even after
maximal use (3 mg/cm2) [98].
Two subsequent, phase III, multicenter, randomized trials (AD-301 and AD-302) were performed to
assess the efficacy and safety of topical crisaborole in patients with mild to moderate atopic
dermatitis [47]. In these trials, a total of 1522 patients ≥2 years of age were randomized to receive
crisaborole 2% ointment twice daily for 28 days. The primary efficacy endpoint (success) was
defined as an investigator's static global assessment (ISGA) score of 0 (clear) or 1 (almost clear)
with a two-grade or more improvement from baseline. At day 29, more patients in the crisaborole
groups than in the vehicle groups achieved success (32.8 versus 25.4 percent in AD-301 and 31.4
versus 18 percent in AD-302). Improvement was noted in pruritus, skin inflammation, excoriation,
and lichenification. Crisaborole-related adverse events occurred in 4.4 percent of patients, were mild,
and were limited to burning or stinging at the site of application.
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The long-term safety of crisaborole was evaluated in a 48-week, open-label, extension study
including 517 patients (60 percent children) who had completed the AD-301 and AD-302 trials
without experiencing adverse effects [99]. Patients with an ISGA score ≥2 initiated crisaborole
treatment twice daily for 28 days. Participants underwent an average of six treatment periods and
used an average of 133 g of crisaborole ointment per month. Adverse events, of which 86 percent
were mild or moderate, occurred in 10 percent of patients. The most frequently reported adverse
events were exacerbation of atopic dermatitis, burning or stinging in the application site, and
application site infection. Diarrhea or vomiting, side effects observed with oral PDE4 inhibitors, were
reported by approximately 1 to 2 percent of patients throughout the study. Rescue therapy with
topical corticosteroids or topical calcineurin inhibitors was needed by 22 and 26 percent of children
and adolescents, respectively, and 13 percent of adults.
Although crisaborole seems to be generally safe for long-term use, its efficacy remains uncertain
due to the strong placebo effect noted in trials [47,100]. Head-to-head studies comparing crisaborole
with established therapies for atopic dermatitis are needed to better define its role in the
management of mild to moderate atopic dermatitis.
Assessing adherence to topical treatment — Poor

adherence to prescribed topical therapies is a major cause of exacerbation of atopic dermatitis.
Assessing the patient's adherence to topical therapy is thus critical when evaluating the response to
initial treatment and need for additional therapy. While "steroid phobia" resulting in insufficient use of
prescribed topical corticosteroids is a common cause of treatment failure, the use of inadequate
amounts of emollients needs consideration as an additional obstacle to treatment success [101-
104].
In a Scottish, population-based study that included 844 patients with moderate to severe atopic
dermatitis who failed treatment in a primary care setting, the analysis of nearly 30,000 verified
prescriptions of relevant topical medications showed significant underuse. The median daily amount
of emollients used was 9.6 g in adults and 17.5 g in children, and the median monthly amount of
topical corticosteroids used was 47 g for male patients and 30 g for female patients, roughly
corresponding to an average daily use of 0.5 to 2 g [102].
Maintenance and prevention of relapses — We

suggest proactive therapy to prevent relapse in adolescents and adults with moderate to severe
atopic dermatitis (picture 1A-B) that responds to continuous therapy with topical corticosteroids or
calcineurin inhibitors (algorithm 1). After induction of remission, we suggest intermittent therapy
with moderate- to high-potency topical corticosteroids (groups 3 to 5) (table 1). The steroid should
be applied once daily to previously affected skin areas for two consecutive days per week (eg,
weekends) and may be continued for up to 16 weeks. Emollients can be liberally used multiple times
per day.
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Flares of atopic dermatitis that occur during intermittent treatment may be treated by resuming
continuous use of topical corticosteroids or calcineurin inhibitors that have been effective for the
patient in the past. Similar strategies for proactive therapy are recommended in multiple national
and international guidelines for the management of atopic dermatitis [2,31,105-107].
In infants and young children with moderate to severe atopic dermatitis (picture 2) who have
frequent flares, proactive, intermittent therapy with low-potency topical corticosteroids (groups 6 and
7 (table 1)) may be beneficial in preventing relapse [108]. The steroid should be applied once daily to
previously affected skin areas for two consecutive days per week (eg, weekends) and may be
continued for up to 16 weeks. Flares of atopic dermatitis that occur during intermittent treatment
may be treated by resuming continuous use of topical corticosteroids that have been effective for
the patient in the past.
In meta-analyses of randomized trials, proactive, intermittent therapy with moderate- to high-potency

corticosteroids or tacrolimus, after achieving disease control with continuous use of these agents,
was effective in reducing the risk of subsequent flares [109]. However, there were fewer adverse
effects with corticosteroids, as illustrated below:
●In a meta-analysis of four randomized trials, topical fluticasone propionate (once daily for two
consecutive days per week for 16 weeks) reduced the risk of a subsequent flare by 54 percent
(relative risk 0.46, 95% CI 0.38-0.55) [109]. No serious adverse events were reported.
●In a meta-analysis of three randomized trials, topical tacrolimus (once daily two to three days per
week for 10 to 12 months) reduced the risk of a subsequent flare by 22 percent (relative risk 0.78,
95% CI 0.60-0.78) [109]. Adverse effects included pruritus, burning sensation, skin infections, and
bronchopneumonia. In addition, four patients developed a cancer. (See 'Long-term safety concerns'
above.)
Treatment of acute exacerbations — In adolescents and

adults, an acute exacerbation of chronic atopic dermatitis can sometimes be aborted by a short
course of systemic glucocorticoids (eg, prednisone 40 to 60 mg/day for three to four days, then 20
to 30 mg/day for three to four days). This strategy is not recommended for infants and young
children. (See "Major side effects of systemic glucocorticoids" and "Management of severe atopic
dermatitis (eczema) in children", section on 'Systemic corticosteroids'.)
PATIENTS WITH MODERATE TO

SEVERE DISEASE Patients with persistent, moderate to severe
disease despite optimal topical therapy may require phototherapy or systemic immunomodulatory
therapy to achieve adequate disease control [3,57,110]. (See 'Phototherapy' below and 'Systemic
therapies' below.)
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Evidence on the efficacy and safety of phototherapy and systemic therapies for children is limited.
Thus, these treatments should be used only in older children in whom other management options
have failed and the disease has a significant impact on the quality of life [111]. (See "Management of
severe atopic dermatitis (eczema) in children".)
Phototherapy — Narrowband ultraviolet B (NBUVB), broadband ultraviolet B (UVB),

ultraviolet A1 (UVA1), or psoralens plus ultraviolet A (PUVA) radiation phototherapy are treatment
options for moderate to severe atopic dermatitis [3,29,112]. (See "UVB therapy (broadband and
narrowband)" and "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA)
photochemotherapy".)
We suggest NBUVB phototherapy rather than other forms of phototherapy as first-line therapy for
adult patients with moderate to severe atopic dermatitis that is not controlled with topical therapy
(algorithm 1). Phototherapy is usually administered two to three times per week. Topical
corticosteroids can be continued as needed during phototherapy. Additional emollients may be
necessary since phototherapy may increase skin dryness.
Phototherapy is not suitable for infants and young children. In older children and adolescents with
atopic dermatitis not controlled with topical therapies, NBUVB phototherapy may be a therapeutic
option, if available. However, the benefits of phototherapy must be weighed against potential
adverse effects. (See "Management of severe atopic dermatitis (eczema) in children", section on
'Phototherapy'.)
Phototherapy for the treatment of moderate to severe atopic dermatitis has been evaluated in a
limited number of randomized trials and systematic reviews. In a 2013 systematic review of 19
randomized trials including 905 patients, medium-dose UVA1 (30 to 60 J/cm2) and NBUVB were
more effective than other phototherapy modalities in reducing the clinical signs and symptoms of
atopic dermatitis as measured with several clinical scores [50].
Disadvantages of phototherapy include cost and need for multiple office visits per week. Moreover,
prolonged treatment may lead to an increased risk of melanoma and nonmelanoma skin cancer
[113-115].
Systemic therapies
Impact of COVID-19 pandemic — The coronavirus disease 2019 (COVID-
19) pandemic has led medical professional organizations, including the American Academy of
Dermatology, to issue provisional guidelines regarding the use of systemic immunomodulatory
drugs and biologic agents during the pandemic [116-118]. General information on the use of
systemic immunomodulatory therapies during the COVID-19 pandemic is provided elsewhere. (See
"Coronavirus disease 2019 (COVID-19): Management in hospitalized adults", section on
'Immunomodulatory agents'.)
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Dupilumab — We suggest dupilumab, rather than conventional immunosuppressant
agents, for patients with moderate to severe disease unresponsive to topical therapy alone for whom
phototherapy is not feasible or acceptable. Dupilumab is also an option for patients who are not
candidates for or failed previous treatment with conventional immunosuppressive agents, such as
cyclosporine, methotrexate, mycophenolate mofetil, or azathioprine. Compared with conventional
immunosuppressive agents, dupilumab has a favorable safety profile and may be used for long-term
treatment of atopic dermatitis [119,120]. However, cost may be a major consideration with
dupilumab.
Dupilumab is administered as subcutaneous injections two weeks apart. In adults, an initial dose of
600 mg is followed by a maintenance dose of 300 mg every other week. In children ≥12 years and in
adolescents, dosing is based on body weight. For patients <60 kg, the initial dose is 400 mg,
followed by a maintenance dose of 200 mg every other week; for patients ≥60 kg, the initial dose is
600 mg, followed by a maintenance dose of 300 mg every other week.
Topical corticosteroids are usually continued as needed during treatment with dupilumab.
Efficacy and adverse effects — Dupilumab is a fully human monoclonal antibody

that binds to the alpha subunit of the interleukin (IL) 4 receptor and inhibits downstream signaling of
IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in
atopic diseases, including asthma and atopic dermatitis. The efficacy of dupilumab for the treatment
of atopic dermatitis has been evaluated in multiple randomized trials and prospective cohort studies
of adult patients:
●The efficacy of dupilumab 300 mg or placebo given by subcutaneous injection weekly or every
other week was evaluated in two phase III trials of identical design, SOLO1 and SOLO2, which
included 671 and 708 adult patients with long-standing, moderate to severe atopic dermatitis not
controlled by topical treatments, respectively [59]. At 16 weeks, more patients in the dupilumab
groups than in the placebo groups achieved the primary endpoint of an Investigator's Global
Assessment (IGA) score of clear or almost clear (approximately 40 versus 10 percent). There were
no differences between trials and between weekly or biweekly dupilumab regimens. A 75 percent
reduction in the Eczema Area and Severity Index (EASI-75) score was achieved by 44 to 52 percent
of patients receiving dupilumab versus 12 to 15 percent of those receiving placebo. Rescue
treatment was required in approximately 50 percent of patients receiving placebo and 15 to 20
percent of those receiving dupilumab. Serious adverse events were rare in all groups; however,
injection site reactions and conjunctivitis occurred more frequently in the dupilumab groups than in
the placebo group. Exacerbation of atopic dermatitis was reported overall in three patients receiving
dupilumab and in eight patients receiving placebo.
●Of note, in an analysis of patients from the two trials described above who were not clear or almost
clear (IGA >1) at week 16 [59], dupilumab, compared with placebo, induced a greater improvement in
secondary outcome measures, including pruritus (numerical rating scale -35 versus -9 percent) and
quality of life (Dermatology Life Quality Index [DLQI] score ≥4-point improvement 59 versus 24
percent) [60].
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●The long-term efficacy and safety of dupilumab was subsequently evaluated in a randomized,
double-blind, multicenter trial (LIBERTY AD CHRONOS) [119]. In this study, 740 patients were treated
with dupilumab 300 mg once weekly, dupilumab 300 mg every two weeks, or placebo for 52 weeks.
All patients received concurrent treatment with topical corticosteroids (or topical calcineurin
inhibitors, if indicated) and were allowed to receive rescue treatments (topical or systemic
medications or phototherapy) after two weeks of dupilumab. The two coprimary endpoints were the
proportion of patients with both an IGA score of 0/1 (clear/almost clear), or a two-point or higher
reduction from baseline at week 52, and the proportion of patients achieving EASI-75 from baseline
to week 52. At week 52, more patients in the dupilumab plus topical corticosteroids groups achieved
the IGA endpoint and EASI-75 compared with those receiving placebo plus topical corticosteroids
(approximately 40 versus 13 percent, and 65 versus 22 percent, respectively). The rates of adverse
events were similar in the three groups (83 to 88 percent); however, patients in the dupilumab groups
experienced an approximately twofold higher frequency of eye disorders and noninfectious
conjunctivitis.
●An open-label, extension study including patients enrolled in previous randomized trials who
continued treatment with dupilumab 300 mg weekly confirmed a sustained efficacy of dupilumab
over time, with more than 60 percent of patients achieving a 90 percent reduction in the Eczema
Area and Severity Index (EASI-90) score at 56 and 76 weeks [120]. Approximately 50 percent of
patients received additional treatment with topical corticosteroids (44 percent) and topical
calcineurin inhibitors (13 percent). Four percent of patients required rescue systemic therapy.
●In a study evaluating the efficacy of dupilumab in 138 consecutive adult patients with difficult-to-
treat atopic dermatitis in a real-life setting, treatment with dupilumab for 16 weeks induced a mean
reduction of the EASI score of 73 percent [121]. A 50 percent reduction in the Eczema Area and
Severity Index (EASI-50) score, EASI-75, and EASI-90 were achieved by 86, 62, and 24 percent of
patients, respectively. Improvement also occurred in patient-reported outcomes, including Patient-
Oriented Eczema Measure (POEM) score, pruritus, and quality of life. The most frequent adverse
effects were conjunctivitis and eye irritation in 34 and 25 percent of patients, respectively.
Exacerbation or new onset of head and neck atopic dermatitis has been reported in adult patients
treated with dupilumab after a median time of 65 days after initiating dupilumab [122].
Studies of dupilumab in children and adolescents with atopic dermatitis are limited [123,124].
In a phase III, randomized trial, 251 adolescents aged 12 to 18 years with moderate to severe atopic
dermatitis were treated with dupilumab 200 or 300 mg every two weeks, dupilumab 300 mg every
four weeks, or placebo for 16 weeks [123]. Most participants had associated comorbidities,
including allergic rhinitis (66 percent), asthma (54 percent), and food allergy (61 percent), The
coprimary endpoints (proportion of patients with ≥75 percent improvement from baseline in the EASI
and an IGA score of 0/1 [clear or almost clear]) were achieved by a higher proportion of patients in
both the every-two-weeks and every-four-weeks groups compared with the placebo group (EASI-75:
42, 38, and 8 percent, respectively; IGA 0/1: 24, 18, and 2 percent, respectively). The most common
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adverse events were atopic dermatitis, skin infection, upper respiratory infection, and conjunctivitis.
The last was more frequent in the dupilumab groups than in the placebo group (10 to 11 versus 5
percent).
Cyclosporine — Oral cyclosporine is a short-term treatment option for patients with

moderate to severe atopic dermatitis (algorithm 1) [57,110]. Cyclosporine is typically given at a dose
of 3 to 5 mg/kg per day in two divided doses for four to eight weeks or longer, until improvement is
noted. The dose is then lowered to the minimum effective dose and maintained until stable
improvement is achieved. After cyclosporine withdrawal, treatment with topical corticosteroids and
emollients can be continued. (See 'Initial treatment' above and 'Maintenance and prevention of
relapses' above.)
Oral cyclosporine is not recommended in infants and young children with atopic dermatitis. In older
children and adolescents, the use of cyclosporine should be reserved for the most severe cases that
failed to respond to optimal topical treatment and where there is a significant, negative impact on
quality of life. (See "Management of severe atopic dermatitis (eczema) in children", section on
'Cyclosporine'.)
Efficacy and adverse effects — The efficacy of oral cyclosporine for the treatment
of atopic dermatitis has been evaluated in randomized trials and systematic reviews. In a 2013
systematic review of 34 randomized trials including 1653 patients with moderate to severe atopic
dermatitis, cyclosporine was more effective than placebo in five trials, with a mean improvement of
50 to 95 percent in different clinical severity scores after short-term treatment (10 days to 8 weeks)
[57]. In head-to-head trials, cyclosporine was more effective than prednisolone, intravenous
immunoglobulins, and phototherapy with ultraviolet A (UVA)/UVB. Higher doses (5 mg/kg per day)
lead to a more rapid response than lower doses (2.5 to 3 mg/kg).
Side effects of cyclosporine include nephrotoxicity, hypertension, hypertrichosis, gum hyperplasia,

and increased susceptibility to serious infections. Monitoring of patients receiving cyclosporine
includes measuring blood pressure and serum creatinine every two weeks for three months,
followed by monthly monitoring. Significant elevations of either are an indication to lower the dose
or stop treatment. (See "Pharmacology of cyclosporine and tacrolimus".)
Methotrexate — Methotrexate is a treatment option for the long-term control of moderate

to severe atopic dermatitis in adults and, less frequently, in adolescents and children [125].
Methotrexate is usually administered in a single weekly dose of 7.5 to 25 mg in combination with
daily supplementation with folic acid 1 mg to reduce the risk of several common methotrexate
toxicities. Methotrexate has a slow onset of action, and benefit may not be noted in the first few
months of treatment.
The use and dosing of methotrexate in children with severe atopic dermatitis is discussed
separately. (See "Management of severe atopic dermatitis (eczema) in children", section on
'Methotrexate'.)
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Efficacy and adverse effects — There is limited, high-quality evidence for the use
of methotrexate for the treatment of atopic dermatitis [125-128].
In an open-label, follow-up study that included 35 of 43 adult participants of a randomized trial

comparing methotrexate and azathioprine for the treatment of moderate to severe atopic dermatitis,
both agents were equally effective in reducing the Scoring of Atopic Dermatitis (SCORAD) score at
five years [127]. Viral respiratory infections were the most common adverse events in both treatment
groups. Serious adverse events requiring hospitalization occurred in 7 of 14 patients in the
methotrexate group and 1 of 11 patients in the azathioprine group and included pneumonia,
myocardial infarction, surgical wound abscess, bladder carcinoma, and exacerbation of atopic
dermatitis.
In a randomized trial comparing oral methotrexate 15 mg per week with cyclosporine 2.5 mg/kg per
day in 97 adult patients with moderate to severe atopic dermatitis, more patients in the cyclosporine
group than in the methotrexate group achieved the primary endpoint of a 50 percent reduction of
SCORAD at eight weeks (42 versus 8 percent, respectively) [126].
Common adverse effects of methotrexate include nausea and stomach upset, increased liver
enzyme levels, headache, fatigue, and malaise. Periodic routine laboratory testing, including
complete blood count and liver function, is required to monitor hematologic toxicity and
hepatotoxicity. (See "Major side effects of low-dose methotrexate".)
Other immunosuppressive agents — Second-line systemic

immunosuppressive agents for the long-term treatment of atopic dermatitis include azathioprine and
mycophenolate mofetil. Their use in children and adults with severe atopic dermatitis is discussed in
detail separately. (See "Management of severe atopic dermatitis (eczema) in children" and
"Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)
PATIENTS WITH SEVERE

REFRACTORY DISEASE The management of severe
refractory atopic dermatitis in children and adults is discussed separately. (See "Management of
severe atopic dermatitis (eczema) in children" and "Evaluation and management of severe refractory
atopic dermatitis (eczema) in adults".)
PREGNANT WOMEN The management of atopic dermatitis

during pregnancy is discussed separately [129]. (See "Recognition and management of allergic
disease during pregnancy" and "Recognition and management of allergic disease during pregnancy",
section on 'Atopic dermatitis' and "Dermatoses of pregnancy", section on 'Atopic eruption of
pregnancy'.)
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MANAGEMENT OF INFECTION Patients with
atopic dermatitis are at increased risk for cutaneous bacterial, viral, and fungal infections. Clinical
signs of bacterial superinfection, most often from S. aureus, include weeping, pustules (picture 3),
honey-colored crusting (picture 4), worsening of dermatitis, or failure to respond to therapy. The
presence of vesicles and punched-out erosions may be a sign of eczema herpeticum.
Staphylococcus aureus — S. aureus is a frequent skin colonizer in

patients with atopic dermatitis. A meta-analysis of 95 observational studies found that 70 percent of
patients with atopic dermatitis carried S. aureus on lesional skin (95% CI 66-74) and 39 percent on
nonlesional skin (95% CI 31-47) [130]. However, in patients without frank clinical infection, the role of
staphylococcal colonization in driving the disease severity is still unclear, although multiple lines of
evidence indicate that a relationship between heavy colonization and eczema severity does exist
[131]. An analysis of data from studies including patients with mild or severe atopic dermatitis found
a pooled colonization rate of 43 percent (95% CI 31-57) in patients with mild atopic dermatitis
compared with 83 percent (95% CI 74-89) in those with severe atopic dermatitis [130].
Clinically infected skin — Because of the universal skin colonization with S.

aureus in patients with atopic dermatitis, routine skin swabs for bacteriologic culture are not
recommended. However, skin and nasal swabs may be useful for recurrent infection, for infection
that does not respond to treatment, or if there is concern about antimicrobial resistance or clinical
suspicion of unusual organisms [132].
For patients with localized clinical infection, we suggest topical mupirocin. Mupirocin 2% cream is
applied twice a day for one to two weeks. A prolonged use of topical antibiotics should be avoided
because of the risk of inducing bacterial resistance. For patients with more extensive infection, we
suggest oral antibiotic therapy with cephalosporins or penicillinase-resistant penicillins [105]. Oral
antibiotics are given for two weeks. (See "Impetigo", section on 'Treatment'.)
Clinically uninfected skin — Multiple observations indicate that in patients

with atopic dermatitis without frank clinical infection there is a relationship between the epidermal
density of S. aureus and eczema severity or flare frequency [133-135]. Since sodium hypochlorite 6%
solution (liquid chlorine bleach) has activity against S. aureus, including methicillin-resistant
Staphylococcus aureus (MRSA), diluted bleach baths (obtained by adding 0.5 cup or 120 mL of 6%
bleach in a full bathtub [40 gallons or 150 L] of lukewarm water, or one-half of a teaspoon of bleach
in one gallon or four liters of lukewarm water) have been suggested as an adjunct to topical
treatment between episodes of clinical infection to reduce the cutaneous load of S. aureus and
improve symptoms [136].
However, studies evaluating the efficacy of bleach baths for atopic dermatitis have been scarce and
inconsistent [137-139]. A meta-analysis of four small, randomized trials (116 participants) found that
bleach baths were not more effective than plain water baths at four weeks in decreasing the severity
of atopic dermatitis as assessed by the Eczema Area and Severity Index (EASI) and by the body
612
surface area involved [140]. Emollients and topical corticosteroids were permitted in all studies.
Three of the four included studies also found a decrease in S. aureus density after both bleach and
normal baths, without a significant difference between groups. Moreover, one of the included trials
found that the addition of bleach baths to topical corticosteroids was not more effective than
corticosteroids alone in reducing the skin colonization in children with moderate to severe atopic
dermatitis [141].
The results of this meta-analysis indicate that bathing per se (with or without bleach) may be
effective in reducing the skin colonization from S. aureus and improving symptoms. However, since
bleach baths are inexpensive, well tolerated, and devoid of adverse effects, we continue to suggest
their use in patients with atopic dermatitis and frequent flares of clinically infected eczema.
The efficacy of other topical antiseptics or oral or topical antibiotics in improving the severity of
dermatitis is uncertain. A systematic review found insufficient evidence to recommend the use of
oral antibiotics for the treatment of atopic dermatitis in the absence of clinical infection [142,143].
The same review found that topical antibiotics or antiseptics reduced colonization with S. aureus in
patients with atopic dermatitis but could not conclude that treatment with these agents in
combination with topical corticosteroids induced greater clinical improvement than topical
corticosteroids alone. However, the systematic review was primarily based on poor-quality studies
and cannot definitively discount antimicrobial therapies for patients without overt infection.
Viral infections — Atopic dermatitis patients with lesions that are infected with
herpes simplex (called eczema herpeticum or Kaposi's varicelliform eruption) should be treated
immediately with oral antiviral therapy. Examination reveals skin with punched-out erosions,
hemorrhagic crusts, and/or vesicles (picture 5A-C). Involved skin may be pruritic or painful, and
lesions may be widespread. The diagnosis should be considered in patients who fail to respond to
oral antibiotics [144]. Cases of life-threatening dissemination have been reported, and intravenous
antiviral therapy may be necessary in severe cases [144]. (See "Treatment of herpes simplex virus
type 1 infection in immunocompetent patients".)
Patients with atopic dermatitis may also develop widespread molluscum contagiosum infections
(picture 6). (See "Molluscum contagiosum".)
Fungal infections — Dermatophyte infections are more common in patients with

atopic dermatitis and can be treated with standard regimens of topical or oral antifungals. (See
"Dermatophyte (tinea) infections".)
In addition, the Malassezia furfur yeast (a normal component of skin flora) may be an exacerbating
factor in patients with head/neck atopic dermatitis [145]. Elevated Malassezia-specific IgE levels
have been reported in these patients [145]. Treatment may result in improvement. (See "Role of
allergy in atopic dermatitis (eczema)", section on 'Malassezia'.)
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IMMUNOTHERAPY Allergen-specific immunotherapy (SIT) with
dust mite extract in sensitized patients with atopic dermatitis has been studied using both
subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) administration with
conflicting results [146-149]. A meta-analysis of eight randomized trials including 385 patients that
compared SIT (mostly using house dust mite allergens) with placebo found that patients in the SIT
group were more likely to experience treatment success, as assessed by patients or investigators,
than those in the placebo group (odds ratio [OR] 5.35, 95% CI 1.61-17.77) [150]. However, there was
considerable heterogeneity among studies regarding types, doses, and pharmaceutical preparations
of allergens; treatment schedules and duration; patients' age and disease severity; and assessment
of outcome. Although this meta-analysis suggests that SIT improves the course of atopic eczema, it
is unclear which patients may benefit from this form of treatment. SIT may be a treatment option for
patients with proven sensitization to house dust mites (eg, positive allergen-specific test,
exacerbation upon natural exposure to the allergen) and severe eczema that is not controlled with
conventional therapies [151]. (See "Subcutaneous immunotherapy for allergic disease: Indications
and efficacy".)
EXPERIMENTAL AGENTS
JAK inhibitors — Tofacitinib and baricitinib are oral small-molecule Janus kinase
(JAK) inhibitors approved for the treatment of rheumatoid arthritis that block multiple cytokine
signaling, including interleukin (IL) 4, IL-5, and IL-13, involved in immune response and inflammation.
A topical formulation of tofacitinib has been shown to have a modest beneficial effect in the
treatment of mild to moderate plaque psoriasis [152].
The efficacy of topical tofacitinib for the treatment of atopic dermatitis has been evaluated in a
phase IIa, randomized trial [153]. In this study, 69 adult patients with clinically stable, mild to
moderate atopic dermatitis were treated with tofacitinib 2% ointment or placebo twice daily for four
weeks. The primary endpoint was the percentage change from baseline in the Eczema Area and
Severity Index (EASI). At week 4, the mean percentage change from baseline in the EASI score was
significantly greater in patients treated with topical tofacitinib than in those treated with placebo (-82
and -30 percent, respectively). Moreover, the proportion of patients with a physician general
assessment score of clear or almost clear was higher in the tofacitinib group than in the placebo
group (73 versus 22 percent). Adverse effects, including infection, increased blood creatine
phosphokinase, and contact dermatitis, were mild and occurred in 31 percent of patients treated
with tofacitinib and 60 percent of those treated with placebo.
A phase II, randomized trial evaluated the efficacy of oral baricitinib plus topical corticosteroids
compared with placebo plus topical corticosteroids for the treatment of moderate to severe atopic
dermatitis in 124 adults [154]. At 16 weeks, more patients treated with baricitinib 4 mg achieved a 50
percent reduction in the Eczema Area and Severity Index (EASI-50) score from baseline (61 versus
37 percent). Baricitinib also improved pruritus and sleep. Adverse events occurred in 71 percent of
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patients in the baricitinib 4 mg group, 46 percent of those in the 2 mg group, and 49 percent of those
in the placebo group. Adverse events related to baricitinib included headache, increased blood levels
or creatine phosphokinase, decrease in the neutrophil count, and nasopharyngitis.
A 16-week, randomized trial evaluated the efficacy of the selective JAK-1 inhibitor upadacitinib given
orally at the dose of 7.5, 15, or 30 mg or placebo in 167 patients with moderate to severe atopic
dermatitis [155]. The percentage improvement of EASI from baseline was 39, 62, and 74 percent for
the upadacitinib 7.5, 15, and 30 mg groups, respectively, versus 23 percent for the placebo group.
Adverse events occurred in 71 to 79 percent of patients in the upadacitinib groups and 63 percent in
the placebo group and included respiratory infections, worsening of atopic dermatitis, and acne.
Although topical and oral JAK inhibitors seem to be promising treatments for atopic dermatitis,
larger studies of longer durations are needed to evaluate their long-term efficacy and safety.
Anti-IL-31 antibodies — Nemolizumab is a humanized monoclonal antibody

against the receptor A of IL-31, a newly discovered cytokine associated with chronic skin
inflammation and pruritus [156]. A phase II, 12-week, randomized trial evaluated the efficacy of
nemolizumab for the treatment of adult patients with moderate to severe atopic dermatitis not
controlled by topical corticosteroids or topical calcineurin inhibitors [157]. In this study, 264 patients
received subcutaneous nemolizumab at a dose of 0.1, 0.5, or 2 mg per kilogram of body weight or
placebo every four weeks or nemolizumab at a dose of 2 mg per kilogram every eight weeks with
placebo given at week 4. The primary outcome was the percentage improvement from baseline in
the score on the pruritus visual-analogue scale. At 12 weeks, pruritus was reduced by 44, 60, and 63
percent in the 0.1, 0.5, and 2 mg groups, respectively, versus 21 percent in the placebo group. The
body surface area affected by atopic dermatitis decreased by 8, 20, and 19 percent in the 0.1, 0.5,
and 2 mg groups, respectively, compared with 16 percent in the placebo group. Adverse events
occurred in approximately 70 percent of patients in all study groups and were generally mild, with
the most frequent being exacerbation of atopic dermatitis and respiratory tract infections.
Although nemolizumab appears to be a promising agent for the treatment of pruritus associated
with atopic dermatitis and the interruption of the itch-scratch cycle, larger studies of longer
durations are needed to evaluate its long-term efficacy and safety.
Anti-IL-13 antibodies — Lebrikizumab is a monoclonal antibody that binds

specifically to soluble IL-13, a pleiotropic T helper 2 cytokine that is likely to play a role in the
pathogenesis of barrier dysfunction and inflammation in atopic dermatitis, asthma, and pulmonary
fibrosis [158]. Lebrikizumab has been investigated for the treatment of asthma with inconsistent
results [159-161].
In a proof-of-concept, phase II, multicenter, randomized trial, 209 patients with moderate to severe
atopic dermatitis received subcutaneous injections of lebrikizumab 125 or 250 mg (single dose), or
125 mg or placebo every four weeks as an add-on to topical corticosteroid treatment [162]. At 12
weeks, more patients in the lebrikizumab 125 mg every four weeks group achieved the primary
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endpoint (EASI-50) compared with the placebo group (82 versus 62 percent). Lebrikizumab was
generally well tolerated; nonsevere infection was the most common adverse event and occurred with
similar frequency in all groups.
In a phase II, randomized trial, 280 adult patients with moderate to severe atopic dermatitis were
treated with lebrikizumab 125 mg every four weeks, 250 mg every four weeks, 250 mg every two
weeks, or placebo every two weeks for 16 weeks [163]. Rescue therapy with topical corticosteroids
was allowed. Compared with placebo, all lebrikizumab groups showed a dose-dependent,
statistically significant reduction in the EASI score at week 16. Common adverse effects in the
lebrikizumab groups included upper respiratory tract infection, nasopharyngitis, headache, injection
site pain, and fatigue.
The results of these studies indicate that lebrikizumab in combination with topical corticosteroids
may provide some additional benefit compared with topical corticosteroids alone; however, its
efficacy as long-term monotherapy for atopic dermatitis needs further confirmation.
Anti-IL-22 antibodies — A small, phase II, randomized trial evaluated the

efficacy and safety of intravenous fezakinumab, an IL-22 antagonist, for the treatment of atopic
dermatitis [164]. Sixty adult patients with at least a six-month history of moderate to severe atopic
dermatitis received fezakinumab (a loading dose of 600 mg at baseline, followed by 300 mg every
two weeks) or placebo for 12 weeks and were followed for 8 additional weeks. At 12 and 20 weeks,
the mean Scoring of Atopic Dermatitis (SCORAD) score decrease from baseline was greater in the
fezakinumab group than in the placebo group (13.8 and 18.8 points, respectively, in the fezakinumab
group versus 8 and 11.7 points, respectively, in the placebo group). Adverse events occurred with
similar frequency in the active treatment and placebo groups and were considered mild to moderate.
UNPROVEN THERAPIES
Complementary and alternative therapies
Probiotics — Probiotic therapy with Lactobacillus and other organisms has been studied
for the treatment of atopic dermatitis in infants and children but has proven to be of limited benefit
[165-169]. In a 2009 meta-analysis of 12 randomized trials including 781 participants, probiotics
were not more effective than placebo in reducing eczema symptoms and sleep disturbance [168]. In
addition, the use of probiotics did not reduce the need for other treatments, such as topical
corticosteroids. A subsequent meta-analysis of 25 randomized trials including 1600 participants
found that probiotics were associated with a modest, clinically insignificant reduction of the baseline
Scoring of Atopic Dermatitis (SCORAD) score (-4.5, 95% CI -6.8 to -2.2) [170].
A 2018 systematic review of 39 randomized trials (2599 participants) evaluated the efficacy of oral
live probiotics or placebo for the treatment of adults and children with mild to severe eczema [171].
The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species taken alone or in
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combination with other probiotics for a period of four weeks to six months. A pooled analysis did not
show a difference between probiotics and placebo in participant- or parent-rated severity of atopic
dermatitis (mean difference in SCORAD part C [pruritus plus sleep loss] score at the end of
treatment -0.44, 95% CI -1.22 to 0.33) or quality of life. Similarly, no difference between treatments
was noted when using clinician-rated disease severity (mean difference in SCORAD part A/B
[eczema extent and intensity] -2.24, 95% CI -4.69 to 0.20). An analysis using the total SCORAD score
suggested only a modest reduction in eczema severity of uncertain clinical significance (mean
difference -3.91, 95% CI -5.86 to -1.96) in patients taking probiotics compared with placebo. (See
"Prebiotics and probiotics for treatment of allergic disease".)
Dietary supplements — Dietary supplements, including vitamins, fish oil, and

plant-derived essential fatty acids, do not appear to be beneficial for the treatment of atopic
dermatitis [172-174]. Evening primrose oil and borage oil, which are rich in the essential fatty acid
gamma-linolenic acid, have been widely used for the treatment of atopic dermatitis as a
complementary and alternative medicine remedy [175,176]. However, studies of supplementation of
gamma-linolenic acid for eczema have provided conflicting results [177]. A meta-analysis of 19
randomized trials of evening primrose oil for the treatment of eczema in children and adults did not
find a significant difference in global eczema symptoms (assessed by both the participants and
clinicians) between the active treatment and the placebo groups [174].
Melatonin — Melatonin is a hormone produced in the pineal gland involved in the regulation
of sleep and circadian rhythms (see "Physiology and available preparations of melatonin"). It has
also been suggested that melatonin has antioxidant, anti-inflammatory, and immunomodulating
properties [178,179]. In children and adults with atopic dermatitis, abnormal melatonin levels have
been correlated with disease severity and degree of sleep disturbance [180-182].
In two small, randomized trials, melatonin supplementation reduced disease severity and improved
sleep in children and adolescents with atopic dermatitis [183,184]:
●In a crossover trial, 48 children with atopic dermatitis involving >5 percent of the body surface area
and a history of sleep disturbance interfering with daytime activities more than three days per week
in the previous three months were treated with oral melatonin 3 mg per day or placebo at bedtime for
four weeks and then, after a washout period of two weeks, were switched to the alternate treatment
for an additional four weeks [183]. Compared with placebo, melatonin was associated with a greater
decrease from the baseline in the total SCORAD score (-9.9 versus -0.7 points) and a greater
decrease of the sleep-onset latency time (-23 versus -1.2 minutes). No adverse effects were
reported.
●Similar results were provided by another randomized trial including 70 children of 6 to 12 years of
age with atopic dermatitis who received oral melatonin 6 mg or placebo an hour before bedtime for
six weeks, while continuing their usual treatment with topical corticosteroids and emollients [184]. At
the end of the study, children in the melatonin supplementation group compared with those in the
placebo group had a greater improvement in the total SCORAD score from baseline (-6.6 versus -2.6
points) and in the total Children's Sleep Habits Questionnaire (CSHQ) score (-5.5 versus -2.7 points)
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but not in the pruritus score. A decrease in the total IgE level and an increase in the total sleep time
per night were also noted in the melatonin group but not in the placebo group. No adverse effects
associated with treatment were reported.
Larger studies with longer follow-up are needed to establish the role and safety of long-term
melatonin supplementation in the management of atopic dermatitis in children and adolescents.
Chinese herbal medicine — Chinese herbal medications for atopic dermatitis

have been used for many years, but their efficacy and safety have not been adequately evaluated in
clinical trials [185,186]. A systematic review found three small, randomized trials and one open-label
trial of a commercial preparation of 10 traditional Chinese herbs (Zemaphyte, no longer available)
[187]. Two trials showed a reduction in erythema and skin surface damage and improvement in
sleep in the active treatment group but not in the placebo group. Another trial did not find any
significant difference between the active treatment and placebo groups. However, all studies were
small (less than 50 patients) and had methodologic flaws. (See "Chinese herbal medicine for the
treatment of allergic diseases", section on 'Therapy for atopic dermatitis'.)
Leukotriene receptor antagonists — Montelukast, an oral

leukotriene receptor antagonist approved for the treatment of asthma and allergic rhinitis in children
and adults, has been evaluated for the treatment of atopic dermatitis in a few randomized trials with
conflicting results.
A systematic review of five randomized trials including 202 adults and children older than six years
with moderate to severe atopic dermatitis evaluated the efficacy of oral montelukast (10 mg/day in
adults and 5 mg/day in children aged 6 to 14 years) given for four to eight weeks compared with
placebo (three studies) or conventional treatment with oral antihistamines and topical
corticosteroids (two studies) [188]. The main outcome measure was a reduction in disease severity
assessed by using validated score systems (ie, SCORAD; Eczema Area and Severity Index [EASI]; six
area, six sign atopic dermatitis [SASSAD]). The pooled analysis of three studies did not show a
difference between montelukast and placebo in improving disease severity (standardized mean
difference 0.29, 95% CI -0.23 to 0.81) and pruritus and in reducing the need for topical
corticosteroids. In the two studies comparing montelukast with conventional treatment, participants
using montelukast experienced improvement in disease severity in one study but no effect in the
other study [189,190]. All trials were of low quality with a significant risk of bias.
Because of the limited and low-quality available evidence, the role of leukotriene receptor
antagonists in the management of atopic dermatitis remains uncertain. While waiting for larger and
well-designed studies, we do not support the use of this class of agents for adults or children with
atopic dermatitis.
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REFERRAL Many patients with atopic dermatitis can initially be treated by a
nonspecialist. We suggest that patients be referred to a specialist (eg, dermatologist, allergist) in the
following circumstances:
●When the diagnosis is uncertain
●When patients have failed to respond to appropriate therapy
●If treatment of atopic dermatitis of the face or skin folds with high-potency topical corticosteroids
is being contemplated
●If treatment with systemic immunosuppressive agents is being considered
PREVENTION
Skin barrier enhancement — Epidermal barrier dysfunction is
recognized as a key factor in the initiation and progression of atopic dermatitis. Two randomized
trials, one performed in Japan and the other in the United States and United Kingdom, found that the
enhancement of a defective skin barrier with daily application of emollients in the first months of life
reduce the incidence of atopic dermatitis in infants at increased risk (ie, those with a parent or
sibling with atopic dermatitis) [191,192].
In the United States and United Kingdom trial, 124 neonates received daily emollients (oil, cream/gel,
or ointment) on the entire body surface. At 24 weeks, the cumulative incidence of atopic dermatitis
was 22 percent in the emollient group versus 43 percent in the control group, with a relative risk (RR)
reduction of 49 percent.
In the Japanese study, 118 neonates at increased risk of atopic dermatitis received a daily
application of an emulsion-type emollient from the first week of life or no treatment [192]. At 32
weeks, 19 of 59 infants in the emollient group and 28 of 59 infants in the control group had
developed atopic dermatitis (32 versus 43 percent, RR reduction 26 percent). There were no
differences between the two groups in the levels of IgE against egg white.
A cost-effectiveness analysis indicated that daily skin moisturization in the first six months of life is
likely a cost-effective strategy for the prevention of atopic dermatitis; among several emollient
products examined in the study, petrolatum was the most cost-effective [193].
However, two subsequent, larger, randomized trials did not confirm these findings:
●In the United Kingdom BEEP multicenter, pragmatic, parallel-group trial, 1394 newborns were
assigned to receive an emollient on the whole body at least once daily or standard skin care for 12
months [194]. At age two years, the primary outcome (eczema in the past 12 months) was present in
a similar proportion in the emollients group and in the control group (23 and 25 percent, respectively;
619
adjusted RR 0.95, 95% CI 0.78-1.16). Subgroup analyses according to the number of first-degree
relatives with atopic disease or eczema, FLG genotype, season of birth, water hardness, and
probiotic use found no evidence of interaction. Skin infections occurred more frequently in the
emollient group than in the control group (adjusted incidence rate ratio [IRR] 1.55, 95% CI 1.15-2.09).
●In the Norwegian PreventADALL randomized trial, 2397 newborns were assigned to four groups:
control group with no specific advice on skin care while advised to follow national guidelines on
infant nutrition; skin intervention group using emollients (bath oil and facial cream at least four days
per week); food intervention group, receiving early complementary feeding of peanut, cow's milk,
wheat, and egg; and combined skin and food intervention group [195]. The rate of atopic dermatitis
at 12 months was similar in all groups (8, 11, 9, and 5 percent in the no intervention, skin
intervention, food intervention, and combined intervention groups, respectively). Compliance to the
interventions was suboptimal, with full protocol adherence in only 27 percent of participants in the
skin intervention group and 32 percent of participants in the food intervention group.
Although the benefit of regular skin moisturization in the first months of life for the prevention of
atopic dermatitis remains uncertain, we are in favor of this simple and inexpensive intervention for
newborns at high risk of atopic dermatitis, especially in dry and cold climate conditions.
Probiotics and dietary supplements — Probiotic

supplementation in pregnant mothers and infants at risk for atopic dermatitis may prevent the
development of the disease in children younger than three years [196]. A 2014 meta-analysis of 16
randomized trials including approximately 3500 participants found that probiotics given in the
prenatal and postnatal period reduced the risk of atopic dermatitis in the first years of life in both
children at high risk of atopic dermatitis and in those from the general population (pooled odds ratio
[OR] 0.56, 95% CI 0.52-0.60) [197].
However, two subsequent, randomized trials did not confirm this finding [198,199]. In one study, a
multispecies probiotic preparation or placebo was given to 454 unselected women at 36 weeks
gestation and their infants to age six months [198]. At two years, the cumulative frequency of
eczema was similar in the probiotic and placebo groups (34 versus 32 percent; OR 1.07, 95% CI 0.7-
1.6). In another randomized trial including 184 children at high risk for allergic disease, probiotic
supplementation with Lactobacillus rhamnosus GG during the first six months of life did not
decrease the cumulative incidence of eczema at two years of age compared with placebo (29 versus
31 percent; hazard ratio [HR] 0.95, 95% CI 0.59-1.53) [199]. The cumulative incidences of asthma at
five years were also not significantly different in the two groups (10 versus 17 percent; HR 0.88, 95%
CI 0.41-1.87). (See "Prebiotics and probiotics for prevention of allergic disease".)
A few small, randomized trials have evaluated the role of vitamin D supplementation in the
prevention of winter-related exacerbation of atopic dermatitis [200-202]. In the largest study, 107
children with a history of atopic dermatitis worsening during winter were treated with 1000
international units daily of vitamin D or placebo for one month [200]. The primary outcome was a
reduction in the clinician-measured Eczema Area and Severity Index (EASI). At the end of the study,
the mean decrease in the EASI score was 6.5 in the vitamin D group and 3.3 in the placebo group.
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Although the results of these trials suggest that winter supplementation of vitamin D may be
beneficial for patients with atopic dermatitis, larger, well-designed studies are needed to clarify the
role of vitamin D in the prevention and treatment of atopic dermatitis.
Nutritional interventions — Previous international guidelines

recommended the use of hydrolyzed formula for the prevention of allergic diseases in high-risk
infants who cannot be exclusively breastfed [203,204]. However, the results of a 2016 systematic
review and meta-analysis of 37 randomized trials evaluating the effect of hydrolyzed formula in
infancy on the risk of childhood eczema, wheezing, allergic rhinitis, or food allergy do not support
this recommendation [205]. This meta-analysis did not find a significant difference between
hydrolyzed formula and standard cow's milk formula in the risk of eczema at age 0 to 4 years (OR
0.84, 95% CI 0.67-1.07) or 5 to 14 years (OR 0.86, 95% CI 0.72-1.02). (See "Introducing formula to
infants at risk for allergic disease".)


●Basics topics (see "Patient education: Eczema (atopic dermatitis) (The Basics)" and "Patient
education: Giving your child over-the-counter medicines (The Basics)" and "Patient education:
Topical corticosteroid medicines (The Basics)")
SUMMARY AND
RECOMMENDATIONS
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●The goals of treatment for atopic dermatitis are to reduce symptoms (pruritus and dermatitis),
prevent exacerbations, and minimize therapeutic risks. (See 'Introduction' above.)
●The optimal management requires a multipronged approach that involves the elimination of
exacerbating factors, restoration of the skin barrier function and hydration of the skin, patient
education, and pharmacologic treatment of skin inflammation (algorithm 1). (See 'General approach'
above.)
●We suggest that patients with mild to moderate atopic dermatitis be initially treated with topical
corticosteroids and emollients (Grade 2B). The choice of the corticosteroid potency should be based
upon the patient's age, body area involved, and degree of skin inflammation:
•For patients with mild atopic dermatitis, we suggest a low-potency (groups 5 and 6 (table 1))
corticosteroid cream or ointment (eg, desonide 0.05%, hydrocortisone 2.5%). Topical corticosteroids
can be applied once or twice daily for two to four weeks.
•For patients with moderate disease, we suggest medium- to high-potency (groups 3 and 4 (table 1))
corticosteroids (eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate 0.05%).
(See 'Topical corticosteroids' above.)
•The face and skin folds are areas that are at high risk for atrophy with corticosteroids. Initial therapy
in these areas should start with a low-potency corticosteroid (group 6 (table 1)), such as desonide
0.05% ointment for up to three weeks. (See 'Topical corticosteroids' above.)
●We suggest that patients with atopic dermatitis involving the face or skin folds that is not
controlled with topical corticosteroids be treated with a topical calcineurin inhibitor (ie, tacrolimus or
pimecrolimus) (Grade 2B). (See 'Topical calcineurin inhibitors' above.)
●We suggest proactive therapy to prevent relapse in adolescents and adults with moderate to severe
atopic dermatitis (picture 1A-B) that responds to continuous therapy with topical corticosteroids or
calcineurin inhibitors (Grade 2A). We suggest medium- to high-potency topical corticosteroids
(groups 3 to 5 (table 1)) rather than topical calcineurin inhibitors for proactive, intermittent therapy
(Grade 2B). Topical corticosteroids are applied once daily for two consecutive days per week for up
to 16 weeks. (See 'Maintenance and prevention of relapses' above.)
●Patients with moderate to severe atopic dermatitis that is not controlled with optimal topical
therapy may require treatment with phototherapy, dupilumab, or systemic immunosuppressants to
achieve adequate disease control (algorithm 1). These treatments are not suitable for infants and
young children. In older children and adolescents, they should be used when other management
options have failed and the disease has a significant impact on the quality of life. (See 'Patients with
moderate to severe disease' above.)
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Management of severe atopic dermatitis (eczema) in children
uptodate.com/contents/management-of-severe-atopic-dermatitis-eczema-in-children/print
Literature review current through: Apr 2020. | This topic last updated: Jan 20, 2020.
INTRODUCTION Atopic dermatitis (AD) is a common, chronic,

inflammatory skin disorder characterized by the presence of pruritic, eczematous dermatitis. In most
patients, the disorder is managed with careful skin care practices, barrier repair strategies, topical
therapies for inflammation, and the elimination of exacerbating factors. Patients with severe disease
that fails to improve with conventional therapy may benefit from second-line therapies, such as
phototherapy or systemic medications.
This topic reviews the causes and treatment of severe, refractory AD in children. The standard
management of AD, including maintenance of skin hydration, control of pruritus, topical anti-
inflammatory therapies, and management of infection, is discussed separately. The clinical
manifestations and diagnosis of AD and the role of allergy in AD are also discussed separately.
623
●(See "Role of allergy in atopic dermatitis (eczema)".)
DEFINITION OF SEVERE ATOPIC

DERMATITIS Most patients with AD have mild to moderate disease. However,
a subpopulation of patients develops severe symptoms. Severe AD may be loosely described as the
presence of widespread skin lesions, unremitting itching, or physically or emotionally disabling
disease that significantly compromises a patient's quality of life (picture 1 and picture 2). Patients
with severe AD that does not respond to first-line topical therapies may be classified as having
severe, refractory disease.
ASSESSMENT OF SEVERITY Clinical studies have

utilized scales for defining the severity of AD, such as the Investigator Global Assessment (IGA), the
Scoring of Atopic Dermatitis (SCORAD) index, and the Eczema Area and Severity Index (EASI) [1].
Although such scales are useful for standardizing the results of research studies, they are not
routinely used in clinical practice. Moreover, these measures may not reflect the disease severity as
perceived by the individual patients. The Patient-Oriented Eczema Measure (POEM), a fully patient-
derived and patient-assessed scale, has been proposed as a core instrument to complement the
clinician-assessed scales in the evaluation of disease severity and response to treatment in patients
with AD [2].
An international study involving over 1000 patients or parents of children with AD from 34 countries
found that the symptoms considered to be important by 80 percent of the participants included itch,
pain/soreness, skin feeling hot or inflamed, bleeding, involvement of visible or sensitive body sites,
cracks, sleep difficulties, amount of the body affected, and weeping/oozing [3]. A practical guide to
visual assessment of eczema severity that also includes the evaluation of disease impact on quality
of life and psychosocial well-being has been proposed by the United Kingdom National Institute for
Health and Care Excellence:
●Mild – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on
everyday activities, sleep, and psychosocial well-being.
●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized
skin thickening); moderate impact on everyday activities and psychosocial well-being, frequently
disturbed sleep.
●Severe – Widespread areas of dry skin, incessant itching, redness (with or without excoriation,
extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation); severe
limitation of everyday activities and psychosocial functioning, nightly loss of sleep.
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POTENTIAL CAUSES OF
REFRACTORY DISEASE Circumstances that may contribute
to severe or refractory AD include financial considerations, poor adherence or incorrect use of
medications, presence of environmental exacerbating factors, secondary infection, and
hypersensitivity reactions to topical treatments or other allergens (table 1). Prior to initiating second-
line treatments for AD, clinicians should ensure that severe, refractory disease is not a result of the
presence of an avoidable or treatable factor.
Poor adherence/incorrect medication use — For

many patients, a lack of adherence to the treatment regimen and basic skin care techniques
contributes to persistent disease. Over 50 percent of patients with AD do not administer treatment
as recommended by their clinicians [4-6]. Specific reasons for inadequate application of treatment
include financial considerations, concerns about medication side effects, patient dislike of topical
preparations, and insufficient time for clinicians to educate patients about skin care [7].
Topical corticosteroid phobia, defined as a concern or fear about using topical corticosteroids, is
common, with a prevalence among patients and caregivers ranging from 20 to over 80 percent
worldwide [8-10]. Corticosteroid phobia is likely a contributing cause of poor adherence to treatment
and treatment failure among patients with AD.
Exacerbating factors/environmental
triggers — Prior to initiating second-line treatments for AD, clinicians should ensure that
severe, refractory disease is not a result of the presence of an avoidable or treatable exacerbating
factor. Circumstances that may contribute to severe or refractory AD include noncompliance with
conventional therapy, secondary infection, hypersensitivity reactions to topical treatments, and
exposure to triggers of disease flares.
Exacerbating factors for AD may include low humidity environments, xerosis (dry skin), overheating
of skin, emotional stress, and exposure to irritating substances, such as harsh chemicals or soaps.
Avoiding these factors is helpful for avoiding acute flares as well as for long-term management,
although this is not always possible. (See "Treatment of atopic dermatitis (eczema)".)
Infection — Patients with AD are at an increased risk for secondary cutaneous bacterial,
viral, and dermatophyte infections. The possibility of secondary infection should be considered in
patients with skin lesions that appear refractory to conventional therapy. In particular, clinicians
should be aware of the possibility of Staphylococcus aureus and herpes simplex virus (HSV)
infections.
625
Colonization with S. aureus occurs more frequently in individuals with AD than in the general
population, and S. aureus is a common cause of secondary infection in these patients. The presence
of purulence or honey-colored crusts suggests S. aureus infection. Even in the absence of overt
infection, colonization by S. aureus may be an exacerbating factor for AD.
Secondary HSV infection (eczema herpeticum) may also occur and, rarely, may lead to life-
threatening dissemination of HSV in patients with AD. Punched-out erosions, hemorrhagic crusts,
and vesicles are indicators of this infection. Rarely, coxsackie virus and vaccinia virus (in smallpox
vaccine) can give a similar clinical picture [11,12]. (See "Treatment of atopic dermatitis (eczema)",
section on 'Management of infection'.)
Hypersensitivity reactions to treatment — Delayed

hypersensitivity reactions to contact allergens in topical emollients or medications are another
cause of an apparent lack of response to treatment. Allergic contact dermatitis can be caused by
vehicles or active ingredients in emollients (eg, lanolin, propylene glycol, fragrances, preservatives),
topical immunosuppressive medications (eg, corticosteroids, calcineurin inhibitors), and topical
antibiotics (eg, bacitracin, neomycin) [13-19].
Contact allergy to a topical emollient, medication, or other allergen (eg, nickel) should be considered
when patients present with AD that fails to respond to, or appears to worsen, with these therapies
[19,20]. The identification and elimination of a contact allergen can lead to rapid clinical
improvement in affected individuals. If a contact allergy is suspected, patch testing should be
performed to identify the responsible allergen. (See "Overview of dermatitis (eczema)", section on
'Allergic contact dermatitis' and "Contact dermatitis in children".)
Food and environmental allergies — In some cases, patients

with refractory AD may have undiagnosed food or environmental allergies that are worsening their
disease. It is therefore important to exclude immediate and delayed hypersensitivity through allergy
testing (skin prick testing, specific immunoglobulin E [IgE] measurement, and patch testing).
However, evidence of allergen sensitization is not proof of clinically relevant allergy. Confirming
clinical reactivity is especially important when food allergies are suspected in young children since
avoidance of food allergens can result in less than optimal nutritional intake.
The role of allergy in AD is discussed in detail separately. (See "Role of allergy in atopic dermatitis
(eczema)", section on 'Food allergies' and "Role of allergy in atopic dermatitis (eczema)", section on
'Environmental allergies'.)
Incorrect diagnosis — An incorrect diagnosis may account for a failure to

respond to conventional therapy. The possibility of other disorders that may present with clinical
features that resemble AD should be considered. These may include conditions such as cutaneous
T cell lymphoma, autoimmune disorders, and nutritional or immune system deficiencies (table 2).
626
GENERAL CONSIDERATIONS Patients with
refractory AD should be seen by a specialist (eg, dermatologist, allergist) familiar with second-line
treatments, such as phototherapy and systemic immunosuppressive agents. Because of the paucity
of randomized trials addressing the management of refractory AD in the pediatric age group, there is
a wide variability among clinicians in the use of second-line therapies for children with severe
disease [21,22]:
●In a European survey conducted among consultant members of pediatric dermatology societies
and special interest groups, including dermatologists (90 percent) and pediatricians (10 percent), 71
percent of the respondents used systemic immunosuppressive therapy for children with severe AD;
most of them stated that their choice of systemic therapies and dosing regimens would be the same
for young children and for older children and adolescents [23]. Cyclosporine was the first-line agent
of choice (43 percent), followed by systemic corticosteroids (31 percent) and azathioprine (22
percent). Cyclosporine was the most commonly used second-line agent (34 percent) and
methotrexate the most commonly used third-line systemic treatment (26 percent).
●A similar survey performed in the United States and Canada among members of the Society for
Pediatric Dermatology found that 86 percent of clinicians used systemic treatments for severe
pediatric AD [24]. The first-line systemic agents were cyclosporine, used by 45 percent of
participants, and methotrexate (30 percent). The most commonly chosen second-line agents were
methotrexate (31 percent) and mycophenolate mofetil (30 percent), whereas azathioprine was the
most commonly used third-line agent (33 percent) followed by mycophenolate mofetil (24 percent).
Only 5 percent of clinicians reported using oral corticosteroids as first-line treatment.
OUR APPROACH
Initial management — Because most of the second-line therapies for AD have
potential adverse effects and nearly all are off-label for this indication in children, patients should be
selected for these treatments only when conventional topical therapy does not provide sufficient
improvement. Thus, after excluding the factors potentially associated with recalcitrant disease, we
attempt a more intensive topical treatment with wet wraps for several days (see 'Potential causes of
refractory disease' above). This will help identify those children who are candidates for second-line
therapies.
Wet wraps — For children with persistent, severe AD despite optimal treatment with topical
corticosteroids and/or topical calcineurin inhibitors and for children with an acute, generalized
exacerbation of AD, we suggest wet wrap therapy with diluted medium-potency topical
corticosteroids (table 3) once to twice daily for 2 to 14 days. Wet wraps can be maintained for two or
more hours, as tolerated, and even overnight if patients feel comfortable. Wet wraps can also be
applied for a shorter time (eg, 15 to 30 minutes) two or three times per day.
627
Wet wraps consist of a bottom wet layer and top dry layer. They are generally applied on top of
emollients or topical corticosteroids and left in place for up to 24 hours [25]. Cotton clothing in two
layers may be sufficient for some cases, but elasticated cotton tubular bandages of appropriate size,
which can be cut to cover any part of the body, may be more convenient in some situations [26].
Special bodysuits for wet wrap therapy for infants and toddlers are also commercially available.
Because of the increased systemic absorption of topical corticosteroids with wet wraps, some
experts suggested that diluting low- to mid-potency topical corticosteroids in emollients (eg, 1:19 for
face and body in infants and young children) and limiting the duration of treatment to a few days
may reduce the risk of hypothalamic-pituitary-adrenal axis suppression [27,28]. Measurement of
early morning fasting serum cortisol before and after treatment may be used to assess systemic
absorption, although it is not generally performed for short-term use.
Data on the efficacy of wet wraps are sparse and inconsistent, due to a wide variability across
studies in the treatment modality (eg, type of bandage used, frequency of application, treatment
duration) and patient characteristics (eg, AD severity, body area involved) [29]. While several
observational studies and a few small randomized trials support their efficacy as a short-term
treatment (2 to 14 days) to induce a rapid remission in children with severe disease, other studies
suggest that wet wraps are as effective as conventional treatment with topical corticosteroids and
emollients [25,30,31]. Adverse effects include increased systemic absorption of topical
corticosteroids, general discomfort, chills, and folliculitis. Temporary decreases in early morning
serum cortisol levels have been reported, although short courses (<2 weeks) of use of diluted low- to
mid-potency corticosteroids have not been associated with prolonged adrenal suppression [25].
Second-line therapies
Phototherapy — For older children (eg, older than six years who can cooperate with
treatment) and adolescents with refractory AD that does not respond to the more intensive topical
regimen with wet wraps, we suggest phototherapy with narrowband ultraviolet B (UVB), if feasible.
Narrowband UVB is usually administered three times per week, with a progressive protocol that
increases the dose with each treatment, as tolerated. The patient is usually reassessed after 20 to 25
treatments. (See "UVB therapy (broadband and narrowband)", section on 'Dosimetry and treatment
protocols'.)
Because of its favorable safety profile and wide availability, narrowband UVB is a more appropriate
initial choice than other forms of phototherapy (eg, ultraviolet A1 [UVA1], psoralens plus ultraviolet A
[PUVA], broadband UVB) for the treatment of severe, refractory AD in children. (See "UVA1
phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
Data on the efficacy of narrowband UVB phototherapy in children with AD are limited to a few
retrospective case series and one prospective study [32-35]. In a small study, 77 children (age 4 to
16 years) with psoriasis or AD were treated with narrowband UVB phototherapy [32]. Of 25 children
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with AD, 17 achieved minimal residual disease after a median of 24 treatments. In another
retrospective study, 50 children with severe AD received more than 10 exposures to narrowband UVB
[35]. Complete clearance or good improvement was reported in 30 children.
Data on the short- and long-term safety of narrowband UVB phototherapy in children are sparse. In
one study, adverse effects included erythema, blistering, herpes simplex reactivation, and anxiety
[32]. There are no studies evaluating the carcinogenic risk of phototherapy in children with AD.
Although a systematic review of four studies assessing the risk of skin cancer among adults and
children with psoriasis treated with narrowband UVB did not find an increased risk of melanoma or
nonmelanoma skin cancer, patients receiving narrowband UVB phototherapy should be monitored
with yearly skin examination [36,37].
Cyclosporine — For children and adolescents with refractory AD for whom phototherapy
is not accessible or impractical, cyclosporine is our first-choice immunosuppressive agent.
Cyclosporine has a rapid onset of action, and its effects can be noticed in the first few weeks of
treatment. Cyclosporine is given at the dose of 3 to 5 mg/kg/day in two divided doses for two to four
months. The dose can then be gradually tapered over several months (eg, by 1 mg/kg/day every one
to three months) and stopped once stable improvement is achieved. Thereafter, intermittent therapy
with 3 mg/kg or 5 mg/kg per day given twice weekly (eg, on Saturdays and Sundays) may be an
option to prevent relapses while minimizing toxicity [38].
Cyclosporine has been shown to be effective in inducing remission in adults and children with
severe AD [39]. In a systematic review and meta-analysis of 15 controlled and uncontrolled clinical
trials including 602 adult and pediatric patients with AD who were treated with cyclosporine, the
mean relative decrease in AD severity (based on AD severity scores) from baseline was 55 percent
(95% CI 48-62) after six to eight weeks of continuous treatment [39]. After the first two weeks of
treatment, disease severity decreased by 22 percent (95% CI 8-36) in patients treated with low-dose
cyclosporine (2.5 to 3 mg/kg) and by 40 percent (95% CI 29-51) in those treated with high-dose
cyclosporine (4 to 5 mg/kg). However, there was considerable heterogeneity among the individual
trials regarding the dose and duration of cyclosporine therapy and the comparator (for studies that
included a control group). Adverse events reported in these studies included gastrointestinal
symptoms (40 percent), elevations in creatinine (11 percent), and newly diagnosed infections (6
percent). Headache and paresthesias were also common. Adverse events were more common in
patients receiving higher doses of cyclosporine. In the three trials that reported on relapse rates after
stopping therapy, approximately 50 percent of patients relapsed within two weeks.
Renal and hepatic function must be monitored during treatment. Cyclosporine trough levels should
be monitored if the clinical response is inadequate [40]. Adverse effects include nephrotoxicity,
hepatotoxicity, hypertension, hypertrichosis, increased risk of infection, and malignancy. (See
"Pharmacology of cyclosporine and tacrolimus".)
Methotrexate — For children with severe AD in whom treatment with cyclosporine is

contraindicated or not tolerated, methotrexate is an alternative treatment option. Methotrexate has a
slow onset of action, and its effects become apparent after six to eight weeks of treatment.
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We usually start with a dose of 0.5 mg/kg given orally once weekly. The dose can be gradually
increased as tolerated, up to a maximum of 25 mg per week. Oral supplementation with folic acid 1
mg per day is recommended to reduce methotrexate toxicity without loss of efficacy [41]. (See
"Major side effects of low-dose methotrexate".)
Methotrexate is a folic acid antagonist that inhibits transmethylation reactions and promotes release
of adenosine. The anti-inflammatory effects of methotrexate may be due to the inhibition of
lymphocyte proliferation and to the anti-inflammatory activity of adenosine. Methotrexate is
generally well tolerated. Adverse effects include gastrointestinal upset, hepatotoxicity, bone marrow
suppression, and, very rarely, acute idiopathic pulmonary fibrosis.
Studies of methotrexate for the treatment of AD in children are limited to a few retrospective studies
[42-47] and one small randomized trial [48]. The quality of these studies is generally low, with high
variability in the dose and duration of treatment, outcome measurement, and length of follow-up [49].
Of note, in the only randomized trial, the doses of methotrexate and cyclosporine were likely
subtherapeutic [48]:
●In a small randomized unblinded trial, low-dose methotrexate (7.5 mg/week) was compared with
low-dose cyclosporine (2.5 mg/kg/day) in 40 children aged 8 to 14 years with severe AD (who had
failed topical therapy) [48]. The primary outcome was the mean change in Scoring of Atopic
Dermatitis (SCORAD) after 12 weeks of treatment. At week 12, the mean absolute reduction in
SCORAD was similar in the methotrexate and cyclosporine groups (26 and 25 points, respectively).
Treatment was well tolerated in both groups.
●In a retrospective study, 47 children 2 to 18 years old with severe AD were treated with a weekly
dose of methotrexate 0.2 to 0.5 mg/kg [42]. The 44 patients who had completed at least three
months of methotrexate treatment reported improvement of eczema, reduced itch, and reduced use
of topical corticosteroids, as assessed by the Investigator Global Assessment (IGA) score, at three to
five months. Sustained improvement was reported at 10 to 14 months among the 30 children who
completed at least 10 months of treatment. Approximately 70 percent of patients experienced a mild
flare-up during methotrexate therapy that was treated with topical corticosteroids, minor
methotrexate dose adjustment, or both. Adverse effects were reported in 83 percent of the patients
and included mild elevation of transaminases and transient hematologic abnormalities.
Gastrointestinal adverse effects, including nausea, vomiting, and abdominal pain, occurred in nearly
30 percent of patients.
●In another retrospective study of 55 children (age 3 to 19.5 years) with severe, longstanding AD
treated with methotrexate at a mean starting dose of 0.37 mg/kg, 42 patients (76 percent) showed
improvement, with a reduction of the mean baseline IGA score from 4.2 to 2.9 after six to nine
months of treatment [46]. Adverse effects occurred in 51 percent of patients, most commonly
gastrointestinal discomfort and nausea (31 percent), followed by fatigue (26 percent) and headache
(16 percent).
Other therapies
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Systemic corticosteroids — We generally avoid using systemic
corticosteroids in children with severe AD. Although frequently used in clinical practice for the
treatment of severe AD in children and adults [23,24,50], there are no high-quality studies evaluating
their role in the management of AD [51]. A consensus statement published by the International
Eczema Council, an international panel of 77 experts, reports that systemic corticosteroids should
be generally avoided, particularly in children and adolescents, but can be occasionally used for a
short period of time in the following circumstances [52]:
●When other options are not available or contraindicated
●As a bridge therapy to other systemic therapies or phototherapy
●For the immediate relief of acute flares
●In the most severe cases
These principles are in agreement with most clinical practice guidelines [40,53-56]. However, the
dose and duration of a "short course" of systemic corticosteroids have not been determined. The
European Task Force on Atopic Dermatitis/European Academy of Dermatology and Venereology
Task Force position statement on the treatment of AD suggests that a typical regimen of systemic
corticosteroids might be methylprednisolone 0.5 mg/kg per day for one to two weeks tapered over
one month [54].
Because of the many and potentially severe adverse effects of systemic corticosteroids in children,
including adrenal suppression, weight gain, growth suppression, and increased susceptibility to
infection, their use is not recommended for the long-term control of AD [57,58]. (See "Major side
effects of systemic glucocorticoids".)
Mycophenolate mofetil — Mycophenolate mofetil inhibits T and B cell

proliferation via the inhibition of inosine monophosphatase dehydrogenase, a key enzyme involved
in de novo purine synthesis. Studies of mycophenolate mofetil for the treatment of AD in children are
limited. A number of small, uncontrolled studies have reported efficacy in adults with AD [59-62].
Two retrospective case series evaluated the use of the drug in children [63]:
●In one report of 14 children treated with an initial dose of mycophenolate mofetil of 12 to 40 mg/kg
per day and up to 75 mg/kg per day (maximum dose 3 g/day), disease improvement occurred in all
but one; the initial response was noted within eight weeks of treatment [63]. Treatment was well
tolerated in all patients. Two patients experienced transient, mild gastrointestinal disturbance during
the initial week of treatment, one patient had a history of recurrent herpes simplex viral infections,
and two had recurrent bacterial superinfections requiring systemic antibiotic therapy.
●In another report, 12 children were treated with mycophenolate mofetil 20 to 40 mg/kg per day for
0.5 to 20 months [64]. Significant improvement was reported in eight patients and no response in
four. Adverse effects included decreased hemoglobin level in one patient and cutaneous infections
in three.
631
Adverse effects of mycophenolate mofetil include gastrointestinal disturbances, myelosuppression,
and infections.
Azathioprine — Azathioprine is an antagonist of purine metabolism that inhibits T cell

proliferation. Its catabolism and concurrent production of active metabolites is regulated by the
levels of thiopurine methyltransferase (TPMT), which vary among individuals according to common
allelic polymorphisms. Evidence supporting the use of azathioprine in children with AD is limited to a
few observational studies [64-68]:
●In a small prospective study, 12 children with severe, recalcitrant AD (baseline SCORAD >40)
started treatment with azathioprine 1 to 2.5 mg/kg per day, depending on their baseline red blood
cell TPMT activity, for up to 16.5 months [65]. Considerable improvement was reported in 11 of 12
children, with a mean decrease in SCORAD of 27.7 points. Treatment was generally well tolerated;
one child had a transitory decrease in the absolute neutrophil count and another had a mild increase
in serum transaminase level.
●In a retrospective study, 28 children aged 3 to 17 years were treated with azathioprine for 1 to 29
months [64]. Seventeen (61 percent) of patients reported significant improvement, six some
improvement, and five no response. Seven patients experienced laboratory abnormalities (eg,
abnormal liver function test, decreased hemoglobin concentration and white blood cell count)
requiring dose adjustment. Twelve patients were transitioned to mycophenolate mofetil for an
average of 10 months after starting azathioprine; of them, eight reported significant improvement
and four no improvement.
Azathioprine has a number of adverse effects, including myelosuppression, hepatotoxicity,

gastrointestinal disturbances, increased susceptibility to infection, and increased risk of cancer
(squamous cell carcinoma, non-Hodgkin lymphoma) especially for long-term treatments.
Pretreatment determination of TPMT activity may be helpful to determine the appropriate dose and
reduce the risk of myelotoxicity [69].
Hematologic parameters and liver function tests must be monitored. In a series of 82 children (mean
age 8.3 years) treated with azathioprine for an average time of approximately two years, 33 (40
percent) had transaminase levels ≥50 international unit/L and/or lymphocyte count <1 x 109/L or
neutrophils <1.5 x 109/L after a median time of five months [68]. Five children discontinued
azathioprine because of adverse effects.
Dupilumab — Dupilumab is an interleukin (IL)-4 and IL-13 receptor-alpha antagonist that

was approved by the US Food and Drug Administration in March 2019 for the treatment of
adolescents aged 12 years and older with moderate to severe atopic dermatitis not adequately
controlled with topical prescription therapies [70]. Data on the use of dupilumab in children are
limited. The results of clinical trials evaluating the safety, pharmacokinetics, and efficacy of
dupilumab in children and adolescents are awaited. (See "Treatment of atopic dermatitis (eczema)",
section on 'Dupilumab'.)
632
Omalizumab — Omalizumab is a recombinant humanized immunoglobulin G1 (IgG1)
monoclonal antibody that binds IgE with high affinity and is approved for the treatment of moderate
to severe asthma inadequately controlled by inhaled corticosteroids in children aged six years or
older with IgE levels up to 1500 international units/mL. Limited studies of omalizumab for atopic
dermatitis have provided conflicting results [71].
A previous small, randomized trial including eight children with severe, refractory atopic dermatitis
showed that omalizumab given at a dose of 150 to 375 mg every two to four weeks was no more
effective than placebo in improving the clinical symptoms of atopic dermatitis, as measured with
SCORAD, despite a marked reduction in the blood levels of IgE and T helper type 2 (Th2)
inflammatory markers [72]. In a subsequent randomized trial including 62 children with severe
atopic dermatitis and elevated IgE levels treated with omalizumab or placebo for 24 weeks,
omalizumab was more effective than placebo in improving the clinical signs of atopic dermatitis
(mean difference in the objective SCORAD index between the omalizumab group and placebo group
-6.9, 95% CI -12.2 to -1.5, after adjusting for baseline SCORAD score, serum IgE level [≤1500 or >1500
international units/mL] and age [<10 or ≥10 years]) [73]. However, in this trial, omalizumab was used
at much higher doses (up to 1200 mg per month), and all patients were allowed to use potent topical
corticosteroids as needed throughout the study.
Maintenance therapy — Once the flare has subsided, patients can resume
topical therapy with a medium-potency topical corticosteroid and/or topical calcineurin inhibitor
(tacrolimus 0.03 or 0.1%, or pimecrolimus 1%) and/or topical crisaborole twice daily for two weeks
and then intermittently (eg, for two consecutive days per week or every other day), as a proactive
therapy to prevent exacerbations [74]. Emollients should be liberally used multiple times per day.
(See "Treatment of atopic dermatitis (eczema)", section on 'Maintenance and prevention of
relapses'.)


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●Basics topics (see "Patient education: Eczema (atopic dermatitis) (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Severe atopic dermatitis (AD) remains a difficult condition to treat. Before initiating second-line
treatments for AD, factors potentially associated with recalcitrant diseases should be assessed and
treated. These include poor adherence to treatment, presence of environmental triggers or allergens,
infected eczema, and incorrect diagnosis. (See 'Introduction' above and 'Potential causes of
refractory disease' above.)
●Because most of the second-line therapies for AD have potential adverse effects and nearly all are
off-label for this indication in children, patients should be selected for these treatments only when
conventional topical therapy does not provide sufficient improvement. (See 'Initial management'
above.)
●For children with persistent, severe AD or acute, generalized exacerbation of AD, we suggest wet
wrap therapy with diluted medium-potency topical corticosteroids (table 3) rather than other
treatments. Wet wraps consist of a bottom wet layer and top dry layer; they are applied once or twice
daily and can be maintained for two or more hours, as tolerated, and even overnight if patients feel
comfortable. Wet wraps can be used until improvement occurs, usually for a few days and to up to
14 days, if tolerated. (See 'Wet wraps' above.)
●For older children (eg, older than six years who can cooperate with treatment) and adolescents who
do not respond to or refuse wet wraps, we suggest phototherapy with narrowband ultraviolet B
(UVB), if available, rather than systemic immunosuppressive therapy (Grade 2C). Narrowband UVB is
usually administered three times per week, with a progressive protocol that increases the dose with
each treatment, as tolerated. The patient is usually reassessed after 20 to 25 treatments. (See
'Phototherapy' above.)
●For children with refractory AD for whom phototherapy is not accessible or impractical, systemic
immunosuppressive therapy is warranted. In this setting, we suggest oral cyclosporine as the first-
choice immunosuppressive agent (Grade 2C). Cyclosporine is given at the dose of 3 to 5 mg/kg in
two divided doses for two to four months and then gradually tapered. (See 'Cyclosporine' above.)
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●For children with severe AD in whom treatment with cyclosporine is contraindicated or not
tolerated, other treatment options include methotrexate, mycophenolate mofetil, azathioprine, and
dupilumab. (See 'Other therapies' above.)
●We generally avoid using systemic corticosteroids in children with recalcitrant AD. However, a short
course of oral corticosteroids can be occasionally used when other options are not available or
contraindicated, for immediate relief of acute flares, or as a bridge therapy to other systemic
therapies or phototherapy. (See 'Systemic corticosteroids' above.)
635
Evaluation and management of severe refractory atopic
dermatitis (eczema) in adults
uptodate.com/contents/evaluation-and-management-of-severe-refractory-atopic-dermatitis-eczema-in-adults/print
Evaluation and management of severe refractory atopic dermatitis (eczema) in adults
INTRODUCTION It is estimated that 2 to 5 percent of adults and older

adults have atopic dermatitis (AD) [1-5]. A prevalence of approximately 9 percent has been estimated
in persons older than 75 years [4]. In adults, AD may present as a chronic, persistent form of
childhood AD, a relapsing form of childhood AD that had apparently resolved, or, less commonly,
"adult-onset" AD [6-9]. Whether adult-onset AD is a distinct phenotypic variant of AD is unclear [10].
Patients may report AD as first appearing in adulthood for several reasons [11]: their childhood AD
was so mild that it is not remembered; in adults from sunny, humid, tropical climates (Southeast
636
Asia and Latin America), AD may appear when they move to drier temperate zones; and AD may
appear or be exacerbated by pregnancy. In most cases, adult AD appears before the age of 40 years
and is often a recalcitrant, difficult-to-treat condition [1,11].
AD, as well as most forms of eczematous dermatitis, is characterized by three primary components:
barrier failure, inflammatory immune response, and pruritus. Specific therapies should be directed at
each of these components and include aggressive topical treatment with wet wraps and soaks,
phototherapy, and systemic immunomodulators [12-14].
This topic will discuss the management of severe AD in adults. The treatment of AD in children is
discussed separately. (See "Treatment of atopic dermatitis (eczema)" and "Management of severe
atopic dermatitis (eczema) in children".)
PATIENT EVALUATION
Is the diagnosis of atopic dermatitis
correct? — When evaluating an adult patient with new-onset dermatitis that is persistent
and relapsing, the diagnosis of atopic dermatitis (AD) should be made with caution, as a variety of
skin conditions may present as an eczematous dermatitis in adulthood (table 1). The most important
clinical features that confirm the diagnosis of AD are (see "Atopic dermatitis (eczema):
Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and
"Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on
'Diagnosis'):
●The skin eruption begins in or affects anatomic sites classically involved by adult AD (hand eczema
(picture 1), eyelid eczema (picture 2), nipple eczema, and flexural eczema (picture 3A-B and picture
4)) [15].
●The morphology is characteristic of AD with lichenified plaques, excoriations, and a propensity for
secondary staphylococcal infection (picture 5A-D).
●Other atopic conditions (asthma, allergic rhinitis, etc) are present.
However, the diagnosis of AD in adults may be difficult due to multiple reasons, including:
●AD can coexist with an exogenous dermatitis, such as allergic contact dermatitis or
photodermatitis.
●Young adult AD patients, especially Asian men, can develop lesions with a nummular morphology
[16]. However, adult men also develop classic nummular dermatitis not associated with AD that
presents with weepy plaques starting on the extremities (usually one leg) (picture 6) and then
generalizing. (See "Nummular eczema".)
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●Drug eruptions, bullous pemphigoid, allergic contact dermatitis, and cutaneous T cell lymphoma
may mimic AD in adults. A high index of suspicion, repeated biopsies, and appropriate laboratory
testing should be performed to rule out these conditions. (See "Exanthematous (maculopapular)
drug eruption" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid" and "Clinical features and diagnosis of allergic contact dermatitis" and "Clinical
manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●Older adult patients with chronic idiopathic pruritus may develop a nonspecific eczematous
dermatitis, the so-called "eruption of senescence" [17]. They usually have associated xerosis and
pruritus that is disproportionately severe compared with the skin eruption. This nonspecific
dermatitis may result from age-related barrier failure and immune imbalance, which lead to a
predominately Th2 reaction pattern in the skin similar to AD [18].
Potential diagnostic pitfalls — Since the prevalence of atopy

exceeds 20 percent in the general population of many developed nations, a positive family history
for atopic disease can lead to a mistaken diagnosis of AD in an adult patient presenting with an
eczematous eruption. Once the diagnosis of AD is placed in the patient's medical record, further
diagnostic considerations may be ignored. As an example, a patient with cutaneous T cell
lymphoma may not be biopsied, or appropriate patch testing may not be performed in a patient with
allergic contact dermatitis.
Moreover, the various skin conditions that may present in adulthood as an eczematous dermatitis
(table 1) have the histopathologic features of acute or chronic dermatitis identical to AD. Thus,
sequential biopsies and additional tests may be required for certain diagnoses, such as mycosis
fungoides or bullous pemphigoid. (See "Psoriasis: Epidemiology, clinical manifestations, and
diagnosis" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
Another potential diagnostic pitfall of biopsy is the misdiagnosis of dermatitis treated with potent
topical steroids, which may show residual dermal inflammation in the absence of the typical
epidermal changes of spongiosis and hyperkeratosis that characterize AD and other eczemas. In
these cases, the biopsy report may be signed out as "urticaria" or "urticarial hypersensitivity."
Identifying the causes of recalcitrant

disease — Many patients with severe adult eczema have had their condition for a long time,
often years. The factors underlying an exacerbation of chronic severe eczema that should be
considered and addressed include [12]:
Lack of compliance with topical treatment and

undertreatment — Topical treatment of severe eczematous dermatitis may be messy,
time consuming, costly, and is required daily, often for years. In addition, topical therapies are often
marginally effective in chronic lichenified eczema. These downsides of topical treatment predictably
638
lead to decreased adherence to treatment over time and persistent or worsening disease. In addition,
concerns about adverse effects may lead to inadequate application of the topical medication.
Topical corticosteroid phobia, defined as a concern or fear about using topical corticosteroids, is
common, with a prevalence among patients and caregivers ranging from 20 to over 80 percent
worldwide [19].
Secondary staphylococcal infection — The skin of patients with AD

and other forms of eczema are colonized with Staphylococcus aureus [12]. The superantigens of the
bacteria enhance the immune response in the skin and reduce the response to topical therapy. When
a severe eczema patient has recurrent staphylococcal infections, decolonization should be
considered. Frequent bathing with or without bleach, regular use of a swimming pool, chlorhexidine
showers, and nasal mupirocin can all be helpful to reduce carriage [20]. Pets can be carriers of S.
aureus, and tubs of creams can be contaminated with bacteria. Often family members are S. aureus
carriers, and treatment of the whole housing unit can stop frequent infections. (See "Treatment of
atopic dermatitis (eczema)", section on 'Management of infection'.)
Allergic contact dermatitis — In patients with severe AD, the impaired skin
barrier increases the penetration of potential allergens through the skin and the risk of sensitization
[21]. The allergens found in many topical over-the-counter and prescription products (eg, lanolin,
corticosteroids, propylene glycol) as well as other common allergens (eg, fragrances, preservatives,
and nickel) may complicate AD. Every effort should be made to patch test patients with severe
eczema before they are placed on immunosuppressive treatments that would lead to false-negative
results on patch testing. (See "Common allergens in allergic contact dermatitis" and "Patch testing".)
Other factors — Factors that may contribute to increased severity of AD include:

●Photosensitivity – When eczematous dermatitis is severe, minimal amounts of ultraviolet (UV)
radiation can trigger a flare in some patients. This may be a clue to the diagnosis of photosensitive
eczema or may simply be a manifestation of severe dermatitis. In such patients, aggressive
photoprotection with good ultraviolet A (UVA) coverage may improve the eczema. Phototherapy will
exacerbate such patients until their skin is improved. (See "Overview of cutaneous photosensitivity:
Photobiology, patient evaluation, and photoprotection" and "Selection of sunscreen and sun-
protective measures".)
●Environmental and psychosocial factors – Patients living in a dry environment understandably

have more xerosis. In a warm climate and when exercising, increased pruritus and frictional irritation
of the skin may occur. Fortunately, most patients with long-standing AD recognize and try to
minimize these exposures. Patients often attribute worsening of AD with psychologic stress [22].
●Vitamin D deficiency – Low vitamin D can be associated with increased severity of AD and more
frequent skin infections in the patient with AD [23-26].
639
Assessment of disease severity — Patients with severe
refractory AD typically have widespread disease that limits daily activities, psychosocial functioning,
and/or sleep, with a considerable negative impact on quality of life, and that has not responded to
standard first-line therapies with emollients and topical corticosteroids. Several disease severity
scales for AD (eg, the Scoring of Atopic Dermatitis [SCORAD] index and the Eczema Area and
Severity Index [EASI]) and patient quality of life measurement scales have been tested and validated
for use in clinical trials, but they are not commonly used in clinical practice and may not accurately
identify patients who need more aggressive topical therapies or systemic therapies [27].
In a practical guide to visual assessment of eczema severity that also includes the evaluation of
disease impact on quality of life and psychosocial wellbeing proposed by the United Kingdom
National Institute for Health and Care Excellence, severe AD is defined as "widespread areas of dry
skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding,
oozing, cracking, and alteration of pigmentation), severe limitation of everyday activities and
psychosocial functioning, [and] nightly loss of sleep" [28].
In clinical practice, in addition to visually evaluating the extent and severity of eczema, clinicians
may assess the impact of AD on the patient's quality of life by asking open-ended questions on the
intensity of symptoms, frequency of flares, impact of disease on daily activities, psychosocial
functioning, and sleep [12]. The burden of treatment, including time spent on treatment, cost of
medications, and frequency of health provider visits, should also be assessed.
APPROACH TO MANAGEMENT
Patient education — Educating patients about their condition and how the
prescribed treatment is targeted to the causes of their skin inflammation will enhance compliance.
Patients should be educated on both the regular treatment of their skin and what to do when flares
occur [12]. To enhance adherence to topical regimens, patients should be provided with medications
in a vehicle (ie, ointment, cream, or lotion) they like and will actually use. In addition, patients may be
instructed to apply the medication only once daily, since there is limited evidence that more frequent
treatment is better [29-32]. Cost may be reduced by once-daily application and also by diluting the
topical corticosteroid with a moisturizer when used under occlusion (eg, wet wraps). These diluted
preparations are not stable long term, but for managing an acute flare that requires large volumes of
a topical agent used with occlusion, this can lead to substantial savings without reducing efficacy
[33,34].
When is systemic therapy warranted? — The decision to

start systemic therapies in adults with severe atopic dermatitis (AD) that is not controlled by topical
therapy is based upon consideration of disease severity, frequency of flares, and impact on the
patient's quality of life. Because systemic immunosuppressive agents, such as oral cyclosporine,
methotrexate, azathioprine, and corticosteroids, are all associated with potentially serious adverse
640
effects and require close clinical and laboratory monitoring, candidates for systemic therapy must
be carefully selected. A reasonable approach to identify patients in whom systemic therapy is
warranted involves a trial of intensive topical therapy and, if available and acceptable to the patients,
phototherapy [12,13]. (See 'Intensive topical therapy' below.)
Systemic therapy is warranted in the following situations (algorithm 1):
●Patients who have persistent severe disease, despite a trial of intensive topical therapy
●Patients for whom phototherapy is not feasible or acceptable
●Patients in whom the initial response to intensive topical therapy cannot be maintained with
standard topical therapy
Goals of therapy — In adult patients with severe eczema, a reduction (rather than
complete clearance) in the signs and symptoms of AD, and in particular of the associated pruritus,
may be an acceptable goal of therapy if the amount of residual disease no longer interferes with
daily activities. As an example, a reduction of approximately 50 percent in pruritus intensity
assessed over a period of 24 hours by using the peak pruritus numerical rating scale (a scale of 0 to
10, with 0 being "no itch" and 10 being "worst itch imaginable") can be a reasonable goal in adults
with recalcitrant AD [35].
INTENSIVE TOPICAL THERAPY The two forms

of topical therapy that can be effective in severe eczema cases are soak and smear/wet wrap
therapy and phototherapy. They can be used in a stepwise manner or in combination.
Soak and smear/wet wraps — We suggest a trial of intensive topical

therapy (ie, soak and smear or wet wraps) for the initial treatment of patients with severe atopic
dermatitis (AD) not controlled by standard topical therapy, rather than phototherapy or systemic
therapies. These approaches are mainly based on evidence from a limited number of studies in
children and adults [36-39]:
●Soak and smear − The patient soaks for 15 minutes in a comfortable tub of water. A high-potency
to super high-potency corticosteroid is applied to the whole body, except the groin, axillae, and face,
in patients with widespread eczema. In patients with more localized disease, topical corticosteroids
may be applied only to affected regions, but the normal skin surrounding the eczematous dermatitis
should also be treated. For example, if the eczema is on the lower leg in spots, treat the whole lower
leg. Once patients have learned the "soak and smear" approach, they can apply it to break flares of
their eczema.
●Wet wrap therapy − For wet wrap therapy, mid-potency to super-potency steroid preparations
(groups 1 to 3 (table 2), usually in an ointment base, are applied to the involved areas. Super-potent
corticosteroids may be diluted with a tolerated moisturizer or petrolatum. The treated areas are then
641
occluded with wet wraps (or moist pajamas covered by dry pajamas). The occlusion should be
maintained for a minimum of four hours and initially should occur twice daily. Such therapy applied
by skilled nurses in a daycare setting is particularly effective. Crude coal tar ointment can be added
to the topical corticosteroids for additional benefit [40,41].
Once improvement is achieved, less aggressive topical therapy may control the eczema in some
patients. Some experts suggest applying medium- to high-potency topical corticosteroids two to
three times per week to normal-appearing skin at sites of frequent flares (proactive therapy) [12].
Those in whom remission cannot be maintained with intermittent use of topical corticosteroids and
liberal use of emollients ultimately require a more aggressive approach with phototherapy or
systemic therapies.
Phototherapy — If available, feasible, and acceptable to the patient, we suggest

phototherapy for the treatment of severe adult eczema that is not controlled by intensive topical
therapy (algorithm 1). Although narrowband ultraviolet B (NBUVB), ultraviolet A1 (UVA1), or psoralen
plus ultraviolet A (PUVA, bath or systemic) have been shown to be effective, we prefer NBUVB and
UVA1 over PUVA, due to their better safety profile [12,42,43]. (See "UVB therapy (broadband and
narrowband)" and "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA)
Phototherapy is administered two to three times per week. The starting doses are generally low and
may be administered in combination with aggressive topical treatment as outlined above. (See "UVB
therapy (broadband and narrowband)", section on 'Treatment initiation, frequency, and dose
increments' and 'Soak and smear/wet wraps' above.)
Initial benefit is usually seen after a minimum of 10 treatments, and up to 24 treatments are required
to judge whether phototherapy will be adequate to control severe eczema. A home light unit may be
considered for patients with severe adult eczema who respond well to phototherapy. Since long-term
light treatment to control eczema is limited by the time commitment (a minimum of once-a-week
treatment is usually required), a home light unit may address this problem. A home light unit is a
cost-effective approach compared with immunosuppressive therapies.
Systemic or bath PUVA are treatment options in patients at low risk of skin cancer (skin types 3 to 6
(table 3)) and if treatments are infrequent. Bath PUVA avoids the need for eye protection. Once
weekly or less frequent bath PUVA treatments can control some cases of severe adult eczema. (See
"Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Bath PUVA'.)
The use of phototherapy for the treatment of severe AD is supported by several randomized trials
and systematic reviews [43-45]. Although the included studies were generally of low quality and
heterogeneous regarding the severity assessment criteria, irradiation techniques, and outcome
measures, all provided some evidence that NBUVB and UVA1 phototherapy are effective for the
treatment of severe AD. In one randomized, eight-week crossover trial, 47 participants with moderate
to severe AD were randomized to receive medium dose UVA1 or NBUVB three times per week for six
weeks [46]. Intention-to-treat analysis showed that the two treatments were equally effective in
642
reducing pruritus and disease severity. Eczema severity (assessed with the Six Area Six Sign Atopic
Dermatitis [SASSAD] score) was reduced from the baseline in both study periods by 44 percent in
the UVA1 group and by 39 percent in the NBUVB group. Whether UVA1 is preferable to NBUVB for
the treatment of acute AD remains uncertain, since most of the studies included in systematic
reviews did not specify if patients had chronic severe AD or acute AD exacerbation.
The evidence supporting oral or bath PUVA for the treatment of AD is limited. In a low-quality,
randomized, crossover trial that compared oral PUVA with medium-dose UVA1 for severe,
generalized AD, PUVA decreased the severity of disease to a greater extent, led to more rapid
improvement, and induced a longer remission period post-treatment [47]. In another small,
randomized, half-side comparison study including 12 patients with severe chronic AD, bath PUVA
was as effective as NBUVB in reducing the signs and symptoms of AD (baseline Scoring Atopic
Dermatitis [SCORAD] reduction at six weeks was 66 and 64 percent, respectively) [48].
Combination therapy — The combination of aggressive soak and smear

treatment and phototherapy with ultraviolet B (UVB) and crude coal tar (modified Goeckerman
regimen) may be helpful in patients failing phototherapy alone. In a small study, five patients with
chronic severe AD unresponsive to NBUVB, broadband UVB, or systemic immunosuppressants were
treated in an outpatient setting with daily broadband UVB followed by a topical regimen of crude
coal tar and potent or super-potent topical corticosteroids for an average of 27 days [49]. All patients
experienced a marked improvement, with an average reduction of the baseline SCORAD score of 75
percent, and remained in remission for 5 to 12 months.
SYSTEMIC THERAPIES Adults with severe recalcitrant

atopic dermatitis (AD) that is not controlled by intensive topical treatment or phototherapy and those
for whom phototherapy is not a viable option require systemic therapies (algorithm 1) [12,50-52].
Choice of treatment — The choice of a systemic treatment depends upon

consideration of AD severity, impact on the patient's quality of life, the patient's age and sex, family
planning issues, presence of comorbidities, the patient's preferences, and costs.
A rational approach involves the initial use of an agent with rapid onset of action (eg, oral
cyclosporine, oral corticosteroids) to achieve rapid control of symptoms. Due to their adverse
effects, these agents should be used for a limited period of time as a rescue therapy for immediate
relief of acute flares or bridge therapy to other agents relatively safer to use over a prolonged period,
if needed [12]. (See "Major side effects of systemic glucocorticoids".)
Cyclosporine — We suggest cyclosporine rather than systemic corticosteroids as

first-choice systemic therapy for AD and other severe eczemas in adults who do not have obvious
contraindications to its use and who will benefit from a rapid resolution of symptoms [53].
643
Contraindications to the use of cyclosporine include abnormal renal function, uncontrolled
hypertension, uncontrolled infection, and concurrent malignancy. (See "Pharmacology of
cyclosporine and tacrolimus".)
The cyclosporine dose ranges from 2.5 to 5 mg/kg per day. Besides systemic corticosteroids,
cyclosporine is the most rapidly acting and effective agent for the management of severe AD. The
dermatitis often begins to improve as quickly as within the first week, and the degree of
improvement can be dramatic (approaching 100 percent) in eight weeks. Itching improves within
days.
Long-term use of cyclosporine (ie, beyond one year) is limited by its side effects, mainly
hypertension and kidney toxicity, especially in older adults. Moreover, as relapse can be very rapid
after discontinuation of treatment, many patients will need to be transitioned to an
immunosuppressive agent with a better safety profile while discontinuing cyclosporine.
As an example, patients who are stable on cyclosporine may also be given a low dose of
methotrexate (eg, 5 to 10 mg per week) for three weeks (see 'Methotrexate' below). The cyclosporine
dose is then halved, and the methotrexate dose is increased to 15 to 20 mg per week. After two
weeks, cyclosporine is discontinued. During this period of dual immunosuppression, prophylaxis to
prevent Pneumocystis pneumonia should be considered. (See "Treatment and prevention of
Pneumocystis pneumonia in HIV-uninfected patients", section on 'Prophylaxis'.)
The efficacy of cyclosporine for the treatment of AD is supported by several randomized trials and
systematic reviews [51,53-55].
In a 2013 systematic review, 14 trials evaluated the efficacy of cyclosporine versus placebo or other
systemic immunomodulating agents (eg, intravenous immunoglobulins [IVIGs], prednisolone,
mycophenolate mofetil) [55]. After short-term treatment ranging from 10 days to 8 weeks,
cyclosporine was found to be more effective than placebo in all trials, with a mean improvement
from baseline of 50 to 95 percent in different clinical severity scores. In head-to-head trials,
cyclosporine was found to be more effective than prednisolone and IVIG and as effective as
mycophenolate mofetil. Higher doses (5 mg/kg per day) induced a more rapid response than lower
doses (2.5 to 3 mg/kg per day).
One well-performed, randomized trial compared prednisolone with cyclosporine in 38 adults with
severe AD [56]. Treatment consisted of a two-week tapering dose of oral prednisolone with a
constant daily dose of cyclosporine for six weeks; patients were allowed to use a mid-potency
topical corticosteroid, emollients, and oral antihistamines. The authors noted that this regimen
reflects a common treatment approach in clinical practice. The primary outcome measure was the
proportion of patients with stable remission, defined as improvement in the Scoring Atopic
Dermatitis (SCORAD) index of at least 50 percent relative to baseline at week 2 in the prednisolone
group and week 6 in the cyclosporine group and no flare within a 12-week follow-up. Although the
response rate was not significantly different in the two groups at the end of the active treatment
period, the relapse rate during the 12-week follow-up was much higher in the prednisolone group
than in the cyclosporine group (89 versus 45 percent).
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Systemic corticosteroids — In patients with severe AD in whom the use
of oral cyclosporine is contraindicated, we suggest a short course of a moderate dose of a systemic
corticosteroid for the rapid control of symptoms. We typically prescribe prednisone 40 to 60 mg per
day for one week and taper the dose over the following two to three weeks. While systemic
corticosteroids are tapered off, patients are transitioned to another immunosuppressive agent with a
better safety profile (eg, methotrexate) for long-term treatment.
Systemic corticosteroids are frequently used in clinical practice for the treatment of severe AD in
children and adults, despite a paucity of studies evaluating their role in the management of AD [56-
58]. Although there is a general consensus among experts that systemic corticosteroids should be
generally avoided, particularly in children and adolescents, they can be occasionally used for a short
period of time in the following circumstances [59]:
●When other options are not available or contraindicated
●As a bridge therapy to other systemic therapies or phototherapy
●For the immediate relief of acute flares
●In the most severe cases
These principles are in agreement with most clinical practice guidelines [60-64]. However, the dose
and duration of a "short course" of systemic corticosteroids have not been determined. The
European Task Force on Atopic Dermatitis/European Academy of Dermatology and Venereology
Task Force position statement on the treatment of AD suggests that a typical regimen of systemic
corticosteroids might be methylprednisolone 0.5 mg/kg per day for one to two weeks tapered over
one month [62].
Methotrexate — Methotrexate is the author's preferred agent for long-term control of

severe AD in adult and older adult patients. Methotrexate is usually administered in a single weekly
dose of 7.5 to 25 mg in combination with daily supplementation with folic acid 1 mg to reduce the
risk of several common methotrexate toxicities. (See "Major side effects of low-dose methotrexate".)
The effect of methotrexate usually starts after a few weeks but may be delayed. The maximum
benefit is often not seen for several months.
Methotrexate and azathioprine were similarly effective in reducing eczema severity in a small
randomized trial including 42 adults with AD who were unresponsive or intolerant to cyclosporine
[65]. Patients were treated for 12 weeks and permitted to use topical corticosteroids and oral
antihistamines. At the end of 12 weeks, the severity of eczema as assessed by the SCORAD score
decreased by approximately 40 percent in both groups. Treatment was continued by 95 percent of
patients in the methotrexate group and 84 percent in the azathioprine group, with reduction in the
SCORAD score at 24 weeks of 48 and 43 percent, respectively. Adverse events, none of which were
serious, included infections, gastrointestinal upset, and increased liver enzyme levels and occurred
645
in equal proportion in both treatment groups, although lymphocytopenia occurred more frequently in
the azathioprine group than in the methotrexate group. Among the 35 patients who continued,
interrupted, or switched treatment reflecting real-life clinical practice and were followed-up at three-
month intervals for an additional two years, the clinical response was maintained at two years in
both groups (SCORAD index reduced by 63 and 53 percent in the methotrexate and in the
azathioprine groups, respectively) [66].
Laboratory monitoring, including complete blood count and renal and liver function, is required (see
"Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease"). New
methods for monitoring for liver fibrosis, such as serum amino terminal peptide of type III
procollagen and ultrasound-based transient elastography, have reduced the need for liver biopsies
[67,68]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic
tests".)
Azathioprine — Azathioprine is an additional option for the treatment of severe AD in

adults. The starting dose is 2 to 3 mg/kg. A baseline thiopurine methyltransferase (TPMT) should be
performed before initiating the treatment to determine if dose adjustment is required. Clinical
response is seen on average in four weeks but may not be seen for six to eight weeks.
The efficacy of azathioprine for the treatment of AD has been evaluated in a few randomized trials
[65,69,70]. One small trial including 37 patients with severe AD reported a reduction of 26 percent in
the Six Area Six Sign Atopic Dermatitis (SASSAD) score in patients treated with azathioprine,
compared with 3 percent in those treated with placebo [69]. However, 16 of 37 patients (43 percent)
withdrew from the study. Adverse effects of azathioprine included nausea, vomiting, and
gastrointestinal disturbances. In another trial, 63 patients with active AD not controlled by optimal
topical therapy were treated with azathioprine (1 mg/kg daily or 2.5 mg/kg daily in patients with
reduced or normal TPMT activity, respectively) or placebo [70]. After 12 weeks, the SASSAD score
was reduced by 37 percent in the azathioprine group compared with 20 percent in the placebo
group. Azathioprine was generally well tolerated. However, two patients developed a drug
hypersensitivity reaction.
Long-term use of azathioprine can be associated with lymphopenia, progressive anemia, and
transient elevation of liver enzymes.
Other therapies
Mycophenolic acid/mycophenolate mofetil — Mycophenolate
mofetil (MMF)andmycophenolic acid (MPA) can be considered as treatment options in patients in
whom other immunosuppressive agents are not tolerated or are contraindicated. MMF and MPA are
usually very well tolerated, and laboratory abnormalities are infrequent. Common adverse effects
include fatigue, flu-like symptoms, and gastrointestinal upset. MMF and MPA are typically given at a
dose of 1 to 2 g/day and 720 to 1440 mg/day, respectively. The response to treatment is usually
delayed, often not seen before six to eight weeks.
646
The response to MMF and MPA seems to be dependent on a uridine diphosphate (UDP)-
glucuronosyltransferase 1-9 (UGT1A9) polymorphism affecting the metabolism of the medication
[71]. Approximately 85 percent of individuals who carry this polymorphism are nonresponders [71].
Patients who respond to treatment usually tolerate a long-term therapy, given the relatively good
toxicity profile of these agents. Nausea (reduced with enteric-coated mycophenolate sodium [EC-
MPS]) is the most common adverse effect. At high doses, usually above 2 g per day, rest tremor can
occur.
The evidence supporting the use of MMF for AD is limited and mainly based upon small
observational studies [72]. No randomized trials have evaluated its efficacy as first-line treatment for
severe AD. One small trial compared EC-MPS with cyclosporine as a maintenance treatment in 55
adult patients with AD unresponsive to potent topical corticosteroids [73]. All patients were treated
for a six-week run-in period with cyclosporine 5 mg/kg per day to achieve rapid remission and then
randomized to cyclosporine 3 mg/kg per day or EC-MPS 1440 mg per day for 30 weeks. The severity
of eczema, measured using the SCORAD index, was comparable in both study arms until the end of
the maintenance phase. After treatment discontinuation, relapse was more rapid in the cyclosporine
group than in the EC-MPS group. There were no serious adverse events.
Dupilumab — Dupilumab is an interleukin (IL)-4 receptor alpha antagonist approved by the

US Food and Drug Administration and by the European Medicine Agency for the treatment of adult
patients with moderate to severe AD not adequately controlled with topical prescription therapies.
Dupilumab is initially administered as a loading dose of 600 mg given by subcutaneous injection,
followed by a maintenance dose of 300 mg every two weeks. Laboratory monitoring is not required.
The efficacy of dupilumab is supported by several manufacturer-sponsored trials involving now

more than 1300 patients [74,75] (see "Treatment of atopic dermatitis (eczema)", section on
'Dupilumab'). In one trial, at least a 75 percent improvement from baseline in the Eczema Area and
Severity Index (EASI-75) was achieved by approximately 50 percent of patients taking dupilumab,
compared with approximately 15 percent of those taking placebo [74].
However, the efficacy of dupilumab for the treatment of severe, recalcitrant eczema remains unclear.
In fact, the trials included a large proportion (over 50 percent) of patients with moderate AD, and no
preplanned or post-hoc subgroup analysis was performed to assess the efficacy of dupilumab in
patients with severe disease [76]. Adverse effects of dupilumab include injection-site reactions,
conjunctivitis, and headache [77]. Dupilumab has been shown to be associated with a reduced risk
of skin infections, including eczema herpeticum [78].
The early experience with dupilumab in the author's clinical practice has mirrored the results of
published trials. However, the high cost of this agent limits its use as first-line therapy. Improvement
may be noted in the first month of treatment, but three months or more may be required to achieve
maximum benefit. Combining dupilumab with an appropriate topical corticosteroid or other agent is
often necessary in more severe cases.
647
INEFFECTIVE THERAPIES
Rituximab, ustekinumab, omalizumab — Despite initial
anecdotal reports of efficacy in atopic dermatitis (AD), rituximab, ustekinumab, and omalizumab
have failed to produce benefit reproducibly and are not recommended for the treatment of adult
eczemas [79-84].

SUMMARY AND
RECOMMENDATIONS
●In adults, atopic dermatitis (AD) may present as a chronic, persistent form of childhood AD, a
relapsing form of childhood AD that had apparently resolved, or, less commonly, "adult-onset" AD.
(See 'Introduction' above.)
●When evaluating an adult patient with new-onset dermatitis that is persistent and relapsing, the
diagnosis of AD should be made with caution, as a variety of skin conditions may present as an
eczematous dermatitis in adulthood (table 1). Once the diagnosis of AD is confirmed, the causes of
recalcitrant disease should be considered and addressed. (See 'Patient evaluation' above.)
●Our approach to the management of adult patients with severe, recalcitrant AD is as follows
(algorithm 1) (see 'Approach to management' above):
•For most patients with severe, recalcitrant AD, we suggest an initial trial of intensive topical therapy
with corticosteroids (ie, soak and smear or wet wraps) rather than systemic immunosuppressive
therapy. (Grade 2C). (See 'Intensive topical therapy' above.)
•For patients with severe eczema that is not controlled by intensive topical therapy, we suggest
phototherapy if it is available, feasible, and acceptable to the patient (Grade 2B). We prefer
phototherapy with narrowband ultraviolet B (NBUVB) due to its superior safety profile. NBUVB can
be used alone or in combination with intensive topical corticosteroid therapy. (See 'Phototherapy'
above and 'Combination therapy' above.)
•For patients who do not improve with intensive topical therapy and/or phototherapy, we suggest
starting systemic treatment with oral cyclosporine rather than other systemic therapies (Grade 2B).
Once improvement is achieved and stable, patients can be transitioned to an immunosuppressive
648
agent with a better long-term safety profile while discontinuing cyclosporine. (See 'Cyclosporine'
above.)
•In patients with severe AD in whom the use of oral cyclosporine is contraindicated, we suggest a
short course of a moderate dose of a systemic corticosteroid for the rapid control of symptoms
(Grade 2C). (See 'Systemic corticosteroids' above.)
•For long-term control of symptoms, we suggest low-dose methotrexate rather than azathioprine
(Grade 2C). The two agents appear to be equally effective, but methotrexate is generally better
tolerated. (See 'Systemic corticosteroids' above and 'Methotrexate' above.)
•Dupilumab, an interleukin (IL)-4 receptor alpha antagonist approved for the treatment of adult
patients with moderate to severe AD, is an additional treatment option, but cost may be a limitation
to its use. (See 'Dupilumab' above.)
649
Basic mechanisms and pathophysiology of allergic contact
dermatitis
uptodate.com/contents/basic-mechanisms-and-pathophysiology-of-allergic-contact-dermatitis/print
INTRODUCTION Allergic contact dermatitis (ACD) is a common

inflammatory skin disease presenting with pruritic, eczematous lesions. ACD results from a T cell-
mediated, delayed type hypersensitivity (DTH) reaction elicited by the contact of the skin with the
offending chemical in individuals who have been previously sensitized to the same chemical. ACD is
common in the general population and is the most frequent occupational skin disease. Its etiology
may be suggested by the body sites of involvement, history of exposure, and morphology and
distribution of the skin lesions.
This topic will discuss the immune mechanisms and pathophysiology of ACD. The clinical
manifestations, diagnosis, and management of ACD are discussed separately. (See "Clinical features
650
OVERVIEW The understanding of the cellular and molecular pathogenesis of
allergic contact dermatitis (ACD) has expanded dramatically. In addition to CD4+ and CD8+ T cells,
other cell types such as natural killer T (NKT) cells, natural killer cells, innate lymphoid cells, and T
regulatory cells have emerged as critical participants (table 1). In the elicitation phase, Langerhans
cells appear to play a role in the development of immune tolerance rather than hypersensitivity
reaction (as was once thought). B cells also appear to be important during the initiation of ACD by
secreting IgM antibody in response to NKT cell-derived interleukin (IL)-4, leading to complement
activation and immune cell chemotaxis. As new mechanisms and molecules emerge as a result of
advances in the understanding of ACD, new pharmacologic targets will become apparent.
HAPTEN-PROTEIN BINDING Hapten binding is the

initial step in the development of allergic contact dermatitis (ACD). Contact allergens are low
molecular weight (<500 Daltons) chemicals called haptens, which are able to penetrate the stratum
corneum barrier of the skin. Haptens are not immunogenic by themselves, but they can be efficiently
recognized by the immune system after binding to a skin protein carrier. Haptens may be naturally
occurring substances such as urushiol found in the resin of poison ivy, synthetic compounds, dyes,
fragrances, drugs, or heavy metal salts.
The binding of haptens to skin proteins (protein haptenation) involves the formation of a covalent
bond between the electrophilic components of the hapten and the amino acid nucleophilic side
chains of the target proteins within the skin [1]. Examples of chemicals containing electrophilic
components are aldehydes, ketones, amides, or halogenated compounds. Metal cations (eg, nickel
[NIi]2+, one of the most common ACD-associated haptens; and chromium [Cr]3+) are also well-known
electrophiles. Some haptens that are not normally electrophilic (prohaptens) can be converted to
protein-reactive species via oxidation or metabolic transformation by epidermal keratinocytes and/or
dendritic cells [1]. Additional factors influencing the sensitizing ability of haptens include
lipophilicity, tridimensional chemical structure, and protein-binding affinity.
The most reactive nucleophilic side chains of proteins are found on lysine, cysteine, and histidine.
The protein nucleophilicity is influenced by the microenvironment pH and protein location within the
epithelium [1].
THE SENSITIZATION (AFFERENT)

PHASE The sensitization phase occurs after the first contact of the skin with a hapten
and leads to the generation of hapten-specific T cells in the regional lymph nodes. Langerhans cells
(LC) and dermal dendritic cells (DC) may be involved in the clinically inapparent sensitization phase.
Both LCs and dermal DCs are professional antigen-presenting cells and express major
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histocompatibility complex (MHC) class I and II molecules, which are required for the activation of
CD8+ and CD4+ T cells, respectively. (See "Antigen-presenting cells" and "The adaptive cellular
immune response: T cells and cytokines".)
LCs are bone marrow-derived, immature epidermal DCs which express langerin (CD207), a C-type
lectin associated with the Birbeck granules. Immature LCs form a dense network in the epidermis,
where they scan the environment by extending and retracting their dendrites and take up antigens
with high efficiency [2]. LCs are able to initiate an adaptive immune response by capturing,
processing, and presenting antigens to naïve T cells in the paracortical areas of lymph nodes [3].
In the sensitization phase of allergic contact dermatitis (ACD), the hapten-protein complex is
engulfed and processed by LCs, which subsequently migrate to the draining lymph nodes where they
present the hapten–peptide–MHC complexes to naïve, allergen-specific T cells (priming). This
process results in clonal expansion of hapten-specific memory/effector T cells, which circulate
throughout the body and are subsequently recruited from the circulation into the skin during the
elicitation phase [4]. (See 'The elicitation (efferent) phase' below.)
After cutaneous exposure to the sensitizing hapten, epidermal LC density decreases by

approximately 50 percent in the following 24 hours as a result of migration to the regional lymph
nodes [5-9]. During migration, LCs undergo a process of maturation and acquire the surface
phenotype of a functionally mature dendritic cell. Cytokines released by keratinocytes, in particular
interleukin (IL)-1, tumor necrosis factor (TNF)-alpha and IL-18, regulate the migration and functional
maturation of dendritic cells. In addition to morphologic changes and decreased ability to capture
additional antigen, mature LCs exhibit increased expression of CD83 (a marker for LC maturation),
adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), and co-stimulatory
molecules including CD40, CD80, and CD86 [10-15]. The expression of these markers is specific to
hapten-exposed LCs, since dermal irritants, which also trigger LC migration, do not result in similar
LC surface marker changes [14]. The increased expression of these signaling molecules on the cell
surface of LCs is important for efficient activation/proliferation of T cells in the local lymph nodes.
Twenty-four hours after sensitization by cutaneous application of a strong hapten, lymph nodes of
mice contain LCs and can transfer sensitization if implanted into allergen-naïve mice [10]. However,
studies in LC-depleted mice indicate that contact sensitization is not abrogated in the absence of
LCs [16]. A population of langerin+ dermal DCs is thought to induce contact sensitization in the
absence of epidermal LCs, which supports the idea that LC may be dispensable in ACD, since there
are other cutaneous antigen-presenting cells that can subserve this function [17,18].
At the end of the afferent phase, hapten-specific T cells that have been primed by hapten bearing
DCs are found in the lymph nodes, in the blood, and in the skin. Upon re-exposure to the same
hapten, T cells will be activated and massively recruited in the skin (the elicitation phase).
652
THE ELICITATION (EFFERENT)
PHASE The clinical manifestations of allergic contact dermatitis (ACD) are the result of a
T cell-mediated inflammatory reaction occurring in the skin upon re-exposure to the offending
hapten (elicitation phase) and mediated by the activation of hapten-specific T cells in the skin.
The inflammatory reaction occurs 48 to 72 hours after exposure. As in the sensitization phase,
haptens enter the epidermis and react with endogenous proteins. The hapten-protein complexes are
then taken up by the antigen-presenting cells (APCs) and presented to the antigen-primed T cells
recruited in the epidermis and dermis.
Although LCs are capable of functioning as APCs, they are not required during the elicitation phase
of ACD. Mice depleted in epidermal LCs by treatment with topical corticosteroids or exposure to UVB
radiation show a paradoxically higher cutaneous hypersensitivity response compared with control
animals, indicating that LCs are dispensable in the elicitation phase and may be involved in the
regulation of ACD [19]. (See 'Regulatory mechanisms of allergic contact dermatitis' below.)
Other cell types that may function as APCs include mast cells, infiltrating macrophage, and
keratinocytes [20]. Keratinocytes, which constitutively express major histocompatibility complex
(MHC) class I, have been shown to express also MHC class II and exhibit APC-like properties in
response to hapten exposure [21]. Instead of inducing T cell activation, class II MHC bearing
keratinocytes induce hapten-specific Th1-lymphocyte clonal anergy, which may play a role in limiting
the magnitude and duration of ACD [22,23].
The primary effector cells of ACD appear to be CD8+ Tc1 cells [24-28]. Experimental studies in mice
indicated that MHC class I-restricted CD8+ T cells infiltrate the skin as early as six hours after the
hapten challenge and induce keratinocyte apoptosis via the perforin/granzyme or the Fas/FasL
pathway [29,30]. Activated T cells release type 1 cytokines, including IFN-gamma and TNF-alpha.
Both cytokines are potent activators of keratinocytes and promote the up-regulation of intercellular
adhesion molecules (ICAM-1) and MHC class II molecules and the release of chemokines, resulting
in a massive recruitment of mononuclear and polymorphonuclear cells and amplification of the
inflammatory response [4].
MHC class I knockout mice, which are deficient in CD8+ T cells, or mice acutely depleted in vivo of
CD8+ T cells are unable to develop a hypersensitivity reaction to the cutaneous application of the
strong hapten dinitrofluorobenzene (DNFB) [24]. Conversely, MHC class II-deficient mice, which are
deficient in CD4+ T cells, develop a strong reaction to DNFB, supporting the hypothesis that CD8+ T
cells are primed in the absence of CD4+ T cells and mediate the cutaneous hypersensitivity
response.
The role of hapten-specific CD4+ T cells is not completely understood. CD4+ T cells appear in the site
of challenge at a later time than CD8+ T cells and may have distinct roles in the inflammatory
process [31]. CD4+ Th1 cells, producing high amounts of IFN-gamma and TNF-alpha, display
653
cytotoxic activity against keratinocytes expressing MHC class II molecules and may cooperate with
CD8+ T cells in amplifying the inflammatory response. By contrast, other subsets of CD4+ T cells
may have a regulatory function (such as FoxP3+ and CD4+ T regulatory cells).
The afferent and efferent phases of ACD are illustrated in the Figure (figure 1). The cell types
involved in ACD and their functions are summarized in the Table (table 1).
THE INNATE IMMUNITY IN

ALLERGIC CONTACT DERMATITIS Innate
immune cells (dendritic cells [DC], mast cells, natural killer [NK], NKT-cells) play a critical role in
allergic contact dermatitis (ACD) (table 1). Innate lymphoid cells are lymphoid cells that are distinct
from conventional lymphocytes in that they lack antigen receptors, are distinct from other innate cell
types, and can play a regulatory role in allergic diseases [32]. They reside in the skin and other
tissues and are emerging as another cell type that may play an important role in the early events of
ACD, as their numbers are increased in positive patch tests to nickel [33,34]. In addition, antigen-
presenting cells (macrophages, DC, monocytes, and B lymphocytes) express membrane-bound
innate immune receptors called pattern recognition receptors (PPR), which include the toll-like
receptor (TLR) family. TLRs are transmembrane receptors that recognize pathogen-associated
molecular patterns such as cell wall components (eg, bacterial endotoxin), proteins, and nucleic
acids of bacteria, parasites, viruses, and fungi [35]. TLRs also recognize damage-associated
molecular patterns, which are released during cell necrosis [36]. TLR signaling results in changes in
the transcription factors that regulate a multitude of genes, including those encoding important
proinflammatory cytokines. (See "Toll-like receptors: Roles in disease and therapy".)
In mouse models of contact hypersensitivity, TLR2 and TLR4 recognize low molecular weight
breakdown products of hyaluronic acid that are produced by reactive oxygen species in response to
exposure to haptens [37-41]. In humans, the TLR4 (hTLR4) has been identified as the receptor for
nickel, which is the most common cause of ACD [42]. Binding of nickel to hTLR4 requires the
presence of two nonconserved histidines (H) in H456 and H458 in the extracellular domain of
hTLR4. The binding of nickel to hTLR4 triggers a signal transduction cascade via the nuclear factor
for the kappa light chain enhancer in B cells, resulting in the production of proinflammatory
cytokines and the activation of DC early in the afferent phase of ACD. Because mice lack H456 and
H458, they do not develop contact hypersensitivity to nickel. Other metal salts, such as cobalt and
palladium, that can induce ACD have also been demonstrated to trigger TLR4 activation similar to
nickel [43]. These data suggest a novel mechanism for the "adjuvancy" (or immune-activating
properties) of common allergens.
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REGULATORY MECHANISMS OF
ALLERGIC CONTACT
DERMATITIS Regulatory T cells (Treg) may have a role in the sensitization and
elicitation phase of allergic contact dermatitis (ACD) and in the downregulation of the inflammatory
response that was initially attributed to the clearance of the hapten from the skin [44,45]. Tregs are a
heterogeneous cell population that includes natural Tregs (CD4+CD25+Foxp3+ cells) and inducible
Tregs (Tr1- and Th3-cells) [4,46]. The skin contains predominantly inducible Tregs, which can be
triggered by Langerhans cells or dermal dendritic cells [47,48]. Following exposure to a contact
allergen, Tregs can lower or suppress the process of sensitization [48-51]. During the elicitation
phase, they can suppress effector T cells in the lymph nodes and inhibit the influx of leukocytes
through IL-10 or CD39 mechanisms [52,53]. Tregs may also be involved in the control and eventual
termination of the inflammatory response in ACD [54].
MECHANISMS OF TISSUE DAMAGE

IN ALLERGIC CONTACT
DERMATITIS In the early phase of allergic contact dermatitis (ACD), tissue
damage is mostly due to CD8+ T cell-induced apoptosis of keratinocytes bearing the hapten-protein
complex on MHC class I molecules, via the perforin/granzyme or the Fas/FasL pathway. The
induction of keratinocyte apoptosis is accompanied by a rapid cleavage of CH1 intercellular
adhesion molecules (E-cadherins). The loss of intercellular adhesion and the infiltration of
lymphocytes in the epidermis are responsible for the intercellular edema and vesiculation as well as
the typical spongiotic appearance of the epidermis in ACD [55].
Type 1 cytokines, released by infiltrating CD8+ and CD4+ T cells, in particular IFN-gamma, stimulate
keratinocytes to release cytokines and chemokines, resulting in the massive recruitment of activated
T cells, neutrophils, macrophages, and eosinophils that form the cellular inflammatory infiltrate in
the dermis.
SUMMARY
●Allergic contact dermatitis (ACD) is a delayed type hypersensitivity reaction elicited by the contact
of the skin with the offending chemical in individuals who have been previously sensitized to the
same chemical. The understanding of the cellular and molecular pathogenesis of ACD has expanded
dramatically. In addition to CD4+ and CD8+ T cells, other cell types, such as natural killer T (NKT)
cells and T regulatory cells, have emerged as critical participants (table 1). (See 'Overview' above.)
655
●Hapten binding is the initial step in the development of ACD. Haptens are low molecular weight
(<500 Daltons) chemicals that are able to penetrate the stratum corneum of the skin. Haptens are
not immunogenic by themselves but can be efficiently recognized by the immune system after
binding to a skin protein carrier. (See 'Hapten-protein binding' above.)
●In the clinically inapparent sensitization phase, Langerhans cells and dermal dendritic cells initiate
an adaptive immune response by capturing, processing, and presenting antigens to naïve T cells in
the paracortical areas of lymph nodes. In the elicitation phase, the clinical manifestations of ACD are
the result of a T cell-mediated inflammatory reaction occurring in the skin upon re-exposure to the
offending hapten and mediated by the activation of hapten-specific T cells in the skin. The primary
effector cells of ACD appear to be CD8+ cells (figure 1). (See 'The sensitization (afferent) phase'
above and 'The elicitation (efferent) phase' above.)
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Clinical features and diagnosis of allergic contact dermatitis
uptodate.com/contents/clinical-features-and-diagnosis-of-allergic-contact-dermatitis/print
INTRODUCTION Allergic contact dermatitis (ACD) is the classic

presentation of a T cell-mediated, delayed-type hypersensitivity response to exogenous agents [1,2].
The words "dermatitis" and "eczema" are often used interchangeably to describe a pattern of
inflammation of the skin characterized acutely by erythema, vesiculation, and pruritus. Chronic
exposure typically leads to moderation of the erythema accompanied by lichenification and
persistence of itch. The clinical presentation may vary depending upon the triggering agent and
individual's reactivity, but, in most cases, the lesions are primarily confined to the site of contact
[3,4].
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This topic will discuss the clinical presentation, diagnosis, and differential diagnosis of ACD. The
pathophysiology, patch testing for, and management of ACD are discussed separately. (See "Basic
mechanisms and pathophysiology of allergic contact dermatitis" and "Patch testing" and
"Management of allergic contact dermatitis".)
EPIDEMIOLOGY AND RISK

FACTORS The incidence and prevalence of ACD in the general population are not
known. Data are often extrapolated from surveillance studies on occupational dermatitis. In
industrialized nations, up to 30 percent of all occupational diseases involve the skin. Irritant and
contact dermatitis account for more than 90 percent of cases [5].
Surveillance studies have reported an annual incidence of contact dermatitis (including irritant and
ACD) of 13 to 34 cases per 100,000 workers [6-8]. The agents most frequently implicated included
latex materials, protective equipment, soap and cleansers, resins, and acrylics. Information on the
main allergens responsible for contact dermatitis in the general population is derived from
retrospective studies of patch testing referral centers. In one study, metals, fragrances, topical
antibiotics, preservatives, chemicals used in hair care products, topical corticosteroids, glues,
plastics, and rubber were the most common allergen groups associated with positive patch test
reaction [9]. In a meta-analysis of 28 studies including over 20,000 patch-tested individuals from the
general population, the pooled prevalence of contact allergy was 20.1 percent (95% CI 16.8-23.7),
with nickel being the most common allergen, followed by fragrance mix, cobalt, and Myroxylon
pereirae [10]. Among children, nickel sulfate, ammonium persulfate, gold sodium thiosulfate,
thimerosal, and toluene-2,5-diamine (p-toluenediamine) are the most common sensitizers [11]. (See
"Common allergens in allergic contact dermatitis".)
Multiple studies from around the world indicate that, of patients presenting for patch testing, 20 to
up to 40 percent will be allergic to nickel [12-17]. In North America, the most common cause of ACD
is from contact with poison ivy, oak, and sumac. (See "Poison ivy (Toxicodendron) dermatitis".)
Risk factors for ACD include:
●Occupation – Workers at highest risk of ACD include health professionals, chemical industry
workers, beauticians and hairdressers, machinists, and construction workers.
●Age – ACD was once considered a disorder of the adult population. Children were thought to be
spared because of a low exposure to potential allergens and an immature immune system. However,
it is now recognized that contact sensitization begins in early childhood via exposures such as
vaccinations, piercing, topical medications, and cosmetics [18,19]. (See "Contact dermatitis in
children", section on 'Allergic contact dermatitis'.)
The incidence of ACD increases with age. Repetitive and prolonged exposure to potential sensitizers
may account for the high rate of ACD in older adults. Medical comorbidities, including stasis
dermatitis and venous ulcerations, are contributing factors [20]. (See "Stasis dermatitis".)
658
●History of atopic dermatitis – The role of atopy in ACD is controversial, although several studies
report a high rate of positive patch tests among atopic individuals [21-26]. However, a 2017 meta-
analysis of 74 studies did not find a difference in the frequency of contact sensitization between
individuals with atopic dermatitis and those without (odds ratio [OR] 0.89, 95% CI 0.77-1.03) [27].
CLINICAL FEATURES
Lesion morphology — Acute ACD lesions consist of erythematous, indurated,
scaly plaques (picture 1A-C). Vesiculation and bullae may be seen in severe cases (picture 2).
Edema may be prominent in areas in which the skin is thin, such as the eyelids, lips, and genitalia
(picture 3).
Repeated or continued exposure to allergens results in chronic disease. The skin becomes dry, scaly,
and thicker as a result of acanthosis, hyperkeratosis, edema, and cellular infiltration in the dermis
(picture 4). Lichenification and fissuring may develop later [28]. Secondary changes include
excoriation or impetiginization (picture 5). Subacute dermatitis has a mixture of both acute and
chronic features [29].
Lesion distribution — ACD is typically localized to the skin areas that come in
contact with the allergen (picture 6A-C). However, patchy or diffuse distributions may occur,
depending upon the nature of the allergen or secondary transfer of the allergen from the primary site
of contact to distant skin areas:
●The involvement of hands, face, or eyelids, which most commonly come in contact with the
environment, occurs most frequently in ACD.
●Allergens applied to the scalp, including hair dyes and shampoos, may elicit dermatitis in adjacent
●Facial lesions may result from direct contact with cosmetic products or tools or from involuntary
transfer of allergens to the face (eg, eyelid ACD from nail polish).
●A pendant-like distribution of lesions (berloque dermatitis) in the neck and chest suggests a
reaction to fragrances in perfumes and lotions (picture 7A-B).
●A diffuse or patchy dermatitis of the trunk, often with accentuation in the axillary folds, may be
caused by cloth dyes or textiles. Rubber components may induce ACD at the site of contact with
elastic waistbands (picture 8).
●Periorificial ACD may be induced by fragrances, detergents, or preservatives in hygiene products,

including moist wipes [30].
●Dermatitis involving the dorsal aspect of the foot suggests ACD related to shoe chemicals (eg,
rubber accelerators or potassium dichromate) (picture 1C).
659
●Involvement of photoexposed areas suggests photoallergic contact dermatitis. (See
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment",
section on 'Photoallergy'.)
●Occupational ACD frequently involves the hands and requires a careful ascertainment of
occupation-specific exposures.
Symptoms — The dominant symptom of ACD is itch. However, ACD may cause a variety
of other symptoms, including burning, stinging, or pain [31].
DISEASE COURSE If left untreated, ACD can evolve from an acute

form to a subacute and then chronic eczematous dermatitis. Chronic dermatitis can negatively
impact an individual's health-related quality of life, particularly in social functioning and
psychological wellbeing [32,33]. Successful allergen avoidance can result in clearance of ACD.
Persistence of dermatitis in the face of dutiful allergen avoidance suggests an alternative diagnosis
(eg, systemic medication allergy, cutaneous lymphoma) or concurrent diagnosis (ie, atopic
dermatitis).
HISTOPATHOLOGY The histology of ACD mirrors the clinical

picture. In acute ACD, the epidermis is of normal thickness, and spongiosis (intercellular edema
leading to the disruption of intercellular adhesion and formation of vesicles) is the dominant feature
(picture 9). An additional feature is the exocytosis of lymphocytes and eosinophils into spongiotic
foci. The upper dermis contains an infiltrate of lymphocytes, histiocytes, and eosinophils, with
perivascular accentuation [34].
In subacute ACD, there are mild to moderate spongiosis, moderate acanthosis (epidermal
hyperplasia from increased mitotic activity of keratinocytes), and a denser dermal lymphohistiocytic
infiltrate. Chronic lesions may show prominent epidermal acanthosis with hyperkeratosis and areas
of parakeratosis. Spongiosis may be present focally but often is minimal. The inflammatory infiltrate
is sparse.
DIAGNOSIS The diagnosis of ACD is based upon a combination of [4]:
●Clinical features (morphology, location, and symptoms) of the eruption
●History of exposure to a putative allergen during work, hobbies, or home activities
●Patch testing results
●Laboratory tests and/or histopathologic examination
660
●Lack of recurrence after empirical treatment of the dermatitis and avoidance of the suspected
allergen
Clues from clinical examination — The morphology, regional

distribution, and temporal course of dermatitis frequently suggest the diagnosis of ACD. (See 'Lesion
morphology' above and 'Lesion distribution' above.)
The typical appearance of ACD is a well-demarcated, pruritic, eczematous eruption localized to the
area of skin that comes in contact with the allergen (picture 1A-C). The eruption may be acute, with
vesiculation and weeping, or chronic (lichenified or scaly plaques).
The eruption may not remain anatomically limited to the initial site of contact. For example, a patient
with a neomycin contact allergy may exhibit a modest eruption at the site of application on the torso
and a diffuse, concomitant dermatitis of the face due to passive transfer of the allergenic ointment
to the face. Body washes or shampoos or cloth dyes and textiles may cause a patchy or diffuse
dermatitis.
Less commonly, ACD may present with a photosensitivity reaction: The eruption is limited to photo-
exposed skin areas and follows the application of sunscreens, fragrances, or topical nonsteroidal
anti-inflammatory drugs (NSAIDs) (picture 10). (See "Photosensitivity disorders (photodermatoses):
Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
History — A comprehensive, multiyear history is helpful for the diagnosis of ACD (table 1).
The source of contact with allergens may be identified by reviewing the patient's activities, including
occupation and hobbies. Products and objects for personal use, including prescription or over-the-
counter topical preparations, cosmetics and toiletries, hair dyes, fragrances, eyeglasses, gloves, and
clothing, should be reviewed. A patient's recall may not be complete, and revisiting the history after
obtaining the results of patch testing may be useful.
A history of long-term exposure to an allergen does not rule out contact allergy, since multiple
exposures are typically necessary for sensitization and dermatitis to occur. In addition, an
individual's susceptibility to ACD may change over time because of aging, customs, or comorbidities
(eg, stasis dermatitis and leg ulcers) [29]. Infrequently, sensitization may occur after a single
exposure.
Health professionals, chemical industry workers, beauticians and hairdressers, machinists, and
construction workers have an increased risk of developing occupational ACD [35]. However,
exposure to common industrial allergens, including cements, glues, plasters, and solvents, may also
occur at home.
A history of improvement during weekends or holidays suggests an occupational origin, whereas

worsening during weekends or holidays suggests recreational exposure to allergens. A seasonal
variation may indicate photo-aggravation or photoallergy [28]. (See "Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)
661
A previous history of contact dermatitis may provide a clue to the origin of a relapse. For example,
earring dermatitis may precede nickel dermatitis of the hands by several years.
Patients with ACD often report a history of atopy (childhood flexural eczema, asthma, hay fever, or
conjunctivitis).
Patch testing — Patch testing is an essential investigation in patients with persistent

eczematous eruptions when contact allergy is suspected or cannot be ruled out [2,36]. Patch testing
may help to identify allergens that should be avoided and is discussed separately. (See "Patch
testing".)
Laboratory tests and biopsy — Laboratory tests are not routinely

necessary in the evaluation of patients for ACD, but may be helpful in excluding other disorders with
similar clinical features. For example, a KOH examination of scale from the eruption or swab
cultures may rule out a fungal or bacterial infection [29].
Histologic examination on itself may provide little help in differentiating ACD from other eczematous
dermatitides (including irritant contact dermatitis (ICD), atopic, nummular, dyshidrotic, and
seborrheic dermatitis), since all present eosinophilic spongiosis as the key feature. However,
histologic examination may be helpful when the diagnosis is not clear.
Response to empiric therapy — When the possible offending

allergen is identified on the basis of clinical features and history, response to empiric therapy may
avoid the need for patch testing. Improvement or resolution of the dermatitis with allergen avoidance
and empiric treatment supports the diagnosis of ACD [37]. (See "Management of allergic contact
dermatitis", section on 'Therapeutic options'.)
DIFFERENTIAL DIAGNOSIS
Clinical — ACD can mimic or complicate other types of eczema and other dermatoses as
listed in the table (table 2 and picture 11A-C) [38].
Differentiating ACD from irritant contact dermatitis (ICD) is particularly difficult since they have a
similar clinical and histopathologic morphology [39]. Patch testing may be useful to confirm the
diagnosis of ACD. There is no specific test for the diagnosis of ICD. (See "Irritant contact dermatitis
in adults".)
Histopathologic — Eosinophilic spongiosis and exocytosis of eosinophils and

lymphocytes are the key features of ACD and other eczematous dermatitides but may be seen also
in other skin diseases.
662
For example, eosinophilic spongiosis may be the only histologic feature in the early, urticarial phase
of bullous pemphigoid [40]. Direct immunofluorescence staining and measurement of circulating
anti-BP antibodies will differentiate ACD from bullous pemphigoid.
Early, patch stage mycosis fungoides (MF) may be difficult to differentiate from subacute or chronic
ACD. Both diseases show minimal or no spongiosis and lymphocytic exocytosis. However, in MF,
lymphocytic exocytosis is more prominent, lymphocytes may have atypical features
(hyperchromatic, cerebriform nuclei), and clusters of atypical lymphocytes (Pautrier
microabscesses) may be seen in the epidermis (picture 12).

SUMMARY AND
RECOMMENDATIONS
●Allergic contact dermatitis (ACD) is a T cell-mediated, delayed-type hypersensitivity response to
exogenous agents. Contact allergens may be found at home or in the workplace and may include
metals, glues, plastics, rubber, fragrances, topical antibiotics, preservatives, and chemicals used in
hair care and cosmetic products. (See 'Introduction' above and 'Epidemiology and risk factors'
above.)
●Acute ACD lesions consist of pruritic, erythematous, indurated, scaly plaques, typically localized to
the skin areas that come in contact with the allergen (picture 1A-C). Vesiculation and bullae may be
seen in severe cases (picture 2). Edema of the eyelids, lips, and genitalia may be prominent (picture
3). In chronic ACD, the skin is dry, scaly, and thicker. Lesions are typically localized in the skin areas
that come in contact with the allergen (picture 6A-B). (See 'Lesion morphology' above and 'Lesion
distribution' above.)
●The source of contact allergens can be identified through a detailed review of the patient's
exposures at home and in the workplace (table 1). (See 'History' above.)
●The clinical diagnosis of ACD is based upon the lesion morphology and distribution. The
involvement of hands, feet, eyelids, and lips, which most commonly come in contact with the
environment, suggest the diagnosis of ACD. However, patch testing may be required to confirm the
diagnosis and differentiate ACD from other types of eczematous dermatitis (table 2). (See
'Diagnosis' above and "Patch testing" and 'Differential diagnosis' above.)
663
Common allergens in allergic contact dermatitis
uptodate.com/contents/common-allergens-in-allergic-contact-dermatitis/print
INTRODUCTION Allergic contact dermatitis is the classic presentation of

a T cell-mediated, delayed-type hypersensitivity response to exogenous agents and the most
frequent occupational skin disease. Health professionals, chemical industry workers, beauticians
664
and hairdressers, machinists, and construction workers have the highest risk of developing
occupational allergic contact dermatitis. However, exposure to common industrial allergens may
also occur at home.
This topic will review the agents that most commonly cause allergic contact dermatitis. The
pathogenesis, diagnosis, and treatment of allergic contact dermatitis are discussed separately.
●(See "Basic mechanisms and pathophysiology of allergic contact dermatitis".)
●(See "Patch testing".)
●(See "Management of allergic contact dermatitis".)
METALS Hypersensitivity reactions to metals are common [1]. Nickel, cobalt, gold, and
chromium are the most prevalent metal allergens, since they are used in a wide range of everyday
items, medical devices, and industrial applications. Co-reactions to metals often occur and should
not be considered cross-reactions [2]. Nickel and other metals released by implanted medical
devices may cause an allergic contact dermatitis over the implant site or a systemic reaction.
Allergic reaction to implanted metals are rarely cause of chronic pain, implant loosening, or failure
[3]. Criteria for diagnosing hypersensitivity reactions in implant devices have been proposed and are
summarized in the table (table 1) [4-6]. The American Contact Dermatitis Society published
management suggestions for both pre- and post-metal-implant patients [7].
Nickel is a ubiquitous allergen. In a cross-sectional analysis of over 44,000 patients patch tested by
the North American Contact Dermatitis Group from 1994 to 2014, the average frequency of nickel
sensitivity was 17.5 percent, and 55.5 percent of reactions were thought to be clinically relevant [8].
Women react more frequently to nickel. Sensitization to nickel has been shown to correlate with
number of body piercings [9]. It is present in jewelry, kitchen tools and silverware, clothing, and food.
Avoidance of costume jewelry, metal fasteners, and other metal objects is usually sufficient for most
nickel-allergic patients. In extremely sensitive individuals, nickel ingestion with foods (eg, chocolate,
nuts, oats, green beans, peas, canned foods) may cause systemic allergic contact dermatitis or, in
rare cases, chronic urticaria [10]. Avoidance of nickel in implanted medical devices is controversial.
Preimplant testing is not indicated for all individuals, only for those with a significant history of
dermatitis where metal touches the skin. Postimplant testing is indicated if metal allergy is
suspected as a cause of device malfunction/failure [7]. External contact with nickel may occur
through stainless steel instruments as well as many skin staples [3].
Systemic reactions to ingested nickel, defined as systemic nickel allergy syndrome (SNAS), is a rare
syndrome associated with dietary nickel exposure. Approximately 6 percent of nickel-allergic
individuals react to gastrointestinal nickel exposure and may benefit from a restricted nickel diet
[11,12].
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Cobalt is a co-reactor with nickel and an allergen itself. It has a blue color and can be found in
cosmetics, especially eye makeup, and blue tattoo pigments. Other potential sources of exposure to
cobalt include wet clay (pottery), plastics manufacturing, bricklaying and other industrial works, and
some hair dyes. Surgical stainless steel and the cobalt-chrome-molybdenum alloys used in
orthopedic implants have high cobalt content.
Chromium is also a ubiquitous allergen. It is the fourth most common material in the crust of the
earth and is present in both the soil and the water [2]. Chromium is used in the industry (eg, cement,
leather tanning, paints), in various types of stainless steel, and as a green coloring agent in soaps,
cosmetics, and tattoo pigments. Chromium is also present in some foods, with the highest
concentrations in brewer's yeast, beef, liver, thyme, black pepper, and cloves, and in dietary
supplements [2].
Gold in precious jewelry may cause allergic contact dermatitis, most often involving the hands, face,
and eyelids [13-15]. Some patients with a positive patch test to gold, however, may tolerate wearing
gold jewelry without problem. Gold dental restorations may be associated with positive patch test
reactions to gold in the absence of clinical signs of allergic contact dermatitis or intraoral disease. In
one study, approximately 30 percent of asymptomatic individuals with gold dental restorations had a
positive patch test to gold [15].
PRESERVATIVES The two main groups of preservatives used to prevent

bacterial and fungal spoilage in topical preparations, cosmetics, and personal care products are
formaldehyde/formaldehyde releasers and nonformaldehyde agents.
Formaldehyde/formaldehyde
releasers — Formaldehyde is a contact sensitizer classified as a known human
carcinogen by the International Agency for Research on Cancer. Formaldehyde itself is generally not
added to consumer products and is rarely listed on labels in the United States and the European
Union, but many chemicals used as preservatives degrade over time and release formaldehyde into
the product. Cross-reactions may occur between formaldehyde and all the formaldehyde releasers,
which are allergens also in their undegraded state. There are regulations in both the United States
and the European Union restricting work-place and environmental exposures to formaldehyde
[16,17].
Cosmetics and personal care products that may contain formaldehyde include nail polishes,
makeup, body washes, deodorants, and shampoos. Of particular concern is formaldehyde exposure
among users of popular hair straightening products (also known as hair relaxers) [18-21]. Rates of
formaldehyde releaser allergy have significantly decreased in the last decade [22].
Common preservatives that cause allergic contact dermatitis are listed in the table (table 2) [1]. The
most common formaldehyde releasers used in consumer products are discussed below:
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●Quaternium-15 – Quaternium-15 (Q15) is often present in cosmetics, personal care products, and
in some metalworking cutting fluids. In 2003, it was the ninth most common preservative used in the
United States and was found in 516 products [23]. Q15 was the most common cause of allergic
contact dermatitis to preservatives, but it was overtaken by methylchloroisothiazolinone (13.4
percent) and iodopropynyl butylcarbamate (3.9 percent) in 2015/2016 data [24]. According to the
North American Contact Dermatitis Group's 2015 to 2016 data, 3.6 percent (4.8 percent in the
2013/2014 data) of patch-tested patients react to Q15 [25]. Q15 may occasionally cross-react with
other quaternary ammonium compounds, such as benzalkonium chloride, often present in eye and
ear preparations.
●Imidazolidinyl urea – Imidazolidinyl urea is the third most common preservative used in the United
States and is present in over 2000 cosmetic and personal care products, including baby lotions,
shampoos, conditioners, and deodorants [23]. At the concentration used in cosmetics (0.03% to
0.2%), imidazolidinyl urea releases free formaldehyde at a level of approximately 5 parts per million
(mg/kg) [23]. This level can be tolerated by most formaldehyde-allergic patients.
●Diazolidinyl urea – Diazolidinyl urea is used in many personal care products, often in combination
with parabens (see 'Parabens' below). Sources and cross-reactions are the same as imidazolidinyl
urea.
●DMDM hydantoin – 1,3-dimethylol-5,5-dimethyl (DMDM) hydantoin is widely used in shampoos,

and may also be found in other personal-care products [23]. The amount of formaldehyde released
depends upon the concentration and presence of protein in the product, and ranges from
approximately 40 to 500 parts per million (mg/kg) [26,27]. Sources and cross-reactions are the same
as for imidazolidinyl urea.
●2-bromo-2-nitropropane-1,3-diol –Although infrequently used, 2-bromo-2-nitropropane-1,3-diol

(Bronopol) may be a cause of allergic contact dermatitis. Products containing Bronopol include
body-cleansing products, in particular baby wipes.
Other preservatives
Isothiazolinones — Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI)
are commonly used preservatives and an important cause of product-related allergic contact
dermatitis. Rates of MCI/MI allergy among patch-tested patients have significantly increased over
the last years, from 2.8 percent in 2005/2006 to 5 percent in 2011/2012 [22], 6.4 percent in
2013/2014, and 7.3 percent in 2015/2016 [24]. In a series of 703 patients tested between December
2014 and January 2015, the prevalence of positive reactions to MCI/MI was 8 percent [28].
Methylisothiazolinone tested alone reacted in 13.4 percent of tested individuals during 2015 to 2016
[24].
Exposure sources include wash-off personal care products, such as hair care products and body
washes, moisturizing creams/lotions, premoistened toilet wipes [29], and laundry detergents. MI was
tested by the North American Contact Dermatitis Group for the first time in 2013 to 2014 with a
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prevalence reported at 10.9 percent, the third most common allergen after nickel and fragrances,
respectively [25]. MI is also used in water-based paints. There are reports of allergic contact
dermatitis from airborne exposure in recently painted indoor environments [30].
Isothiazolinones are also used in industrial applications with the trade names Kathon CG, Euxyl
K100, or Grotan K. The combination of MCI and MI (Kathon CG) is a sensitizer, as are the individual
agents alone. Cross-reactions with other isothiazolinones, such as benzisothiazolinone, may occur
[31].
Parabens — Parabens are the most common preservatives in cosmetics and

pharmaceuticals, but are the least frequent cause of allergic contact dermatitis [23,32]. They are
tested in a mix of four related chemicals: methyl-4-hydroxybenzoate, propyl-4-hydroxybenzoate,
ethyl-4-hydroxybenzoate, and butyl-4-hydroxybenzoate.
In addition to personal care products, parabens are also found in foodstuffs (table 3) [33,34].
However, it is uncertain whether oral avoidance of parabens is necessary in sensitized individuals
[23]. Parabens may cross-react with the "para" amino group of related chemicals, such as para-
phenylenediamine, the ester class of anesthetics (especially benzocaine), and sulfonamides,
although the incidence of this is low [23,35]. (See 'Hair care products' below and 'Anesthetics' below.)
Methyldibromo glutaronitrile — Methyldibromo glutaronitrile is a non-

formaldehyde-based preservative with activity against fungi, bacteria, and yeasts. In the past, it was
widely used in both the United States and in the European Union in leave-on products, often mixed
with phenoxyethanol (Euxyl K400). It was also used in products for industrial use (eg, cutting fluids,
coolants, glues and adhesives).
Common sources include facial and body lotions, cleansers and wipes, moistened toilet paper, fabric
softeners, and liquid soaps. In 2007, the European Union established a "no safe use" policy for
methyldibromo glutaronitrile and banned it from all personal care products. In the United States, its
use is becoming less frequent and it has been removed from some of the commercially available
patch testing series.
Thimerosal — Thimerosal (sodium ethylmercury thiosalicylate) is a mercurial antiseptic

and antifungal agent widely used in the past as a preservative in topical preparations, cosmetics,
injectable immunoglobulins, and vaccines. Mercury containing agents such as Thimerosal are
regulated by the US Environmental Protection Agency and are rarely used in topical preparations
both in the United States and Europe. Thimerosal may be found at low or trace concentration in
vaccines [36]. Cross-reactions include other mercurial compounds such as phenylmercuric acetate
or dental amalgam.
Iodopropynyl butylcarbamate — Iodopropynyl butylcarbamate (IPBC) is a

broad-spectrum bactericide and fungicide, used initially in industrial applications [37]. In the last 20
years, its use has spread into many consumer products [38]. Although the chemical structure of
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IPBC is similar to thiurams and carbamates used as rubber accelerators, there is controversy about
true cross-reactions between these chemicals [38].
FRAGRANCES Allergy to fragrance-related chemicals is common. Perfumes

and scented personal care products (eg, body washes, hair care products, moisturizing lotions) are
obvious sources of exposure. However, many products that are apparently unscented may contain a
masking fragrance. Labels indicating "fragrance free" or "unscented" are not always safe for a
fragrance-allergic individual to use.
Fragrance allergens and ingredients commonly tested in patch test screening include:
●Fragrance mix 1 (cinnamic alcohol, cinnamic aldehyde, hydroxy citronellal, amyl cinnamaldehyde,
geraniol, eugenol, isoeugenol, and oakmoss absolute)
●Fragrance mix 2 (Lyral, Citral, citronellol, farnesol, coumarin, cinnamic aldehyde)
●Myroxylon pereirae, also known as balsam of Peru
●Limonene and linalool, fragrances that are being used more frequently in personal care products as
well as in perfume/colognes
Patients with a suspected reaction to fragrances should use completely fragrance-free personal care
products for six to eight weeks until complete clearance of the allergic rash. Of note, "unscented"
products are not necessarily fragrance free and should be avoided. After this wash-out period, a
prudent use of questionable products may be tried (eg, one or two per week) to identify the cause of
the allergic reaction. Lists of fragrance-free products are available from the Contact Allergen
Management database. (See 'Contact Allergen Management Program (CAMP)' below.)
Myroxylon pereirae — Myroxylon pereirae (balsam of Peru) is one of the most

common contact allergens. It is a resinous sap obtained by cutting the bark of the Myroxylon pereirae
tree and is a complex blend of over 400 chemicals classified within the vanilla, cinnamon, benzoate,
and eugenol groups. It is largely used in perfumes, cosmetics, flavoring agents in baked goods
(vanilla, cinnamon), citrus flavored carbonated beverages, and in some spices [39,40].
Balsam of Peru may also cause systemic dermatitis by oral ingestion. Cross-reactions between
balsam of Peru and common foods or spices are listed in the tables (table 4A-B). Systemic allergic
dermatitis due to cinnamon ingestion limited to the eyelids may occur [41].
HAIR CARE PRODUCTS P-phenylenediamine is an azo dye

intermediate, most commonly used in permanent hair dyes as a black dye. It is also used in black
rubbers, photographic developers, fabric dyes, epoxy resin curing agents, oils and greases, and
gasoline. Potential cross-reactions include preservatives of the paraben family, para-aminobenzoic
acid, sulfonamides (including diuretics and diabetes agents), and benzoic acid ester group
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anesthetics (see 'Parabens' above and 'Anesthetics' below). It is important for the patient to
understand that even if the hair product is "PPD free" other phenylenediamine variants (eg, Toluene-
2,5-diamine sulfate) may cause reactions.
P-phenylenediamine is often found or reported as an additive in henna and "black henna" and may
cause a reaction mistakenly interpreted as henna allergy. The use of pure, uncontaminated Lawsonia
inermis (henna tree) should not cause reactions in p-phenylenediamine allergic patients and may
actually be a reasonable alternative as a hair dye for some patients [42]. Pure henna is an extremely
rare cause of allergic contact dermatitis. Use of henna followed by indigo (Indigofera tinctoria most
commonly) may provide a PPD-free alternative for black hair coloring.
Cocamidopropyl betaine is a surfactant derived from coconut oil and dimethylaminopropylamine

[43]. It was originally used in "no more tears" formulations and has since been used as a foaming
agent in many wash-off personal care products (eg, shampoos, body washes, toothpastes), an
antistatic agent in conditioners, and an emulsifier in cosmetics. The actual allergenic molecule in
cocamidopropyl betaine has not been determined. Amidoamine or dimethylaminopropylamine
contamination is considered the most likely cause of allergic reactions to cocamidopropyl betaine-
containing products [44].
Oleamidopropyl dimethylamine is an emulsifier and surfactant used in personal care products. It is a

common ingredient and an increasingly important allergen, often linked with eyelid dermatitis [45].
Glucosides (lauryl glucoside, decyl glucoside, cetearyl glucoside, coco glucoside) are the third most
common surfactant group that are used as surfactants in wash-off products, such as body
cleansers and shampoos, and in some leave-on products, such as moisturizers and sunscreens.
They were ranked the American Contact Dermatitis Society's contact allergen of the year in 2017
[45,46].
Glyceryl thioglycolate is used in acidic permanent wave solutions, usually in the salon. A similar
chemical, ammonium thioglycolate, is used in basic permanent wave solutions and causes allergic
contact dermatitis at a much lower rate, although irritant reactions are common. The allergen can
persist in treated hair for up to three months. The basic permanent wave solutions are also available
for home use.
PROPYLENE GLYCOL Propylene glycol is a viscous, colorless,

and virtually odorless alcohol. It is an excellent vehicle, humectant, and preservative. It is commonly
added to topical corticosteroid preparations to increase the penetration of corticosteroid into the
epidermis and is also an ingredient of underarm deodorant products. Propylene glycol is used as a
preservative and solvent for food flavoring agents (E1520). Topical exposure may cause irritant or
allergic contact dermatitis and ingestion may cause systemic dermatitis and urticarial reactions [47].
Other common uses include personal lubricants and conduction gels for electrocardiography or
transcutaneous electrical nerve stimulation [2]. Cross-reactions rarely occur with 1,3-butylene glycol
and no clear cross-reaction occurs with polyethylene glycol.
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TOPICAL MEDICATIONS
Anesthetics — Local anesthetics, particularly the benzoic acid ester group (eg,
benzocaine, procaine, tetracaine) may cause allergic contact dermatitis. Benzocaine is widely used
in over-the-counter preparations for itch and pain relief (eg, Vagisil, Lanacane) and as a sexual
desensitizing agent. A positive reaction to benzocaine is detected in 0.5 to 4 percent of patients
undergoing routine patch testing [1,48,49]. Benzocaine may cross-react with other local anesthetic
agents and with para-aminobenzoic acid (PABA) derivatives such as p-phenylenediamine and PABA-
based sunscreens (see "Allergic reactions to local anesthetics"). Local anesthetics of the amide
group (lidocaine and others) cause allergic contact dermatitis at a lower rate.
Antibiotics — Neomycin is a topical aminoglycoside antibiotic often used in "triple

antibiotic" type preparations. Positive patch test reactions to neomycin are found in approximately 9
percent of patients tested [1]. Other aminoglycoside antibiotics such as gentamicin or tobramycin
may cross react with neomycin.
Bacitracin is a topical antibiotic produced by the Tracey strain of Bacillus subtilis. It is often included
in the triple antibiotic products [50]. It is a common allergen, reacting in approximately 8 percent of
patients tested [1,22]. Polymyxin B, which is produced by Bacillus polymyxa, can co-react with
bacitracin and rarely causes allergic contact dermatitis itself [50].
Mupirocin ointment does not cross-react with bacitracin or neomycin. This may be a useful
substitute for individuals needing a topical antibiotic, as it is an extremely rare cause of allergic
contact dermatitis.
Corticosteroids — Topical corticosteroid preparation may induce allergic

sensitization. Although vehicles and preservatives are most often the sensitizing agents, an allergic
reaction to the corticosteroid itself can occur [51-54]. Topical corticosteroids have been grouped into
four chemically similar, cross-reacting groups (A, B, C, D), ranked from A to D in order of decreasing
potential for contact sensitization (figure 1).
Oral or parenteral corticosteroids may rarely induce a systemic contact dermatitis in individuals
previously sensitized to the same corticosteroid applied topically [55]. (See "Topical corticosteroids:
Use and adverse effects", section on 'Cutaneous'.)
Other — Propolis is produced by bees as an adhesive and sealant for small open spaces when
building their hives. It is derived from pollens and resins of coniferous, poplar, or other trees, and is a
complex mix of chemicals, containing approximately 180 different substances [56]. Propolis is
largely used in traditional medicine for its antibacterial and antiinflammatory effects, and is found in
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many lip-care products. The main sensitizers in propolis are 3-methyl-2-butenyl caffeate and
phenylethyl caffeate; benzoic, caffeic, cinnamic, coumaric, and ferulic acids are other sensitizers
present in propolis [56].
Propolis may cross react with balsam of Peru, with which it shares more than 20 substances, and
fragrances. Cross reaction with natural beeswax is unusual, but may occur if beeswax is
contaminated with propolis. Synthetic beeswax should be safe for propolis allergic patients.
RUBBER ACCELERATORS Rubber accelerators are

chemicals used to speed the polymerization process (vulcanization) in natural latex, synthetic latex,
and nonlatex rubber products. They include thiurams, carbamates, and mercaptobenzothiazoles.
Thioureas, which are used in the production of neoprene, and antioxidants such as N-Isopropyl-N-
phenyl-4-phenylenediamine also may cause allergy to rubber.
Thiurams and carbamates are the most common cause of accelerator allergic contact dermatitis,
according to the 2011-2012 patch-test results of the North American Contact Dermatitis Group, with
a prevalence of 2.9 and 4.7 percent, respectively [22].
Thiurams most commonly screened are tetramethylthiuram monosulfide, tetramethylthiuram

disulfide, tetraethylthiuram disulfide, and dipentamethylene thiuram disulfide. Disulfiram, a thiuram
used orally as an aversive agent in the treatment of alcohol use disorder, may cause a systemic
contact dermatitis in sensitized individuals.
Carbamates are commonly tested as a carba mix, which includes 1,3-diphenylguanidine, zinc dibutyl
dithiocarbamate, and zinc diethyldithiocarbamate. If carbamate allergy is strongly suspected, 1,3-
diphenylguanidine should be tested separately. In addition to latex rubber products, also nitrile
materials may contain carbamates. Thus, it can be extremely difficult to find carbamate-free
examination or sterile surgical gloves. No clear cross-reactions between carbamates and other
chemicals are known, although iodopropynyl butylcarbamate, used as a preservative in cosmetics,
has been questioned as a cross-reactor.
Mercaptobenzothiazole can be found in latex and nonlatex gloves. Nitrile gloves and shoes are the
most common source of exposure [42]. Mercaptobenzothiazole is also used as a corrosion inhibitor
in cutting oils, antifreeze mixes, greases, adhesives, film emulsions, and in veterinary preparations
such as flea and tick powders and sprays.
Dialkyl thioureas are rubber accelerators and antidegradant agents that are screened in a mix of
diethyl- and dibutyl thioureas. They are used in both natural and synthetic rubber systems, as well as
in adhesives, commercial paint, glue remover, detergents, fungicides, insecticides, and copy papers
[42,57]. The most common sources of exposure are shoes and neoprene (polychloroprene) braces.
Co-sensitization with other rubber accelerator chemicals and para-tertiary butylphenol formaldehyde
resin are common, as well as cross-reactions in the thiourea group [57].
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ADHESIVES
Phenol-formaldehyde resins — Para-tertiary butylphenol
formaldehyde resin (PTBFR) is a synthetic polymer mainly used in adhesives. Common sources of
exposure include neoprene braces, sleeves, and wetsuits and glued leather products. Other sources
include motor oil, printing inks, fiberglass, plywood, and masonry sealants.
PTBFR can induce both type I and IV reactions [2]. Cross-reactions may occur with formaldehyde,
resin monomer, and other formaldehyde-based resins, such as phenol formaldehyde resin, urea
formaldehyde resin, melamine formaldehyde resin, and cashew nut oil-formaldehyde resin.
Colophony (rosin) — Colophony (rosin) is derived from the sap of pine trees. It
is a solid residue of distillation of turpentine and its major chemical constituent is abietic acid.Rosin
is commonly used in adhesives (especially some adhesive bandages), plasticizers, fabrics,
asphalt/cements, chewing gum, leather cleaners, photo paper coating, mascaras, and newsprint.
Rock climbers, gymnasts, dancers, and baseball players commonly use powdered rosin to improve
grip. Violinists and players of other string instruments use rosin on the bow hair. Colophony in
sanitary pads may cause vulvar dermatitis [58]. Cross-reactions include balsam of Peru, turpentine,
wood tars, pine resins, and propolis.
Epoxy resin — Epoxy resin systems are composed of one or more monomers, such as
bisphenol A and epichlorohydrin, curing (hardening) agents, and diluents or additives. It is believed
that only the monomer, but not the polymer, is allergenic. However, since the polymerization process
is often incomplete, the monomer is often present in small amounts in the final product and can
elicit an allergic reaction. Epoxy resin plastics and adhesives are frequently used in making sporting
goods (eg, tennis rackets), vehicle parts, and in building construction. Nitrile gloves should be used
for protection from epoxy resin [59].
ACRYLATES Acrylates are used in plastics, adhesives, paints and coatings,

paper finishes, dental materials, artificial nails, and many consumer products. Acrylate monomers
(eg, acrylic acid, methyl methacrylate, and acrylonitrile) react to form polymers that are elastic,
resistant to breaking, and transparent. Artificial nail application and nail sculpting with acrylic gels
are among the most common exposures to acrylates [60-63]. In a European study, 67 percent of
cases of acrylate allergic contact dermatitis were caused by nail acrylates, occurred in women in the
vast majority of cases, and were associated with nonoccupational (recreational) use of cosmetic nail
products in approximately one-half of the cases [64]. Facial allergic contact dermatitis may be
caused by involuntary transfer of acrylates from the nails to the face [65]. In occupational settings,
latex gloves do not protect from acrylates.
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Ethyl acrylate and methyl methacrylate are included in many standard patch testing series. Ethyl
acrylate is used in dentures and hearing aids, artificial nail products, dental fillings, glues, and inks.
Methyl methacrylate is a component of orthopedic bone cement, medical adhesives, corneal contact
lenses, intraocular lenses, and hearing aids. Cross-reactions between acrylates are common.
However, for patients with a positive reaction to ethyl acrylate and methyl methacrylate, a more
extensive patch testing may be helpful in determining which monomers can be tolerated. In a United
Kingdom study, the top acrylates eliciting a positive reaction were 2-hydroxyethyl methacrylate (1.7
percent), 2-hydroxypropyl methacrylate (1 percent), and 2-hydroxyethyl acrylate (1 percent) [66].
Cyanoacrylates (ethyl-) are fast-acting glues that have many industrial applications and are also
often used in artificial nail systems. They do not cross-react with ethyl acrylate or methyl
methacrylate but are an important cause of allergic contact dermatitis in and of themselves [64]. The
surgical wound sealer Dermabond is primarily octyl-cyanoacrylate and may cause allergic contact
dermatitis reactions both on the skin as well as with internal applications. (See "Minor wound repair
with tissue adhesives (cyanoacrylates)".)
Patch testing with the standard ethyl cyanoacrylate is a poor screening allergen for Dermabond
allergy. Instead, octyl cyanoacrylate should be used for better screening sensitivity [67].
FABRIC DYES AND FINISHES Disperse dyes,

particularly disperse blue 106 and 124, are strong sensitizers and a common cause of contact
allergy to textiles [68]. Disperse dyes are water insoluble and typically used to dye acetate and
polyester fibers [69]. Cross-reactions may occur with p-phenylenediamine, an ingredient of
permanent hair dyes, which is a good screening allergen for textile dye allergy [70]. (See 'Hair care
products' above.)
Textile allergic contact dermatitis typically involves sites that are in close contact with clothing (eg,
axilla with sparing of the vault, thighs) and is worsened by friction and sweating. In infants and
young children, disposable diapers may be a source of exposure to disperse dyes [71,72].
Ethylene urea melamine formaldehyde and other formaldehyde textile resins such as dimethylol
dihydroxyethyleneurea, areused as fabric finishes to prevent wrinkling, decrease shrinkage, and
improve fabric strength [73]. They are usually found in "permanent press" and "wash-and-wear" type
clothing and most often in fabrics that are blends of synthetic and natural fibers.
A nonevidence-based method for possibly removing formaldehyde from new clothing is soaking in
dissolved powdered milk (one-quarter cup powdered skim milk dissolved in approximately 3 gallons
of cold water). Clothes should be soaked for approximately 12 hours in a covered container, then
rinsed well. While there are no studies proving this method is effective, it is helpful for some.
Cross- or co-reactions may occur with formaldehyde and formaldehyde-containing or releasing

chemicals. (See 'Formaldehyde/formaldehyde releasers' above.)
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EMERGING ALLERGENS There are many substances that
have the potential to elicit allergic contact dermatitis beyond those discussed in this topic review.
The American Contact Dermatitis Society updates a suggested patch testing series that may be
helpful for those looking to patch test beyond the thin-layer rapid-use epicutaneous (TRUE) test
series [74]. New allergens added in 2017 were polymyxin B sulfate, lavender, sodium benzoate,
ethylhexylglycerin, and benzoic acid.
ALLERGEN AVOIDANCE TIPS

Reading labels — Individuals with contact allergy should use only personal care
products and prescription topicals that have a complete ingredient list included in the packaging.
Ingredients are usually listed from the highest to lowest concentration and should be indicated with
the accepted chemical name determined by the Personal Care Products Council. However,
fragrances and flavorings are not required to be listed by specific chemical name and are often
generically indicated as "fragrance."
Contact Allergen Management Program

(CAMP) — The Contact Allergen Management Program (CAMP) of the American Contact
Dermatitis Society, which requires membership, allows the clinician to create an individualized list of
products that are free of specific allergens. Patients can update their list at any time by going to the
CAMP website and entering codes provided with the original printout. A similar product, called the
Contact Allergen Replacement Database (CARD) (www.allergyfreeskin.com), is commercially
available.
SUMMARY AND
RECOMMENDATIONS
●Allergic contact dermatitis is a T cell-mediated, delayed-type hypersensitivity response to
exogenous agents and the most frequent occupational skin disease. (See 'Introduction' above.)
●Metals, preservatives, fragrances, and topical antibiotics are the most frequent causes of allergic
contact dermatitis. P-phenylenediamine, commonly used in hair dyes, is also a common sensitizer.
(See 'Metals' above and 'Preservatives' above and 'Fragrances' above and 'Topical medications'
above and 'Hair care products' above.)
●Avoidance is the mainstay of treatment of allergic contact dermatitis. Individuals with contact
allergy should use only personal care products and prescription topicals that have a complete
ingredient list included in the packaging. (See 'Allergen avoidance tips' above.)
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Contact dermatitis in children - UpToDate
uptodate.com/contents/contact-dermatitis-in-children/print
INTRODUCTION Contact dermatitis refers to inflammation of the dermis

and epidermis as a result of direct contact between a substance and the surface of the skin. In fact,
almost all dermatitis is the result of skin surface injury from epicutaneous exposures. Contact
dermatitis is divided into two broad categories: irritant contact dermatitis and allergic contact
dermatitis. Irritants cause immediate inflammation of the skin; allergens cause an inflammatory
response that is delayed by days.
This topic will discuss irritant and allergic contact dermatitis in children. Contact dermatitis in adults
is discussed separately.
●(See "Irritant contact dermatitis in adults".)
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●(See "Common allergens in allergic contact dermatitis".)
IRRITANT CONTACT DERMATITIS Irritant

contact dermatitis results from exposure to substances that cause physical, mechanical, or
chemical irritation of the skin. Diaper dermatitis and dry skin dermatitis are two common forms of
irritant contact dermatitis in children.
Diaper dermatitis — Diaper dermatitis is the prototype for irritant contact

dermatitis in children. Diaper dermatitis is discussed in detail separately. (See "Diaper dermatitis".)
Dry skin dermatitis — In dry skin dermatitis, also called xerosis, the surface of
the skin appears dry and cracked; erythematous areas often appear within the surface cracks.
Common causes of dry skin dermatitis in children include frequent soaping of the skin, and frequent
wet-to-dry episodes (eg, lip licking, thumb-sucking, and playing in water).
Pathogenesis — The cells on the surface of the skin, called corneocytes, have the ability
to bind three times their weight in water. Water binding involves corneocyte surface lipids, such as
ceramides, and the proteins of the outer corneocyte envelope, such as involucrin and filaggrin [1]. In
a case-control study, loss-of-function mutations in the filaggrin gene were associated with
susceptibility to chronic irritant contact dermatitis [2]. The bound water provides almost all of the
skin surface moisture. It is unrelated to the state of internal hydration. Air humidity of 60 percent is
ideal for the skin.
Corneocyte disruption occurs when air humidity falls below 15 percent and/or corneocyte surface
lipids are removed from the surface of the skin by soap or chemicals that cause the corneocytes to
shrink from one another [3]. Disruption of corneocytes causes release of the inflammatory cytokines,
tumor necrosis factor-alpha (TNFa), and interleukin-1 (IL-1), which are stored in corneocytes.
Clinical features — In children with dry skin dermatitis, a history of excessive soaping
of the skin, frequent water exposure, or excessive sweating may be obtained. On examination, the
skin surface appears dry, cracked, and chapped with a macular erythema. Involvement may be
limited to the hands in compulsive hand-washers, to the feet in children who have excessive
sweating or water exposure of the feet (juvenile plantar dermatosis) (picture 1A-B), or to the lips and
perioral area (lip-licking dermatitis) (picture 2). Symptoms include burning, stinging, or discomfort. In
contrast to allergic contact dermatitis, itching is usually modest or absent.
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Diagnosis and differential diagnosis — The diagnosis of dry skin
dermatitis is usually straightforward, based upon the clinical finding of localized areas of dry,
cracked, and erythematous skin in children with a history of excessive exposure to water and
detergents, or excessive sweating. Patch testing is not routinely performed in children with irritant
contact dermatitis.
The differential diagnosis includes allergic contact dermatitis, atopic dermatitis, and the ichthyoses.
Patch tests to relevant environmental allergens are typically positive in children with allergic contact
dermatitis. In contrast to dry skin dermatitis, which typically affects a localized area, the entire
surface of the skin may be affected in atopic dermatitis [4,5]. Atopic dermatitis and the ichthyoses
are discussed in detail separately. (See "Atopic dermatitis (eczema): Pathogenesis, clinical
manifestations, and diagnosis" and "Overview and classification of the inherited ichthyoses".)
Treatment — Restoration of water and lipid to the skin surface and prevention of
transepidermal water loss are essential to the treatment of dry skin dermatitis. This is best
accomplished with application of moisturizers at least twice per day (table 1) [4,6,7]. In one
randomized trial, the use of moisturizing cream reduced transepidermal water loss, normalized skin
Corneometer values, and decreased irritant reactions [8]. The use of nanoemulsions of lipids
improves skin hydration, elasticity, and erythema [9]. Overall, preparations that restore moisture to
the skin surface also enhance delivery of steroids and other active topical medications into the skin
[10].
In addition, elimination of factors that may predispose to dryness, such as excessive washing of the
skin with soap, is critical to the success of therapy. Moisturizers that are accidentally ingested cause
no problem other than greasy stools.
ALLERGIC CONTACT
DERMATITIS Allergic contact dermatitis (ACD) is an acquired, inflammatory
reaction of the skin that requires absorption of antigen from the skin surface and recruitment of
previously sensitized, antigen-specific T lymphocytes into the skin. (See "Basic mechanisms and
pathophysiology of allergic contact dermatitis".)
Epidemiology — The exact incidence and prevalence of ACD in children are not
known [5,9]. Incidence and prevalence of ACD depend upon exposure to contact allergens, which
varies according to geography (eg, poison ivy) and cultural practices (eg, jewelry wearing, use of
fragrances) [11]. It has been estimated that ACD accounts for at least 20 percent of all cases of
childhood dermatitis [12,13].
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Although as many as 25 percent of randomly selected asymptomatic children who undergo
epicutaneous patch testing react to one or more antigens, the true prevalence of ACD is not known
[11,12,14-16]. A positive patch test reaction that is not found to be clinically relevant is termed
"contact allergy" rather than ACD [17]. One specific example of an allergen that induces contact
sensitization that is rarely clinically relevant is thimerosal.
The North American Contact Dermatitis Group reported that of 883 children tested from 2005 to
2012, 62 percent had ≥1 positive patch test and 57 percent had ≥1 relevant positive patch test [18]. In
a single institution study of 2614 children under 10 years of age who underwent patch testing for
suspected allergic contact dermatitis, 1220 (47 percent) developed at least one positive reaction,
which was deemed to be relevant in approximately 50 percent of cases [19]. The frequency of
positive reaction was similar among children with or without a history of atopic dermatitis. The most
common allergens were nickel sulfate (23 percent), cobalt chloride (11 percent), and potassium
dichromate (10 percent). A study of 343 Israeli children confirmed these results, with nickel ACD
more common in girls than in boys (38 versus 16 percent) [20].
ACD has been reported in one-week-old infants [21,22], and sensitization often begins as early as six
months of age [16]. By two years of age, many children are already sensitized to at least one
common allergen (eg, nickel) [16].
Pathogenesis — An intact immune system is required for the development of ACD,

which occurs in two phases: the sensitization phase and the elicitation phase [23]. (See "Basic
mechanisms and pathophysiology of allergic contact dermatitis".)
●The sensitization phase begins with initial exposure to the antigen and may begin in infancy [16].
Contact antigens are usually low-molecular-weight substances that penetrate the outer layer of the
skin and are taken up by Langerhans cells (LC). Sweating may enhance this process [23]. After
processing the antigen and migrating to regional lymph nodes, LC present the antigen to T
lymphocytes. These antigen-specific T lymphocytes undergo clonal expansion, creating a pool of
cells with immune memory that can generate an immune response upon re-exposure to the allergen
(the elicitation phase). Preliminary studies indicate that macrophages and neutrophils are also
important in the pathophysiology of contact allergy [24]. Antigen-presenting cells and the cellular
immune response are discussed in detail separately. (See "Antigen-presenting cells" and "The
adaptive cellular immune response: T cells and cytokines".)
●In the elicitation phase, the sensitized T lymphocytes proliferate and release inflammatory
mediators, producing a localized dermatitis. The resulting dermatitis begins 12 to 24 hours after
allergen exposure, peaks in three to five days, and may last three to four weeks if untreated
[23,25,26]. The potency of the allergen determines the number of exposures necessary for this
process to occur. A strong antigen, such as poison ivy, requires only one exposure, while weaker
antigens require numerous exposures over weeks to years. Once sensitization occurs, however, it is
thought to be long-lived [9,23,25,26].
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Allergens — Contact allergens are found in both the natural and man-made environment
(table 2) [27]. The most common plant contact allergen is urushiol, a pentadecylcatechol found in
plants of the Toxicodendron species, such as poison ivy, poison oak, and poison sumac (figure 1 and
picture 3A-C). (See "Poison ivy (Toxicodendron) dermatitis".)
Other common childhood contact allergens in the United States and Europe include metals such as
nickel [28], cobalt, and potassium dichromate (also tanning agent in leather); topical antimicrobials
such as neomycin and bacitracin; fragrances (fragrance mix and Myroxylon pereirae [balsam of
Peru]), preservatives (formaldehyde and formaldehyde-releasing preservatives,
methylchloroisothiazolinone [MCI] and methylisothiazolinone [MI]), colophony (rosin from wood),
wool alcohol (lanolin), and several others [14,17,29-31]. MCI and MI are preservatives found in infant
products such as wet wipes, protective creams, liquid soaps, and shampoos (a fixed 3:1 combination
of MCI/MI is known as Kathon CG). In an analysis of 1100 positive patch tests in children, 96 (9
percent) were positive to MCI/MI or MI alone [32]. (See "Common allergens in allergic contact
dermatitis".)
Additional allergens of potential importance in the pediatric population are cocamidopropyl betaine,
a non-ionic surfactant used in cleansing products for children and disperse dyes that are found in
diaper material and colored garments [17]. The active ingredients of chemical sunscreens (eg,
oxybenzone, octocrylene), although uncommon causes of childhood ACD, are increasingly reported
causes of ACD [33-35]. Despite the widespread use of personal care products, such as diaper wipes
in infants and cosmetics in teens, adverse skin reaction reports to the US Food and Drug
Administration (FDA) are infrequent (166 reports from 2004 to 2016) [36].
Clinical findings — ACD presents as pruritic dermatitis most commonly localized

to the site of allergen contact with the skin, but can also present as a generalized dermatitis (see
'Autoeczematization ("id" reaction)' below). The configuration and location of the dermatitis often is a
clue to the offending allergen (table 2 and picture 4A-B) [37]. Regional lymph nodes may be enlarged
but are not tender [23].
ACD may be acute, subacute, or chronic:
●Acute ACD to potent allergens (eg, poison ivy, poison oak, poison sumac, nickel) is characterized by
erythema and edema with vesicles or bullae (picture 5) that often rupture, leaving a crust.
●Subacute and chronic ACD, which are more common, are characterized by lichenification,
erythema, and scaling (picture 6), and are produced by less potent antigens.
Autoeczematization ("id" reaction) — A more generalized dermatitis,

termed autoeczematization, may develop distal to the original site of contact one or more weeks
after the appearance of the initial localized dermatitis. This secondary dermatitis is also called
autosensitization dermatitis or an "id" reaction. Autoeczematization is particularly common among
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children with nickel dermatitis who have subacute dermatitis at the initial site for several weeks
before appearance of a more widespread dermatitis [37]. Autoeczematization is treated in the same
manner as widespread ACD. (See 'Management of allergic contact dermatitis' below.)
Diagnosis — A history of allergen exposure and the pattern of the eruption are important
factors in making the correct diagnosis. Patterns of dermatitis that are suggestive of ACD include
persistent, localized dermatitis that has not responded as expected to therapy, and dermatitis in an
unusual pattern or distribution (picture 4A-B) [37]. In contrast with ACD, which often has a bizarre or
asymmetrical distribution, atopic dermatitis is typically symmetric. ACD also should be considered
in any child who has a persistent dermatitis regardless of the pattern, as well as facial, eyelid, or
palmo-plantar dermatitis [29].
Considering the child's hobbies, activities, occupation, and other exposures is important in
assessing and diagnosing allergic contact dermatitis.
Patch testing — Although the offending allergen may be suspected through history,
epicutaneous patch testing may be necessary to identify specific antigens or, in some cases, to
make the diagnosis of ACD [17,27,30,33,37-41]. The most common allergens in children in North
America are nickel, cobalt, neomycin, Myroxylon pereirae (balsam of Peru), lanolin, fragrance,
bacitracin, carmine, p-phenylenediamine, quaternium 15, propolis, and formaldehyde [17]. (See
"Patch testing".)
Identifying the offending allergen is important, since allergen avoidance is the key to preventing
recurrence. However, we recommend not patch testing for poison ivy or poison oak (urushiol)
because the reaction can be extreme and someone who is not sensitive may be sensitized by the
testing.
Epicutaneous patch testing involves placement of suspected and standard allergens on the skin
surface for 48 hours. The patches are then removed and the skin evaluated for irritant or early
positive reactions. The final read at 72 to 96 hours is important to document positive reactions
(picture 7). Reevaluation is recommended after four to five days to detect reactions to weaker
antigens and to permit irritant reactions to clear [23]. Children should avoid bathing and strenuous
activity while the patches are in place.
Because of the potential pitfalls in interpretation of patch tests, epicutaneous patch testing should
only be performed by clinicians who are experienced in the procedure and interpretation of the test,
and knowledgeable about the relevance of the antigens [42,43]. In a retrospective case series, 80
percent of positive patch test reactions in children were relevant (with relevance determined by the
presence of the allergen in the child's environment and/or improvement on allergen avoidance or
exacerbation upon re-challenge) [41].
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Differential diagnosis — The clinical morphology of ACD is identical to
other forms of dermatitis (eg, irritant dermatitis and atopic dermatitis). Other conditions that may be
considered in the differential diagnosis of ACD include [23]:
●Cellulitis, an infection of the deep dermis and subcutaneous tissue that manifests as skin areas of
erythema, edema, and warmth, often accompanied by lymphangitis and inflammation of regional
lymph nodes. Fever and leukocytosis, common in cellulitis, are not features of ACD. (See "Cellulitis
and skin abscess: Clinical manifestations and diagnosis".)
●Herpes simplex virus, herpes zoster, impetigo (if blistering lesions are present). (See "Epidemiology,
clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Epidemiology,
clinical manifestations, and diagnosis of herpes zoster" and "Impetigo".)
●Fixed drug eruption, which typically recurs in the same location. (See "Fixed drug eruption".)
Management of allergic contact dermatitis — The

treatment of ACD involves two main principles:
●The allergen must be identified and avoided to prevent recurrence.
●The dermatitis must be treated for at least 14 to 21 days.
Allergen avoidance — Identifying the offending allergen is important, since allergen

avoidance is the key to preventing recurrence. Although the offending allergen may be suspected
through history, epicutaneous "patch" testing may be necessary to identify specific antigens [40].
(See 'Patch testing' above.)
Once the allergen is known, the patient should be educated about potential sources and avoidance
of the antigen. Complete avoidance is possible in many circumstances once the source of the
allergen is known. Avoidance may involve placing a barrier between the allergen and the skin.
Examples include wearing long pants when out in the woods to prevent poison ivy dermatitis and
using a cloth patch or nail enamel to cover the exposed portions of metal snaps or fasteners in a
child allergic to nickel. (See "Management of allergic contact dermatitis", section on 'Avoidance'.)
Therapeutic options — Although avoidance of the offending allergen is the

mainstay of management of ACD, treatment is required in most cases to achieve rapid control of
symptoms. The treatment of ACD follows the general principles of eczema treatment and includes:
●Topical corticosteroids – Topical corticosteroids are the mainstay of treatment of ACD. Through
various mechanisms, corticosteroids decrease the production of cytokines and halt lymphocyte
proliferation, limiting the inflammatory response to contact allergens [44]. In two small trials, the
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application of topical corticosteroids resulted in decreased transepidermal water loss, clinical
improvement, and suppression of allergic reaction compared with the application of placebo in
patients with ACD [45,46].
Topical corticosteroids are classified according to strength, with group 1 corticosteroids being the
strongest and group 7 the least strong (table 3). Examples of moderate-potency topical
corticosteroids include fluocinolone acetonide 0.025% (group 4), triamcinolone acetonide 0.1%
(group 4), and mometasone furoate 0.1% (group 3). Side effects of topical corticosteroid therapy are
reviewed in detail separately. (See "Topical corticosteroids: Use and adverse effects", section on
'Adverse effects'.)
●Topical calcineurin inhibitors – Two macrolide immunosuppressants, tacrolimus and

pimecrolimus, are potential alternatives to corticosteroids in the treatment of subacute and chronic
ACD [47,48].
•Tacrolimus is used systemically to prevent organ rejection after transplantation. It inhibits

calcineurin, thereby halting the transcription of IL-2 and decreasing the responsiveness of T
lymphocytes to antigenic stimuli [47]. A topical ointment in two concentrations, 0.03% and 0.1%, is
approved for the treatment of atopic dermatitis, but only the 0.03% version is indicated for use in
children aged 2 to 15 years.
•Pimecrolimus, an ascomycin analog, down-regulates the production of various cytokines that are
released as a result of antigen-specific stimulation of immune-memory T cells [49]. A 1% cream is
approved for the treatment of mild to moderate atopic dermatitis in children two years and older [50].
There is limited evidence from poor-quality randomized studies for efficacy of topical tacrolimus, but
not pimecrolimus, in the treatment of ACD [51-53]. Tacrolimus appears to be as effective as mid-
potency corticosteroid ointments (eg, triamcinolone acetonide 0.1% or fluocinolone acetonide
0.025%) for the treatment of ACD in adults [52].
In addition, in 2005 the FDA issued boxed warnings about the possible link between topical use of
calcineurin inhibitors and cancer in children and adults, but no definite causal relationship has been
established so far [54]. An analysis of data from 7500 children enrolled between 2004 and 2014 in
the Pediatric Eczema Elective Registry (PEER), an ongoing post-marketing cohort study, found a
trend toward increased risk for lymphoma and leukemia that was not statistically significant
compared with incidence in the general population based on the Surveillance, Epidemiology, and End
Results (SEER) database [55].
While awaiting data from a larger study, according to the FDA recommendations, it seems prudent to
use topical calcineurin inhibitors only as second-line therapy for the management of atopic
dermatitis in areas at high risk for skin atrophy when treated with topical corticosteroids. They
should not be used in children younger than two years of age or in immunocompromised individuals.
●Other therapies – Adjunctive treatments that may be beneficial in alleviating the symptoms
associated with ACD, such as burning or pruritus, include:
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•Sedating antihistamines, such as diphenhydramine or hydroxyzine, decrease itching and allow the
patient to sleep through the night. As an alternative to standard dosing, we have found a single dose
of hydroxyzine 1 to 2 mg/kg, given 30 minutes to 1 hour before bedtime, to be effective in this
regard.
•Wet dressings are also soothing and help relieve itching, reduce redness, debride crusts, and limit
access to the skin. Dampened cotton garments are worn over the affected area and covered with a
dry garment. The patient may use these dressings overnight or change them every eight hours
during the day. The author prefers wet dressings to topical agents such as calamine or colloidal
oatmeal baths because wet dressings limit access to the skin and are more soothing, hydrating, and
antipruritic.
Children with acute allergic contact dermatitis

Localized allergic contact dermatitis — For localized eruptions, we suggest
mid-potency topical corticosteroids. Corticosteroid ointments (not creams) are applied two times
daily for two to three weeks. As with systemic therapy, the topical therapy must be continued for two
to three weeks, since stopping the therapy too quickly may cause rebound dermatitis.
Widespread allergic contact dermatitis or allergic contact

dermatitis involving the face — When the dermatitis involves 20 percent or more of
the skin surface, systemic corticosteroids are indicated. A single morning dose of prednisone (1 to 2
mg/kg, up to a maximum dose of 60 mg) for 7 to 10 days, followed by a taper over the next 7 to 10
days, is usually sufficient. Systemic corticosteroids may be preferred to topical corticosteroids for
patients with acute ACD involving the face to achieve a rapid relief of symptoms.
Children with subacute and chronic allergic contact

dermatitis — Subacute and chronic ACD is often the result of repeated exposures to
modest or weak contact allergens, making treatment challenging. Depending upon the part of the
body affected, low- or mid-potency topical corticosteroids (groups 4 to 7, (table 3)) can be applied
twice daily for two to three weeks. Intermittent twice-daily application of topical corticosteroids (eg,
during the weekends) may be helpful to maintain long-term remission. Emollients can be liberally
used in conjunction with topical corticosteroids.
Appropriate long-term use of low- or mid-potency topical corticosteroids does not cause
hypothalamic-pituitary-adrenal suppression in infants and children [56], although localized side
effects such as atrophy are possible. Allergic contact dermatitis to topical corticosteroids is also a
possible complication of therapy and, if suspected, may be evaluated with patch testing to identify
the culprit preparation, as well as other corticosteroids that the patient can tolerate [57]. The
classification of topical corticosteroids in cross-reacting groups is also useful in the choice of the
preparation the patient may tolerate (figure 2).
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Second-line therapy for subacute and chronic ACD involving the face or intertriginous areas may
include topical calcineurin inhibitors.


●Basics topics (see "Patient education: Diaper rash (The Basics)" and "Patient education: Poison ivy
(The Basics)" and "Patient education: Eczema (atopic dermatitis) (The Basics)")
●Beyond the Basics topics (see "Patient education: Contact dermatitis (including latex dermatitis)
(Beyond the Basics)" and "Patient education: Diaper rash in infants and children (Beyond the
Basics)" and "Patient education: Poison ivy (Beyond the Basics)" and "Patient education: Eczema
(atopic dermatitis) (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
Irritant dermatitis
●A diagnosis of irritant contact dermatitis should be considered in children who have localized
macular erythematous rashes in which the skin is dry, cracked, and chapped. (See 'Dry skin
dermatitis' above.)
●We recommend the use of moisturizers (table 1) for the treatment of dry skin dermatitis (Grade 1B).
Moisturizers should be applied at least twice per day. (See 'Treatment' above.)
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●Avoidance of the irritant (eg, frequent bathing, lip licking, soaps, etc) is essential in the treatment of
dry skin dermatitis. (See 'Treatment' above.)
Allergic dermatitis
●Allergic contact dermatitis (ACD) is an acquired, inflammatory reaction of the skin that requires
absorption of antigen from the skin surface and recruitment of previously sensitized, antigen-
specific T lymphocytes into the skin. (See 'Pathogenesis' above and 'Allergens' above.)
●ACD presents as pruritic dermatitis localized to the site of allergen contact with the skin. The
configuration and location of the dermatitis often is a clue to the offending allergen (picture 4A-B).
(See 'Clinical findings' above.)
●The diagnosis of ACD should be considered in children who have localized pruritic dermatitis 12 to
24 hours after exposure to a contact allergen to which they have been sensitized. Epicutaneous
patch testing may be necessary to make the diagnosis of ACD or to identify specific antigens. Patch
testing should be performed by clinicians with experience in its performance and interpretation. (See
'Diagnosis' above.)
●Avoidance of the allergen is essential in the treatment of ACD. (See 'Allergen avoidance' above.)
●We recommend topical corticosteroids as the first-line therapy for acute localized ACD (Grade 1B).
Mid-potency corticosteroids (group 4, (table 3)) are applied twice daily for a minimum of 14 to 21
days. (See 'Localized allergic contact dermatitis' above.)
●For patients with widespread acute ACD or acute ACD involving the face, we suggest systemic
corticosteroids (Grade 2C). A single morning dose of prednisone (1 to 2 mg/kg, up to a maximum
dose of 60 mg) for 7 to 10 days is usually sufficient. (See 'Widespread allergic contact dermatitis or
allergic contact dermatitis involving the face' above.)
●We suggest topical therapy with a mid-potency corticosteroid ointment (group 4, (table 3)) for
subacute or chronic ACD (Grade 2C). (See 'Children with subacute and chronic allergic contact
dermatitis' above.)
●Sedating antihistamines, such as diphenhydramine or hydroxyzine, and wet dressings are adjuncts
to therapy for ACD. (See 'Therapeutic options' above.)
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Irritant contact dermatitis in adults
uptodate.com/contents/irritant-contact-dermatitis-in-adults/print
INTRODUCTION Irritant contact dermatitis (ICD) is a localized

inflammatory skin response to a wide range of chemical or physical agents [1]. ICD results from
direct cytotoxic effect of irritants and, unlike allergic contact dermatitis, is not immune mediated. ICD
is a multifactorial disorder influenced by the physical and chemical properties of the irritating
substance, host-related susceptibility factors, and environmental factors.
The clinical manifestations of ICD are similar to those of other acute or chronic eczematous
dermatitides, including atopic dermatitis and allergic contact dermatitis.
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and management of ICD
in adults. Atopic dermatitis and allergic contact dermatitis are discussed separately. Diaper
dermatitis, the prototype of ICD in infants and young children, is discussed separately [2].
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●(See "Diaper dermatitis".)
EPIDEMIOLOGY Irritant contact dermatitis (ICD) is the most common

type of contact dermatitis. ICD represents approximately 80 percent of occupational contact
dermatitis and is considered the most frequent cause of hand eczema [2,3]. In the general
population, the estimated prevalence of hand eczema is approximately 4 percent; women are more
frequently affected than men [3]. The risk of occupational ICD is highest among those with "wet
work" exposures, such as food handlers, health care workers, mechanical industry workers, cleaners,
and housekeepers (table 1) [4].
PATHOGENESIS Multiple mechanisms, some of which are not

completely understood, are involved in the development of irritant contact dermatitis (ICD), including
[5,6]:
●Disruption of the epidermal barrier
●Damage of keratinocyte cell membranes
●Cytotoxic effect on keratinocytes
●Cytokine release from keratinocytes
●Activation of innate immunity
The disruption of the epidermal barrier (stratum corneum) by occlusion or chemical or physical
irritants, resulting in increased skin permeability and transepidermal water loss (TEWL) and
reduction of the natural moisturizing factor, is considered the initiating event of ICD [7].
In experimental animal and human models, the acute disruption of the epidermal barrier from
exposure to surfactants (eg, sodium lauryl sulfate) induces the release of preformed cytokines, such
as interleukin (IL)-1-alpha, IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha, from keratinocytes
[8-11]. IL-1-alpha and TNF-alpha act as primary signals for the release of proinflammatory
chemokines (eg, CCL20, CCL21, and CXCL8), which attract mononuclear and polymorphonuclear
cells at the site of injury [11,12]. In addition, TNF-alpha induces the expression of intercellular
adhesion molecule 1 (ICAM-1) on keratinocytes, which promote the infiltration of leukocytes into the
epidermis.
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Anti-inflammatory cytokines, such as IL-10 and the IL-1 receptor antagonist (IL-1RA), are also
released in response to irritant exposure and may be involved in the resolution of the inflammatory
process [13].
The pathogenesis of chronic ICD is not completely understood. One hypothesis is that chronic
exposure to mild irritants or wet work downregulates the inflammatory response and stimulates cell
proliferation and differentiation. A few studies have compared the cytokine levels in normal skin and
in skin areas repeatedly exposed to sodium lauryl sulfate. In chronically irritated skin, the levels of IL-
1-alpha and TNF-alpha were lower and the levels of IL-1RA were higher than those measured in
nonirritated skin [13,14].
Some individuals develop a tolerance to chronic exposure to irritants. The adaptation of the skin to
repeated irritant exposures is called the "hardening phenomenon." The mechanisms underlying the
hardening phenomenon are unknown. Irritant-induced changes in skin morphology (eg, acanthosis
and hyperkeratosis), lipid composition of the stratum corneum, barrier permeability, and expression
of inflammatory mediators may contribute [15,16].
PREDISPOSING FACTORS The development of irritant

contact dermatitis (ICD) is influenced by host-related and environmental factors.
Host-related factors
●Age – The skin reactivity to irritants is highest in infants and tends to decrease with age. The
reactivity to irritants is lower among individuals >65 years than in those <30 years [17].
●Sex – The prevalence of ICD in general and of hand dermatitis in particular is greater in women
than in men. However, the higher risk in women is probably due to increased domestic and
occupational exposure to detergents and "wet work" rather than to genuine sex differences in
susceptibility [3]. The clearance rate and prognosis are similar in men and women [18].
●Body site – The response to irritants varies from site to site on the body, reflecting differences in
the thickness of the stratum corneum and barrier function. The face, dorsum of the hands, and
finger webs are more prone to irritation from chemical substances than the palms, soles, or back
[2,19].
●Atopy – Individuals with atopic dermatitis have a chronically impaired barrier function that
increases their susceptibility to irritants [20,21]. In a population-based study of patients with
occupational skin disease, 64 percent of the subjects with ICD reported a personal or family history
of atopic dermatitis or had typical and/or minor signs of atopic dermatitis [22].
●Genetic factors – Twin studies indicate that genetic factors other than atopy (eg, cytokine gene
polymorphisms) may influence the susceptibility to ICD [23]. Individuals with a low threshold for the
irritant effect of sodium lauryl sulfate and benzalkonium chloride have a high prevalence of a tumor
necrosis factor alpha (TNFA) gene polymorphism that is correlated with increased tumor necrosis
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factor (TNF)-alpha production [24,25]. Another study examining the genetic basis of irritant
susceptibility in a larger population of health care workers identified nine significant single
nucleotide polymorphisms in seven candidate genes involved in inflammation and skin homeostasis
[26].
Environmental factors — Environmental factors, such as temperature, air

flow, humidity, and occlusion, affect the skin response to irritants [27].
High temperatures and air flow appear to decrease the skin barrier function and increase the
penetration of irritants, such as sodium lauryl sulfate (a surfactant contained in many detergents)
[28-30]. Cold temperatures and low ambient humidity increase the transepidermal water loss (TEWL)
and the skin susceptibility to irritants [31,32].
Increased humidity (eg, sweating from prolonged wearing of occlusive gloves) can disrupt the skin
barrier and enhance the inflammatory response to chemical or mechanical irritants [33].
HISTOPATHOLOGY The histologic features of irritant contact

dermatitis (ICD) vary according to the stage and severity of skin lesions:
●Acute ICD is characterized by mild spongiosis, intraepidermal vesicles or bullae, and necrosis of
keratinocytes. A perivascular mononuclear cell infiltrate may be seen. Electron microscopy shows a
condensed cytoplasm containing aggregated keratin filaments, lipid vacuoles, and membrane-bound
vesicles; disrupted cell membranes; and pyknotic nuclei with condensed chromatin [34].
●Chronic ICD is characterized by hyperkeratosis, parakeratosis, hypergranulosis, and acanthosis.
None of the histopathologic features of ICD can differentiate it from allergic contact dermatitis [35].
(See "Clinical features and diagnosis of allergic contact dermatitis", section on 'Histopathology'.)
COMMON IRRITANTS Irritants are physical or chemical agents

that are capable of producing cellular perturbation if applied to the skin for sufficient time and in
sufficient concentration. Common chemical irritants include water and wet work, detergents and
surfactants, solvents, oxidizing agents, acids, and alkalis. Physical irritants include metal tools,
wood, fiberglass, plant parts, paper, and dust or soil. Occupations at high risk for irritant contact
dermatitis and common irritants encountered are listed in the table (table 1) [4].
MECHANISM OF ACTION OF
IRRITANTS The level of irritancy for an individual substance depends upon its
chemical properties (eg, acid dissociation constant, ionization status, molecular size, or
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liposolubility) and the duration of the contact [2]. High concentrations of most chemicals are
sufficient to induce an irritant reaction in almost all individuals, whereas mild irritants may induce an
inflammatory response only in susceptible individuals or after repeated or prolonged contact [36].
Different chemicals may act synergistically in inducing dermatitis. Solvents remove the lipids from
the stratum corneum whereas detergents remove both lipids and hygroscopic (water-holding)
substances (eg, filaggrin breakdown products). The combined exposure to solvents and detergents
produces an additive effect [37].
Chemical irritants
●Water and wet work – Water is hypotonic and acts as a cytotoxic agent on eroded skin. On intact
skin, prolonged contact with water causes swelling of the stratum corneum, disruption of the
intercellular lipids, and enhancement of skin permeability and susceptibility to irritants [38]. Wet
work is defined as skin exposure to liquids or wearing occlusive gloves more than two hours daily or
hand washing or disinfection more than 20 times daily [39]. Food handling and preparation, health
care-related occupations, cleaning, and hairdressing are examples of wet work.
●Detergents and surfactants – Detergents used for domestic and industrial cleaning remove lipids
and hygroscopic substances in the stratum corneum, denature proteins, and damage the cell
membranes.
●Solvents – Solvents remove lipids and hygroscopic substances and damage cell membranes.
Their irritating capacity depends upon their chemical structure; aromatic solvents (eg, benzene or
toluene) are stronger irritants than alcohols or ketones (eg, acetone).
●Oxidizing agents – Oxidizing agents, such as sodium hypochlorite (bleach) or benzoyl peroxide, are
cytotoxic agents
●Acids – Strong acids (eg, sulfuric acid) cause protein coagulation and cell necrosis.
●Alkalis – Alkaline solutions saponify the surface lipids, dissolve water-holding substances, break
the cross-linkages of keratin, and cause swelling of cells. Soap, soda, ammonia, potassium and
sodium hydroxides, cement, and chalk are examples of alkaline substances.
Physical irritants — Chronic microtrauma or friction damages the stratum

corneum, impairs the skin barrier, and induces the release of preformed cytokines from
keratinocytes [40]. Physical agents that may cause skin irritation include [41-43]:
●Metal tools
●Wood
●Fiberglass
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●Plant parts (eg, thorns, spines, sharp-edged leaves) [41,42]
●Paper
●Dust/soil
Physical irritants may act synergistically with chemical irritants, such as detergents or water, in
inducing a more severe disruption of the skin barrier [33].
CLINICAL MANIFESTATIONS The clinical

manifestations of irritant contact dermatitis (ICD) range from mild skin dryness and erythema to
acute or chronic eczematous dermatitis and even skin necrosis (chemical burn) (picture 1A-D). The
type of skin response, nature of the irritant, and exposure pattern define several clinical variants,
which are summarized in the table (table 2). However, acute and chronic ICD are the most common
forms encountered in clinical practice.
Acute ICD often results from a single exposure to an irritant or caustic chemical. Clinical features
include erythema, edema, vesicles, bullae, and oozing (picture 1A-B). The reaction is generally
limited to the site of contact and is associated with a sensation of burning, stinging, or pain. Mild
cases may present with only transient erythema.
Chronic or cumulative ICD, also called "wear and tear" dermatitis, results from repeated exposures to
mild irritants or low concentrations of strong irritants. Clinically, chronic ICD is characterized by
erythema, scaling, lichenification, hyperkeratosis, and fissuring (picture 1C-D). Sites commonly
affected are the dorsum of the hands, fingertips, and finger webs. The face may be involved in
individuals exposed to volatile irritants or cosmetics.
Chronic ICD is particularly frequent in certain categories of workers (table 1). However, host and
environmental factors, such as history of atopic dermatitis and exposure to friction, dust, or
temperature extremes, are contributing factors in the persistence of ICD.
DIAGNOSIS The diagnosis of irritant contact dermatitis (ICD) is in most cases

based upon the clinical finding of a localized dermatitis in a patient with a history of exposure to
chemical or physical irritants (table 3). Complete skin examination and accurate history taking are
crucial to making the correct diagnosis.
Patch testing is performed in most patients to exclude allergic contact dermatitis. In some cases,
skin biopsy for histologic examination is necessary to exclude other skin disorders. (See 'Differential
diagnosis' below.)
Bioengineering methods to assess the skin barrier function, such as the measure of transepidermal
water loss (TEWL), are mainly used in experimental settings. (See 'Laboratory tests' below.)
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Skin examination — A complete skin examination should be performed to
evaluate the extent of the skin involvement and concomitant skin disorders. The morphology,
localization, and temporal course of dermatitis often suggest the diagnosis of ICD. In most cases,
the affected sites are exposed areas, such as the dorsum of hands, face, and neck. However, irritants
may be transferred to other skin sites by contaminated hands or clothes (eg, genitalia or
intertriginous areas). Additional clinical criteria that favor the diagnosis of ICD include [44]:
●Onset of symptoms within minutes to hours of exposure
●Pain, burning, stinging, or discomfort exceeding itching
●Glazed, parched, or scalded appearance of the epidermis
●Predominance of scaling, hyperkeratosis, or fissuring over vesicular changes
History — Important aspects of the history in a patient with suspected ICD include:
●Daily activities, including occupation and hobbies
●Types of substance or machinery used at the workplace
●Workplace environment (temperature, humidity, dusts)
●Use of protective gloves or gear
●Wet work (including use of occlusive gloves)
●Hand washing habits
●Use of cleansers and skin protecting creams
●Accidental exposure
●Previous atopic dermatitis, atopic respiratory disease, or other inflammatory skin disease
For occupational exposures, the material safety data sheets or the list of ingredients may be useful
in identifying offending irritants (table 4). In some cases, visiting the work site may be needed.
Common irritants encountered in occupational settings are listed in the table (table 1).
Laboratory tests
●Patch testing – Patch testing is often necessary to exclude allergic contact dermatitis. Standard
series of allergens are usually used for initial screening. Testing for additional series or specific work
site allergens may be required based upon the patient's exposure history. The techniques and
interpretation of patch testing are discussed separately. (See "Patch testing".)
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●Histologic examination – Skin biopsy is not routinely performed for the diagnosis of ICD. However,
in some cases histologic examination is useful to differentiate ICD from psoriasis or other types of
inflammatory dermatoses. (See 'Histopathology' above.)
●Bioengineering methods – Several noninvasive techniques have been developed to measure the
irritant response, including the TEWL, erythema, and hydration of the stratum corneum [45]. These
techniques are not routinely used in clinical practice but are often employed in research settings and
in the cosmetic industry:
•TEWL is measured by means of a device called an evaporimeter and expressed in g/m2/hour. Many
variables influence the measurement of TEWL, including the type of evaporimeter (eg, open- or
closed-chamber systems), operating conditions, age, and anatomic site. The lack of a standardized
method for TEWL measurement limits the clinical usefulness of the test [46-48].
•The intensity of erythema can be measured by laser Doppler flowmetry, reflectance spectroscopy,
or colorimetric methods [49-51].
•The hydration of the stratum corneum is evaluated by measuring its capacitance (insulating
property of dry stratum corneum) or conductance (conductive property related to the water content)
with a device called a Corneometer [52].
●Tandem repeated irritation test – Tandem repeated irritation tests (TRITs) are based on the
observation that combined mechanical irritation, detergents, and occlusion cause complementary
effects on the epidermal barrier disruption [33]. TRITs simulate real conditions in everyday life or
workplaces and are used in research settings to evaluate the synergistic effect of irritants or the
efficacy of barrier creams.
DIFFERENTIAL DIAGNOSIS The most common

disorders that should be differentiated from irritant contact dermatitis (ICD) include:
●Allergic contact dermatitis – Differentiating ICD from allergic contact dermatitis may be
challenging because they have similar clinical and histopathologic features (table 5 and picture 2A-
B). A positive patch test to the relevant exposure is generally diagnostic of allergic contact
dermatitis, although a positive patch test to a relevant allergen may not by itself exclude ICD.
Moreover, the possibility of false positive (irritant) and negative patch test reactions should be
evaluated. Rarely, ICD and allergic contact dermatitis can coexist, especially in individuals exposed
to wet work [53]. As an example, allergic contact dermatitis to glove allergens and topical
medications used for therapy may complicate irritant hand dermatitis in health care workers. (See
"Patch testing", section on 'Patch test interpretation' and "Patch testing", section on 'Determining the
clinical relevance' and "Clinical features and diagnosis of allergic contact dermatitis", section on
'Diagnosis'.)
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●Atopic dermatitis – History of atopic dermatitis and/or involvement of flexural areas suggest the
diagnosis of atopic dermatitis. However, individuals with a history of atopic dermatitis are prone to
the development of ICD when exposed to irritants (eg, wet work). (See 'Host-related factors' above
and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on
●Psoriasis – Nonpustular palmoplantar psoriasis may be extremely difficult to differentiate from

hyperkeratotic, chronic ICD (picture 3A-B) [54]. The presence of psoriatic plaques at distant sites (eg,
elbows and knees) and/or nail changes are clues to the correct diagnosis (picture 4). (See
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical
manifestations'.)
●Hand eczema – Acute and chronic (dyshidrosiform or psoriasiform) hand eczema (picture 3C) can
be difficult to differentiate from ICD. However, acute dyshidrotic eczema is characterized by vesicles
and bullae on palms and soles, extending to the interdigital spaces, without involvement of the
dorsal aspect of hands and feet. It occurs more frequently in adolescents and young adults, with
exacerbations in the spring and summer months and spontaneous remission in fall and winter.
Chronic hand eczema may have an irritant component along with an "endogenous" or idiopathic
predisposition. (See "Overview of dermatitis (eczema)", section on 'Dyshidrotic eczema'.)
●Fungal infection – Tinea manuum or pedis are typically unilateral or asymmetrical (picture 3D).
Potassium hydroxide (KOH) examination of scales can clarify the diagnosis. (See "Dermatophyte
(tinea) infections", section on 'Tinea pedis'.)
●Scabies – Scabies in the interdigital spaces can simulate an irritant dermatitis (picture 5). In
scabies, pruritus is the dominant symptom, whereas pruritus is less common and less intense in
ICD. Skin scraping, adhesive tape test, or dermoscopy can provide the correct diagnosis. (See
"Scabies: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations' and
"Scabies: Epidemiology, clinical features, and diagnosis", section on 'Diagnosis'.)
MANAGEMENT
Overview — The management of irritant contact dermatitis (ICD) includes:
●Identification and avoidance of the offending irritant(s)
●Treatment of skin inflammation
●Restoration of the epidermal barrier function
●Prevention of further exposure
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Avoidance — Avoidance of offending irritants and adoption of protective measure are
critical in the management of ICD. For hand dermatitis, general measures include:
●Minimizing contact with detergents or other cleaning agents, polish, or solvents
●Using plastic gloves with cotton lining if wet work cannot be avoided (plastic gloves are less likely
than rubber gloves to cause allergic contact dermatitis)
●Wearing gloves in cold weather
●Using lukewarm water and small amounts of mild, soap-free skin cleansers for hand washing
●Rinsing and drying hands thoroughly and gently after washing
●Using moisturizers multiple times per day
In occupational settings, first-line prevention strategies are based on technical and organizational
hazard control. Automation of processes to reduce the need of workers to expose their skin to
irritants and replacement of dangerous substances by less toxic ones are examples of primary
prevention strategies.
Individual avoidance measures may include the use of gloves and/or other personal protective
equipment, such as suits, face masks, and goggles.
The choice of glove material depends upon the type of chemical exposure. As an example, rubber
gloves provide protection from hydrosoluble substances but are inappropriate for organic solvents.
Information on appropriate gloves is available from glove suppliers and may be found on the
material safety data sheet, which provides important safety information about chemical compounds
used in the workplace (table 4). (See 'Gloves' below.)
Active treatment — Active treatment of ICD is aimed at reducing the signs and
symptoms of inflammation and restoring the epidermal barrier. Topical corticosteroids and
emollients are used empirically. Calcineurin inhibitors are not used to treat ICD. They have not been
proven effective and, in some studies, have been found to be irritants [55].
Topical corticosteroids — The management of ICD with topical corticosteroids

depends upon the severity and location as described below. In general, ointments are preferred to
creams:
●For severe, acute ICD or chronic ICD with conspicuous skin thickening (lichenification) not
involving the face or flexural areas, we suggest a super high-potency (group 1 (table 6)) topical
corticosteroid (eg, clobetasol propionate). Topical corticosteroids are applied once or twice daily for
two to four weeks.
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●For milder forms of ICD not involving the face or flexural areas, we suggest high-potency (groups 2
and 3 (table 6)) corticosteroids (eg, fluocinonide or betamethasone dipropionate). Topical
corticosteroids are applied once or twice daily for two to four weeks.
●For acute or chronic ICD involving the face or flexural areas, we suggest medium- or low-potency
(groups 5 and 6 (table 6)) topical corticosteroids. Topical corticosteroids are applied once or twice
daily for one to two weeks.
The use of topical corticosteroids in the treatment of ICD is controversial. Data evaluating the
efficacy and safety of topical corticosteroids in ICD are limited to a few small randomized and
nonrandomized studies of experimentally induced ICD that did not find measurable improvements in
restoring the epidermal barrier [55-57]. In one study, ICD was induced in 36 healthy volunteers with
sodium lauryl sulfate and nonanoic acid. Triamcinolone acetonide, clobetasol propionate, glycerol,
vehicle, and no treatment were applied by each participant on separate sites of irritated skin. After
10 days, the treated and untreated sites showed a similar improvement in irritation, evaluated by a
visual assessment score and measurement of transepidermal water loss (TEWL) and stratum
corneum hydration [55].
Despite the lack of proven benefit in clinical trials, topical corticosteroids are used in clinical practice
because of their anti-inflammatory properties and their efficacy in other forms of eczematous
dermatitis. These potential benefits must be weighed against the adverse effects of topical
corticosteroids. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Emollients and moisturizers — Emollients and moisturizers are beneficial

in all patients with ICD. They soften the stratum corneum, reduce the TEWL, and attract water to the
stratum corneum (table 7). Emollients and moisturizers are used to decrease irritation and improve
or restore the skin barrier function in ICD. Because they are effective only when present on the skin,
emollients and moisturizers should be liberally applied multiple times per day, particularly after hand
washing and after work at home, to support the regenerative capacities of the skin.
Occlusive emollients (eg, petrolatum, lanolin, mineral oil, vegetable oils, beeswax, ceramides, and
silicones) retard the TEWL; humectants (eg, glycerin, sorbitol, propylene glycol, or topical urea) are
hygroscopic substances with a high capacity to attract water to the stratum corneum from the
atmosphere and from the deeper epidermis and dermis. They are combined with occlusive
emollients in many commercially available products. Petrolatum-based products are preferred to
emollients containing lanolin or fragrances to reduce the risk of contact sensitization. Petrolatum-
based products are widely available and inexpensive.
The efficacy of moisturizers has been evaluated in several studies of experimentally induced skin
irritation [58]. In one representative study, six different lipid-rich moisturizers were effective in
reducing erythema, scaling, and TEWL in skin irritated by sodium lauryl sulfate [59]. This study did
not find a difference between moisturizers containing physiologic lipids (eg, cholesterol, ceramide,
oleic acid, or palmitic acid) and those containing nonphysiologic lipids, such as petrolatum.
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PREVENTION Gloves and barrier creams combined with adequate skin care
are widely recommended as the most important measures of personal protection in occupations at
increased risk of irritant contact dermatitis (ICD). The use of personal protective equipment, such as
suits, face masks, and goggles, also may be beneficial in preventing exposure.
Gloves — Adequate protection from contact with irritants is a key measure to prevent ICD.
Since the hands are most frequently exposed to irritants in workplaces and households, the use of
appropriate gloves is generally recommended to prevent ICD. The patient should be instructed to use
gloves in connection with wet or dirty work at the workplace or at home. Tight-fitting gloves should
be used as long as necessary but for the shortest time possible to limit sweating and maceration
[60]. Thin cotton gloves should be worn under tight-fitting gloves and changed as soon as they
become damp.
The efficacy of gloves in preventing ICD in the workplace has not been evaluated in clinical trials.
Guidelines and recommendations on glove use are generally based upon local rules and regulations
or clinical experience. It is important to remember that occlusive gloves can be themselves a cause
of occupational hand dermatitis if not used properly.
Manufacturers of protective gloves provide lists of applications, hazards, and chemicals for which
their gloves have been tested (eg, www.bestglove.com or www.ansell.com). Additional information
can be obtained from the material safety data sheet, which provides important safety information
about chemical compounds used in the workplace (table 4).
For optimal protection, the gloves must be used, maintained, and replaced according to the
manufacturer's instructions. Failure to provide protection may be due to [61]:
●Wrong glove material
●Misuse (eg, contamination of the glove interior from incorrect wearing and/or removal)
●Physical damage
●Degradation
●Permeation
Barrier creams — To prevent ICD of the hands, we suggest the use of barrier
creams. They are typically applied before work and two to three times during work time, when
necessary. They should be applied in adequate amounts and cover all the skin surface exposed to
irritants. (See 'Emollients and moisturizers' above.)
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Barrier creams include a variety of preparations designed to reduce the penetration of hazardous
materials into the skin and help restore a damaged stratum corneum [62]. Some are specifically
formulated for individual chemical exposures. In general, barrier creams contain silicones (eg,
dimethicone), liquid paraffin, aluminum chlorohydrate, or other water-repellant compounds, such as
perfluoropolyethers, that form a thin occlusive layer on the skin surface.
In a 2018 systematic review and meta-analysis of nine randomized trials including nearly 3000
participants in various occupational settings (metalworkers, print and dye industry workers, gut
cleaners in swine slaughterhouses, cleaners and kitchen assistants, hospital employees, and
apprentice hairdressers), rates of ICD were slightly lower among workers using barrier creams
compared with controls, though the difference was not statistically significant (29 versus 33 percent;
risk ratio [RR] 0.87, 95% CI 0.72-1.06) [63]. Similar results were noted with the use of moisturizers
(RR 0.71, 95% CI 0.46-1.09). However, the individual studies were small and had methodologic
limitations.
Barrier creams are generally well tolerated. Side effects are mild and include transient itching,
stinging, and dryness [64].
PROGNOSIS The prognosis of acute irritant contact dermatitis (ICD) is

generally good if the offending irritant is removed and preventive measures are adopted. The
recovery of the barrier function after acute ICD is achieved approximately four weeks after irritant
exposure, whereas skin hyperreactivity in the affected areas may persist for 10 weeks [65,66].
The prognosis of chronic ICD is variable. In a one-year follow-up study of patients with occupational
ICD, 43 percent reported improvement, 26 percent reported persistent dermatitis, and 11 percent
reported aggravation [67]. History of atopic dermatitis was the most important determinant of
persistence or aggravation.
In a long-term study of occupational hand eczema, healing occurred in 35 percent of patients 7 to 14

years after the initial diagnosis [68]. Negative prognostic factors were history of respiratory or skin
atopy, disease duration, food-related occupation, and maintaining the same occupation.
INCONTINENCE-ASSOCIATED
DERMATITIS Incontinence-associated dermatitis (IAD) is a specific type of
irritant contact dermatitis (ICD) caused by prolonged contact of the skin with urine or feces and
friction [69]. The mechanism of skin injury involves both chemical and physical irritation that leads
to disruption of the epidermal barrier and increased skin permeability, inflammatory changes, skin
breakdown, and increased risk of bacterial colonization and secondary infection [69-71]. (See
"Evaluation of females with urinary incontinence" and "Urinary incontinence in men".)
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The prevalence of IAD varies across different countries, health care settings, and patient
populations. A prevalence of approximately 6 percent has been estimated among residents of
nursing homes and hospitalized patients, but rates as high as 20 to 50 percent have been reported in
acute care settings and are highest among persons with limited mobility [72,73]. Independent risk
factors for the development of IAD include older age, diabetes, liquid stools, smoking, and not using
diapers [74].
Clinical presentation — Mild IAD is characterized by persistent erythema and

edema of the skin but without skin breakdown; in more severe cases, vesicles, bullae, and erosions
may develop [69,70] (figure 1). The sites involved include the perianal skin, buttocks, genitalia, upper
thigh, and skin folds between genitalia and thigh [73]. Colonization and secondary infection with
bacteria and yeasts can occur in severe IAD.
Diagnosis — The diagnosis of IAD is generally obvious, based upon the clinical
presentation (figure 1). However, IAD must be differentiated from stage I and II pressure ulcers in
patients with incontinence who are also at risk for pressure ulcers (table 8). (See "Clinical staging
and management of pressure-induced skin and soft tissue injury".)
Other forms of intertriginous dermatitis that should also be considered in the differential diagnosis
of IAD include inverse psoriasis and seborrheic dermatitis. (See "Psoriasis: Epidemiology, clinical
manifestations, and diagnosis", section on 'Inverse (intertriginous) psoriasis' and "Seborrheic
dermatitis in adolescents and adults".)
Treatment and prevention — A structured skin care regimen is the

mainstay of treatment and prevention of IAD. It should include [69]:
●Gentle cleansing of the genital, perianal, and groin area using mild or soap-free cleansers. Regular
soaps that have an alkaline pH should be avoided, as they can worsen the irritant effect of urine and
stools on the skin. Vigorous washing and rubbing of skin should also be avoided.
●Drying the skin carefully after washing using a soft cloth without rubbing.
●Hydrating the skin by applying moisturizers or barrier creams. Creams are generally preferred to
ointments and should be gently applied (without rubbing) on the affected areas in a thin layer. An
excess of moisturizers can promote skin maceration. Exuding lesions may benefit from the
application of zinc oxide-based barrier lotions or sprays.
These steps can be repeated two to three times per day.
There is a paucity of high-quality studies evaluating the efficacy of different skin care measures for
the treatment and prevention of IAD. A systematic review of 13 clinical trials, including 1295 patients
who were incontinent for urine, stool, or both and were residents in a nursing home or hospitalized,
found that structured skin care regimens consisting of gentle skin cleansing and application of
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moisturizing and protective topicals was more effective for the treatment and prevention of IAD than
the use of soap and water [75]. However, the included studies were generally of low quality and
showed considerable heterogeneity in the type of skin care products used, skin care procedures, and
outcome measurement.
Patients with IAD should be frequently evaluated for signs of bacterial or fungal secondary infection.
Topical antiseptics (eg, povidone iodine) or topical antimycotics can be used for superficial, localized
infections. Severe bacterial skin infections require systemic antibiotic therapy. (See "Cellulitis and
skin abscess in adults: Treatment".)

SUMMARY AND
RECOMMENDATIONS
●Irritant contact dermatitis (ICD) is a localized inflammatory skin response to exposure to a wide
range of chemical or physical agents. ICD is the most common type of occupational dermatitis,
particularly among food handlers, health care workers, mechanical industry workers, cleaners, and
housekeepers (table 1). The most important predisposing factor for ICD is a history of atopic
dermatitis. (See 'Introduction' above and 'Epidemiology' above and 'Predisposing factors' above.)
●The mechanisms involved in the development of ICD include the disruption of the epidermal barrier,
damage of keratinocytes, release of inflammatory cytokines, and activation of innate immunity. (See
'Pathogenesis' above.)
●Common chemical irritants include water and wet work, detergents and surfactants, solvents,
oxidizing agents, acids, and alkalis. Physical irritants include metal tools, wood, fiberglass, plant
parts, paper, and dust or soil (table 1). (See 'Chemical irritants' above and 'Physical irritants' above.)
●Acute and chronic ICD are the most common clinical variants (table 2). Clinical features of acute
ICD include erythema, edema, formation of vesicles and bullae, and oozing (picture 1A-B). In chronic
ICD, lichenification, hyperkeratosis, and fissuring are usually seen. Sites commonly affected are the
dorsum of the hands, fingertips, and finger webs (picture 1C-D). (See 'Clinical manifestations' above.)
●In most cases, the diagnosis of ICD is based upon the clinical finding of a localized dermatitis in a
patient with a history of exposure to chemical or physical irritants (table 3 and picture 1A-B). Patch
testing may be necessary to exclude allergic contact dermatitis. (See 'Diagnosis' above.)
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●The most common disorders that should be differentiated from ICD include allergic contact
dermatitis, atopic dermatitis, psoriasis, endogenous eczema, and fungal infection (picture 2B, 3A-D).
(See 'Differential diagnosis' above.)
●The management of ICD includes the identification and avoidance of the offending irritant(s),
treatment of skin inflammation, restoration of the epidermal barrier, and prevention of further
exposure. (See 'Overview' above and 'Avoidance' above.)
●For most patients with ICD, we suggest treatment with emollients and moisturizers plus topical
corticosteroids rather than either therapy alone or no treatment (Grade 2C). Treatment with
emollients and moisturizers alone is a reasonable alternative to combination therapy, particularly for
patients who are concerned about side effects of topical corticosteroids. Petrolatum-based products
are widely available and inexpensive. Emollients are liberally applied to the affected skin multiple
times per day, particularly after hand washing and after work. (See 'Emollients and moisturizers'
above and 'Topical corticosteroids' above.)
●The choice of topical corticosteroid is dependent on the severity and location of the ICD (see
'Topical corticosteroids' above):
•For severe acute ICD or chronic ICD with conspicuous skin thickening (lichenification) not involving
the face or flexural areas, we generally use a super high-potency (group 1 (table 6)) topical
corticosteroid. Topical corticosteroids are applied once or twice daily for two to four weeks.
•For milder forms of ICD not involving the face or flexural areas, we generally use high-potency
(groups 2 and 3 (table 6)) corticosteroids. Topical corticosteroids are applied once or twice daily for
two to four weeks.
•For acute or chronic ICD involving the face or flexural areas, we generally use medium- or low-
potency (groups 5 and 6 (table 6)) topical corticosteroids. Topical corticosteroids are applied once or
twice daily for one to two weeks.
●Prevention measures for ICD include the use of appropriate gloves, barrier creams, and emollients.
Glove manufacturers provide lists of applications, hazards, and chemicals for which their gloves
have been tested. We suggest the use of barrier creams and emollients rather than gloves alone for
the prevention of ICD in individuals exposed to wet work or other chemical or physical irritants
(Grade 2C). Barrier creams and emollients are applied before work and multiple times per day if the
exposure continues. (See 'Gloves' above and 'Barrier creams' above.)
●Incontinence-associated dermatitis (IAD) is a specific type of ICD caused by prolonged contact of

the skin with urine or feces and friction. It is characterized by persistent erythema and edema of the
skin and, in severe cases, bullae or erosions on the perianal skin, buttocks, and genitalia (figure 1).
IAD must be differentiated from stage I and II pressure ulcers in patients with incontinence who are
also at risk for pressure ulcers (table 8). A careful skin care regimen consisting of gentle skin
cleansing with soap-free cleansers followed by the application of moisturizers and barrier creams is
the mainstay of treatment and prevention of IAD. (See 'Incontinence-associated dermatitis' above.)
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to acknowledge Papapit Tuchinda, MD, who contributed to an earlier version of this topic review.
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Chronic hand eczema - UpToDate
uptodate.com/contents/chronic-hand-eczema/print
INTRODUCTION Hand eczema or hand dermatitis is a common

inflammatory disorder involving skin of the hands [1]. The term chronic hand eczema is appropriate
in cases that persist for more than three months or recur two or more times within a 12-month time
frame [2]. Typical clinical signs include redness, thickening of the skin, scaling, edema, vesicles,
areas of hyperkeratosis, cracks (fissures), and erosions.
Hand eczema is the most frequent occupational skin disease, especially among workers exposed to
"wet work," such as health care workers, food handlers, and hairdressers. It can have profound
economic consequences, including medical costs; costs associated with disability, workers'
705
compensation, and rehabilitation; absence from work; and job loss [3]. Severe hand eczema can
affect the patient's psychosocial functioning and general wellbeing.
This topic will review the clinical manifestations, diagnosis, and management of chronic hand
eczema. Acute palmoplantar eczema, irritant contact dermatitis, and allergic contact dermatitis are
●(See "Acute palmoplantar eczema (dyshidrotic eczema)".)
EPIDEMIOLOGY Hand eczema is a common problem in the general

population. Based upon studies performed between 1964 and 2007, the point prevalence of hand
eczema is approximately 4 percent; the one-year prevalence and the lifetime prevalence are
approximately 10 and 15 percent, respectively [4]. Cohort studies of adolescents and young adults
followed-up for approximately 15 years estimated an incidence of hand eczema of approximately 9
to 12 per 1000 person-years [5,6].
Hand eczema is also the most common occupational skin disease. The incidence of occupational
hand dermatitis has been estimated between 0.7 and 1.5 cases per 1000 workers per year [7].
Incidence is highest among workers performing "wet work" (eg, health care workers, food handlers,
hairdressers). A Danish study of health care workers found a one-year prevalence of hand eczema of
21 percent and a lifetime prevalence of 35 percent [8]. A similar study of Hong Kong nurses found a
prevalence rate of 22 percent [9]. In a study of hand eczema in hairdressers, active disease was
reported by 38 percent of current hairdressers and by 48 percent of former hairdressers [10].
Because these numbers represent only the cases reported, they are likely an underestimate of the
true prevalence. Studies have shown that occupational hand dermatitis is often underreported. In
one study involving over 2000 hairdressers with chronic hand eczema, only 21 percent had reported
their hand eczema as occupational to the workers' compensation authority [11]. A similar study of
health care workers found that only 12 percent reported their hand eczema [8].
PATHOGENESIS The pathogenesis of hand eczema is multifactorial and

involves both genetic and environmental factors. There is an association between the susceptibility
to hand eczema and loss-of-function mutations in the filaggrin gene (FLG), which is important for the
integrity of the epidermal barrier [12]. Filaggrin is involved in terminal differentiation of the skin with
appropriate keratin filament alignment and stratum corneum hydration. Loss-of-function filaggrin
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polymorphisms predispose to xerosis, ichthyosis vulgaris, and atopic eczema [13]. (See "Atopic
dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Epidermal
barrier'.)
Repetitive wet work exposure is recognized as a predisposing factor for hand eczema. Water
exposure for more than three hours per day can induce physiologic changes in the normal skin and
increase the susceptibility to skin irritation [14]. Studies of occupational hand eczema in health care
workers have found an association with hand-washing practices, such as the daily number of hand
washes with soap at work and time working with disposable gloves [15]. Unprotected wet work for
more than two hours a day in hairdressers has been shown to be a significant risk factor for the
development of hand eczema [16].
Irritants often play an important role in both the development and persistence of hand eczema. In
addition to water, important irritants include detergents, fragrances, and preservatives in hand
soaps; harsh chemicals found in common household and industrial cleaners, such as ammonia and
solvents; raw fruits, vegetables, spices, and plants; and physical irritants (eg, metal tools, wood,
fiberglass, dust/soil). (See "Irritant contact dermatitis in adults".)
Hand eczema may also be a manifestation of allergic contact dermatitis, a specific T cell-mediated,
delayed-type hypersensitivity reaction. Contact sensitization has been reported in 40 to 60 percent of
patients with hand eczema [17,18]. (See "Clinical features and diagnosis of allergic contact
dermatitis".)
Chronic or recurrent hand eczema is also the most frequent clinical manifestation of contact
urticaria/protein contact dermatitis (CU/PCD), a distinct type of dermatitis induced by a type I
immediate hypersensitivity reaction to high-molecular-weight allergens, such as animal or plant
proteins in previously sensitized individuals [19,20]. CU/PCD occurs predominantly in food handlers,
cooks, veterinarians, or farmers [21]. Patients with CU/PCD usually have a positive prick test or
specific serum immunoglobulin E (IgE) to certain foods but negative patch tests [22,23]. The reaction
usually starts as an urticarial allergic response, but, with repeated episodes over time, the clinical
appearance is that of chronic eczema.
Frequent relapses of acute palmoplantar eczema (dyshidrotic eczema) may also result in chronic
hand dermatitis lichenified. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
CLINICAL MANIFESTATIONS In the acute stage,

hand eczema typically presents with erythema, edema, weeping, and vesiculation (picture 1 and
picture 2). As lesions become subacute or chronic, the lesion morphology shifts to scaling,
thickening, and fissuring of the skin (picture 3).
Lesions are usually bilateral and may involve the palmar or dorsal surface, or both. In longstanding
disease, nail changes may be seen, including loss of the cuticle, thickening of the nail folds (chronic
paronychia), and ridging and thickening of the nail plate (picture 4). Symptoms may include itching,
burning, or stinging.
707
Clinical variants of hand eczema include [24]:
●Chronic fissured hand eczema (picture 3)
●Recurrent vesicular hand eczema (picture 5)
●Hyperkeratotic palmar eczema, also called psoriasiform or tylotic hand dermatitis (picture 6)
●Pulpitis (hyperkeratotic eczema of the fingertips) (picture 7)
●Interdigital eczema (picture 8)
●Nummular hand eczema (picture 9)
The pattern and distribution of the hand lesions may vary depending upon the etiology [25]:
●Irritant contact dermatitis is variable and can involve the dorsal hands or palms. The distal aspect
of the dorsum of the fingers is often involved. (See "Irritant contact dermatitis in adults".)
●Allergic contact dermatitis often involves the dorsal aspect of the hands and fingers and the volar
aspect of the wrists (picture 2). (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Chronic atopic hand dermatitis usually involves the dorsum of the hands and fingers (picture 10)
and/or the side of the fingers. It presents with erythema, scaling, and fissuring. Chronic paronychia
and nail dystrophy are often associated. (See "Atopic dermatitis (eczema): Pathogenesis, clinical
●Dyshidrotic eczema typically presents with a sudden outbreak of intensely itchy, deep-seated
vesicles on the palms and/or soles (picture 11). Frequent relapses may result in chronic hand
dermatitis, characterized by erythematous, lichenified, and scaling patches or plaques with fissures
(picture 12). (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
PATHOLOGY The histopathologic findings of hand eczema may vary according

to the stage of the disease. In the acute stage, a classic spongiotic reaction pattern is seen,
including intercellular edema, microvesicle formation, and a superficial dermal infiltrate of
lymphocytes, with or without eosinophils. As the dermatosis progresses to the chronic stage, the
degree of spongiosis is often mild and epidermal acanthosis, parakeratosis, and hyperkeratosis
predominate, with a superficial perivascular lymphohistiocytic inflammatory infiltrate. It is important
to note that psoriasiform hand dermatitis is often a histologic challenge, and biopsy often provides
confusion and/or contradictory information [26].
DIAGNOSIS The diagnosis of chronic hand eczema is based upon a detailed

history, physical examination, and patch testing. A skin biopsy may be necessary to exclude other
dermatoses involving the hands that may mimic chronic hand eczema. (See 'Differential diagnosis'
708
below.)
History — A detailed personal, occupational, and recreational history, focused on exposure

to irritants and allergens, should be obtained from all patients presenting with hand eczema.
Patients should be questioned about the type of work or hobbies, potential exposures to irritants or
allergens, duration and frequency of exposure, and type of personal protective equipment.
An important element of history is a personal or family history of atopy, such as asthma, hay fever,
allergic rhinoconjunctivitis, or childhood eczema. The results of previous allergy testing, including
patch testing, prick testing, and radioallergosorbent testing (RAST), should also be recorded.
Precise information regarding the onset of dermatitis, duration, associated symptoms (burning,
itching, stinging, swelling), and relieving factors should be obtained. In occupational cases, patients
may have a clear history of improvement on weekends and time off work.
Physical examination — When examining the patient's hands, the clinician

should assess the extent of hand involvement and whether the skin changes extend to the wrist, the
finger webs are involved, and the nails are normal or abnormal [25]. In addition, a complete skin
examination should be performed, looking for skin changes in other body areas that may be related
to the hand disorder (eg, flexural dermatitis suggesting atopic dermatitis, erythematous plaques
surmounted by silvery white scales suggesting psoriasis).
Laboratory tests — Patch testing should be considered to identify a possible

relevant allergen, as it is often impossible to determine if there is an allergic component by history
and exam alone. Common allergens associated with hand dermatitis are preservatives, fragrances,
metals (eg, nickel, cobalt), rubber, and topical antibiotics (eg, bacitracin, neomycin). Prick/puncture
skin testing and determination of serum food-specific immunoglobulin E (IgE) levels are indicated in
patients with suspected contact urticaria/protein contact dermatitis (CU/PCD). (See "Patch testing"
and "Common allergens in allergic contact dermatitis" and "Diagnostic evaluation of food allergy",
section on 'Prick/puncture skin tests' and "Diagnostic evaluation of food allergy", section on 'In vitro
testing'.)
A potassium hydroxide (KOH) preparation may be useful to exclude a dermatophyte infection.

Bacterial cultures may be useful to guide treatment in patients with superinfected hand eczema.
(See "Clinical features and diagnosis of allergic contact dermatitis".)
Biopsy — Skin biopsy is not routinely performed in patients with hand eczema. However, in
some patients, a skin biopsy for histopathologic examination may be necessary to exclude other
conditions that may mimic chronic hand eczema. (See 'Differential diagnosis' below.)
709
ASSESSMENT OF SEVERITY For the management
of the individual patient with chronic hand eczema, it is important that clinicians evaluate the extent
and characteristics of the eruption and ask general questions about the impact of the disease on the
patient's professional and everyday activity, psychosocial functioning, and general wellbeing.
Although infrequently used in clinical practice, several tools have been developed to assess the
clinical severity of hand eczema and response to treatment [27]. They include the hand eczema
severity index (HECSI) [28], the Physician Global Assessment (PGA) [29], the Clinical Photo Guide
[30], and several instruments measuring the health-related quality of life in patients with skin
diseases, such as the Dermatology Life Quality Index (DLQI) [31].
The PGA is a relatively simple tool that involves the evaluation of the intensity of the skin changes
and the extent of involvement [29]:
●Mild eczema is defined by the presence of two or more mild skin changes (erythema, scaling,
hyperkeratosis, lichenification, vesiculation, edema, fissures, pruritus, and pain) involving <10
percent of the hand surface.
●Moderate eczema is defined by the presence of two or more mild to moderate skin changes
(erythema, scaling, hyperkeratosis, lichenification, vesiculation, edema, fissures, pruritus, and pain)
involving 10 to 30 percent of the hand surface.
●Severe eczema is defined by the presence of two or more moderate to severe skin changes
(erythema, scaling, hyperkeratosis, lichenification, vesiculation, edema, fissures, pruritus, and pain)
involving >30 percent of the hand surface.

for hand eczema includes:
●Palmoplantar plaque psoriasis – Palmoplantar psoriasis presents with thick, scaly papules or
plaques on an erythematous base. Lesions may be present on the palmar or dorsal surface of the
hand (picture 13). The presence of nail pitting and/or classic psoriatic plaques on other body sites is
a clue to the diagnosis. In patients with isolated hand involvement, a skin biopsy may be helpful in
rendering the correct diagnosis. (See "Psoriasis: Epidemiology, clinical manifestations, and
diagnosis".)
●Palmoplantar pustulosis – Palmoplantar pustulosis is a chronic inflammatory dermatosis

characterized by the development of recurrent crops of discrete 1 to 10 mm sterile pustules limited
to the palms and/or soles (picture 14A-C). It is often viewed as an isolated subset of acral psoriasis.
Usually, it can be differentiated from chronic hand eczema on clinical grounds. In atypical cases, a
skin biopsy showing an intraepidermal pustule filled with polymorphonuclear leukocytes associated
with epidermal spongiosis can clarify the diagnosis. (See "Palmoplantar pustulosis: Epidemiology,
710
●Tinea manuum – Tinea manuum is a dermatophyte infection that typically involves one hand and
presents with erythema and fine scaling of the palm. In most cases, patients have a concomitant
infection of the feet and toenails (picture 15). A potassium hydroxide (KOH) examination of
scrapings from the lesions confirms the diagnosis. (See "Dermatophyte (tinea) infections".)
MANAGEMENT The management of chronic hand eczema involves

patient education about avoidance of irritants and allergens, skin protection measures, and topical
or systemic anti-inflammatory therapy.
Patient education — A change in behavior is an important component of the

management of chronic hand eczema, when irritant or allergic factors are present. Patients should
be educated about the causes of hand eczema, avoidance of potential triggers, adoption of
preventive strategies and skin protection measures, and importance of adherence to treatment [32].
The efficacy of education programs in the prevention and management of hand eczema has been
evaluated in multiple clinical trials [33-35]. In one trial, 255 health care workers with hand eczema
were randomly assigned to an education program with individual counseling and usual treatment or
to usual treatment alone. At follow-up, the mean score on the hand eczema severity index was
significantly lower in the intervention group than in the control group.
General measures
Avoidance of irritants and allergens — Patients should be counseled
on potential triggers found within the home and work environment. Common chemical irritants
include water and wet work, detergents and surfactants, solvents, oxidizing agents, acids, and
alkalis. Physical irritants include metal tools, wood, fiberglass, plant parts, paper, and dust or soil.
Common sources of allergens include soaps and detergents, foods, industrial solvents and oils,
cement, metals, topical medications, gloves, and cosmetics. (See "Irritant contact dermatitis in
adults", section on 'Common irritants' and "Common allergens in allergic contact dermatitis".)
Harsh soaps should be avoided and handwashing habits modified. Patients should wash with
lukewarm water using a mild, unscented and fragrance-free bar soap or a liquid nonsoap (synthetic)
detergent. Drying should be a gentle pat dry with attention to removing excess moisture from the
interdigital spaces.
Hand washing and drying should be followed immediately by the application of a generous amount
of heavy hand cream or ointment, such as petroleum jelly. Excessive or habitual hand washing
should be discouraged. Overuse of soap and water can prevent the restoration of the epidermal
barrier and healing of hand eczema. If the hands are not visibly soiled, an alcohol-based hand
sanitizer can be substituted to minimize overexposure to soap and wet-to-dry cycles [36,37].
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Skin protection — Use of personal protective equipment is also paramount in the
management of hand eczema. Gloves should be worn during cooking, gardening, and cleaning to
minimize exposure to irritants such as raw meat, vegetables, and chemicals.
Gloves — Vinyl or other nonlatex gloves are suitable for many routine exposures. Vinyl gloves
are generally preferred to latex or rubber gloves due to the lesser presence of potential allergens.
When protective gloves are to be used for intervals longer than 10 minutes, a thin cotton glove
should be worn underneath. This will provide an absorbent layer and prevent sweat from irritating
the skin with longer glove use. The cotton gloves can be washed and reused.
For occupational exposures, environmental hazards need to be considered when making the choice
for protective glove recommendations. The patient should be encouraged to discuss appropriate
protective equipment with their employer. The material safety and data sheet (MSDS) for a given
chemical can be helpful and may list appropriate glove guidelines.
Certain materials readily penetrate various glove types, and not all gloves are suitable for all tasks.
For example, acrylates that may be utilized in dentistry and orthopedics can easily penetrate many
rubber and vinyl gloves. Therefore, if an individual is allergic to acrylates, a foil-type 4H chemical-
resistant glove may be required under vinyl or rubber gloves [38]. It is also important that protective
gloves be intact without holes, clean and dry on the inside, and the appropriate size.
Moisturizers and barrier creams — Moisturizers and skin barrier repair creams
are also important to the management strategy of hand eczema. In healthy skin, the normal
epidermal barrier is the stratum corneum, which is primarily composed of protein-rich cells and
intercellular lipids. Moisturizers work to improve the quality of this barrier by use of humectants and
emollients. Humectants include ingredients such as glycerin, topical urea, and pyrrolidone carboxylic
acid (PCA). The primary function of humectants is to attract water and hydrate the stratum corneum.
Emollients smooth the dry, flaking skin and also provide some occlusion to prevent water loss.
Petrolatum, dimethicone, and waxes are common emollient ingredients.
Skin barrier repair creams work to mimic the intercellular lipids, which are composed of ceramides,
free fatty acids, and cholesterol. Studies have shown that appropriate use of moisturizers and skin
barrier repair creams can significantly increase the disease-free time interval [39,40].
Barrier creams (also known as protectant creams) are applied at least twice a day on all exposed
skin areas and are formulated to be either water-repellent or oil-repellent. The goal is to limit
penetration of hazardous chemicals into the epidermis. While these creams are minimally effective
and cannot be used to replace gloves and other personal protective equipment, they may be utilized
to augment protection against low-grade irritants [41].
Examples of water-repellent, barrier-protectant creams include North 201, SBS-44, and Kerodex 71.
Oil- or solvent-protectant creams include North 222, SBS-46, and Kerodex 51. Dermashield and Tetrix
are marketed as barrier-protectant creams with protection against both oil- and water-based irritants
712
and sensitizers. A drawback of these products, however, is the possibility that they contain allergens
that may exacerbate eczema in sensitized individuals.
Patients with mild to moderate disease — We suggest

high-potency or super high-potency topical corticosteroids (groups 1 to 3 (table 1)) as a first-line
treatment for mild to moderate hand eczema. Topical corticosteroids can be applied once or twice a
day for two to four weeks or until a stable improvement is achieved. Emollients should be applied
liberally multiple times per day.
After induction of remission, we suggest maintenance intermittent therapy with a super high-
potency or high-potency topical corticosteroid two to three times per week (eg, every other day, or
during weekends) to prevent relapses. Intermittent therapy can be continued for several months.
Relapses are treated resuming daily use of topical corticosteroids. However, long-term use of topical
corticosteroids, especially high- or super high-potency preparations, may induce skin atrophy,
especially on the thinner skin of the dorsal hand. (See "Topical corticosteroids: Use and adverse
effects".)
Although topical corticosteroids are widely used as a first-line therapy for hand eczema, data from
randomized trials supporting their use are limited. In an open-label randomized trial, 120 patients
with chronic hand eczema initially treated with daily mometasone furoate 0.1% fatty cream for up to
nine weeks or until the dermatitis cleared were randomly assigned to a 30-week maintenance period
with intermittent mometasone furoate (once daily on Sunday, Tuesday, and Thursday or on Saturday
and Sunday) or vehicle. At the end of the study, more patients in the groups using mometasone
furoate three times or two times weekly than in the group using the vehicle were free of recurrence
(83, 68, and 26 percent, respectively) [42].
Although there are limited data supporting their efficacy in the treatment of chronic hand eczema,
topical calcineurin inhibitors (pimecrolimus 1% cream and tacrolimus 0.1% ointment) may be used
as a steroid-sparing treatment option [43,44].
In a small uncontrolled study of 29 patients with occupational chronic hand dermatitis treated with
tacrolimus 0.1% ointment for four weeks, only 12 patients were clear of eczema at the end of the
study [43]. In another small study including 30 patients with allergic contact hand eczema,
tacrolimus 0.1% ointment was as effective as mometasone furoate 0.1% ointment in reducing
erythema, infiltration, vesiculation, desquamation, fissuring, and itching at three months [44].
In a randomized trial, 652 patients with mild to moderate chronic hand dermatitis were treated with
pimecrolimus 1% cream or vehicle twice daily with overnight occlusion for six weeks. At the end of
the study, the treatment was successful as stated by investigator's global assessment in 30 percent
of patients in the pimecrolimus group and 23 percent in the vehicle group [45].
713
Patients with severe or recalcitrant
disease — Patients with severe or recalcitrant hand eczema that does not respond to
superpotent topical corticosteroids may require systemic therapies, including oral corticosteroids,
immunosuppressants, and retinoids, or phototherapy with narrowband ultraviolet B (UVB) or
psoralen plus ultraviolet A (PUVA) [46]. (See "UVB therapy (broadband and narrowband)" and
"Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
Secondary bacterial infection, usually with Staphylococcus aureus,may be associated with

recalcitrant disease. A course of systemic antibiotics may be given to patients with clinical signs of
bacterial superinfection. (See "Impetigo", section on 'Systemic antibiotics'.)
Systemic therapy — For patients with severe, disabling hand eczema that does not
respond to superpotent topical corticosteroids, we suggest a short course of oral corticosteroids to
achieve a rapid improvement. Treatment is started with prednisone (or equivalent dose of other
systemic corticosteroids (table 2)) at a dose of 0.5 to 1 mg/kg per day (maximum 60 mg per day) for
seven days. The dose may be tapered and discontinued over the following two weeks. Treatment
with superpotent topical corticosteroids can be resumed as oral corticosteroids are tapered off.
There are no randomized trials evaluating the efficacy of oral corticosteroids for severe hand
eczema. However, in clinical practice, they are beneficial in inducing a rapid improvement in patients
with extensive allergic contact dermatitis or acute flares of atopic dermatitis. (See "Management of
allergic contact dermatitis" and "Treatment of atopic dermatitis (eczema)".)
Other immunosuppressants (eg, methotrexate, cyclosporin, azathioprine) have been occasionally

used in the management of patients with severe hand eczema [47]. However, immunosuppressants
have not been evaluated in high-quality studies, and there is insufficient evidence of benefit to
suggest their use in refractory cases. In a six-week randomized trial including 41 patients with
chronic hand eczema, oral cyclosporin 3 mg/kg per day was equally effective as topical
betamethasone dipropionate in reducing the baseline disease activity score (average reduction 43
and 42 percent, respectively) [47].
Alitretinoin (9-cis-retinoic acid) is an oral retinoid with anti-inflammatory, immunomodulatory,

antiproliferative, and apoptotic effects [48]. It is licensed in Europe and Canada for the treatment of
severe chronic hand eczema that is unresponsive to potent topical corticosteroids but is not
available in the United States.
Evidence for the use of alitretinoin for the treatment of hand eczema comes from a single
randomized trial including 1032 patients with severe chronic hand eczema unresponsive to topical
steroids [29]. Patients received alitretinoin 30 or 10 mg per day or placebo for 12 to 24 weeks. All
patients were given an emollient cream and instructed to apply it frequently. After 24 weeks, a
greater proportion of patients in the alitretinoin 30 and 10 mg groups achieved the primary end point
714
of clear or almost clear hands than those in the placebo group (48, 28, and 17 percent, respectively).
Headache was the most frequent adverse effect of alitretinoin. Serious adverse events were rare, but
alitretinoin was associated with increases in both total cholesterol and triglycerides.
Alitretinoin is teratogenic. All female patients of childbearing potential must commit to the use of at
least one form of effective contraception for at least one month prior to starting alitretinoin therapy,
during therapy, and for one month after therapy, and have a pregnancy test each month during
treatment.
Phototherapy — For patients with severe or recalcitrant hand eczema for whom oral
corticosteroids are contraindicated or patients who prefer not using oral corticosteroids, we suggest
local narrowband UVB phototherapy, or oral or topical PUVA therapy. Phototherapy is administered
two to three times per week for at least 12 weeks. Adverse effects of phototherapy include erythema,
pruritus, hyperpigmentation, and increased risk of skin cancer. Nausea is a potential adverse effect
of oral PUVA. (See "UVB therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A
(PUVA) photochemotherapy".)
The use of phototherapy for patients with chronic hand eczema is largely supported by its use in the
treatment of other inflammatory dermatoses. However, there are a few small clinical trials that have
demonstrated clinical improvement with PUVA or narrowband UVB in patients with hand or
palmoplantar eczema of various etiologies [49-51].
PROGNOSIS Hand eczema often has a very prolonged course. The reported
average duration is approximately 12 years [52,53]. Moderate to severe eczema is the strongest
predictor of persistent disease [4]. Cigarette smoking also appears to be an unfavorable prognostic
factor [54].
Chronic hand eczema may have significant psychosocial consequences, such as long-term sick
leaves, involuntary job rotation, and early retirement, and a profound impact on quality of life [55-59].

SUMMARY AND
RECOMMENDATIONS
●Hand eczema or hand dermatitis is a common inflammatory disorder involving skin of the hands. It
is the most frequent occupational skin disease, especially among workers exposed to "wet work,"
such as health care workers, food handlers, and hairdressers. (See 'Introduction' above and
715
'Epidemiology' above.)
●In the acute stage, hand eczema typically presents with erythema, edema, weeping, and
vesiculation (picture 1 and picture 2). As lesions become subacute or chronic, scaling, thickening,
and fissuring of the skin become the predominant clinical signs (picture 3). (See 'Clinical
manifestations' above.)
●The diagnosis of hand eczema is based upon a detailed history, physical examination, and patch
testing. (See 'Diagnosis' above.)
●The management of chronic hand eczema involves patient education about avoidance of irritants
and allergens, skin protection measures, and anti-inflammatory therapy. (See 'Patient education'
above and 'Avoidance of irritants and allergens' above and 'Skin protection' above.)
●For patients with mild to moderate chronic hand eczema, we suggest high-potency or super high-
potency topical corticosteroids (groups 1 to 3 (table 1)) as a first-line treatment rather than lower-
potency topical corticosteroids or topical calcineurin inhibitors (Grade 2C). Topical corticosteroids
can be applied once or twice per day for two to four weeks or until a stable improvement is achieved.
Emollients should be applied liberally multiple times per day. After induction of remission, we
suggest maintenance intermittent therapy with a super high-potency or high-potency topical
corticosteroid (Grade 2B). (See 'Patients with mild to moderate disease' above.)
●For patients with severe, recalcitrant hand eczema that does not respond to superpotent topical
corticosteroids, we suggest a short course of oral corticosteroids or phototherapy (Grade 2C).
Alternative systemic treatments include oral immunosuppressants (eg, methotrexate, cyclosporin,
azathioprine) or oral retinoids. (See 'Patients with severe or recalcitrant disease' above.)
716
Patch testing - UpToDate
uptodate.com/contents/patch-testing/print
INTRODUCTION Patch testing is an essential investigation to identify

specific allergens in allergic contact dermatitis (ACD) or, in some cases, to make the diagnosis of
ACD. Patch testing is based upon the principle that in sensitized individuals, primed antigen-specific
T lymphocytes of the Th1 phenotype circulate throughout the body and are able to recreate a
delayed-type hypersensitivity reaction when nonirritating concentrations of the antigen are applied
to normal skin.
This topic will discuss indications, techniques, and interpretation of patch testing. The basic
mechanisms, clinical manifestations, diagnosis, and management of ACD are discussed separately.
(See "Basic mechanisms and pathophysiology of allergic contact dermatitis" and "Clinical features
INDICATIONS FOR PATCH

TESTING Indications for patch testing may include:
●Persistent eczematous eruptions when contact allergy is suspected [1]
●Any chronic dermatitis, especially when involving the hands, feet, face, or eyelids
●Eczematous dermatitis in individuals involved in high-risk occupations for contact dermatitis (eg,
health care workers, dental assistants, cosmetologists, machinists, or rubber and plastic workers)
717
●Dermatitis of unknown etiology
●Worsening of a previously stable dermatitis
Patch testing also may be indicated when allergic contact dermatitis (ACD) is suspected as a
complication of:
●Atopic dermatitis
●Stasis dermatitis
●Nummular eczema
●Asteatotic eczema
●Psoriasis
SELECTION OF ALLERGENS Observational studies

have identified more than 4350 chemicals as contact allergens with varying potential to cause
allergic contact dermatitis (ACD) [2]. However, a high proportion of ACD are caused by a relatively
small number of allergens commonly found in the environment.
Standard (baseline) series of allergens — Standard

(baseline) or screening series of contact allergens, which are designed to include the most common
sensitizers responsible for ACD in a given region, are recommended as the initial battery for patients
undergoing patch testing. The standard series are revised on a regular basis, as new allergens are
identified as a cause of ACD.
There are several baseline series throughout the world, including the North American Contact
Dermatitis Group and the European standard series of approximately 35 allergens (determined by
consensus of the European Society of Contact Dermatitis and the European Environmental and
Contact Dermatitis Research Group). Details on the standard series most commonly used can be
found at www.dermnetnz.org/dermatitis/standard-patch.html. The American Contact Dermatitis
Society (ACDS) (www.contactderm.org) has developed a recommended core series of 80 allergens
divided into eight panels [3].
The thin-layer rapid-use epicutaneous (TRUE) test, which includes 35 allergens and one control, is a
commercially available ready-to-use test widely used in basic standard patch testing among
dermatologists and allergists. Although it is easy to apply, it may have lower sensitivity than other
standard series [4].
718
Additional series of patch testing — Supplemental series of
patch tests suitable for specific exposures, including workplace exposures, are available to
complement the standard series (eg, hairdressers, dental, or cosmetic series). The patient's clinical
presentation and history help to determine whether testing with supplemental series and/or
products provided by the patient is necessary [5]. (See "Clinical features and diagnosis of allergic
Individualized patch testing — In the event that a standard series

and supplemental series do not identify an offending antigen, patients may be patch tested with their
own products. As a general rule, when patch testing patients with their own products, it is
acceptable to use products that are left on the skin (eg, lotions, creams). However, products that
typically are rinsed off the skin (eg, soap) should not be patch tested; when left on the skin these
products may act as irritants. Rinse-off products may be tested with open testing. (See 'Open test'
below.)
Specific allergens can also be customized [6].
PATCH TEST PROCEDURE

Preparing the patient — Patients need to be informed that patch testing is a
time consuming process that requires at least three visits during a specified week. Patients should
avoid showering, exercising, and extremes of heat and humidity, and should be alerted that positive
reactions can result in itching and discomfort.
Patch testing is usually performed on the back. If the back is excessively hairy it may be difficult to
achieve adequate skin contact with the patches. To avoid irritation it is advisable to clip the hair from
the back one or two days before patch testing.
Effect of systemic immunosuppression — The effect of systemic

immunosuppression on the accuracy of patch testing has not been well established. Potent topical
corticosteroids applied to the test site or oral corticosteroids ideally should be discontinued at least
two weeks before patch testing [7,8]. Topical treatment with potent corticosteroids or systemic
treatment with corticosteroids or other immunosuppressant drugs may cause weak or negative
reactions [1,7]. Studies on poison ivy, which usually induces strong positive reactions, have indicated
that it may be acceptable to perform patch testing with doses of prednisone up to 20 mg per day.
However, this practice may be suboptimal for allergens that are weaker than poison ivy, and
generally should be discouraged [9,10]. In two small studies, positive patch test reactions were seen
in patients taking prednisone, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil,
infliximab, adalimumab, and etanercept [11,12]. An additional study found no difference in the
prevalence or intensity of positive patch test reactions in psoriasis patients on etanercept, infliximab,
719
adalimumab, and ustekinumab [13]. A small case series and a few case reports suggest a variable
and potentially allergen-specific effect of dupilumab on patch testing results [14-16]. This suggests
that it may be preferable to patch test patients prior to the initiation of dupilumab.
Effect of oral antihistamines — Oral antihistamines may be continued

during patch testing, as they have minimal if any effect on the mechanisms of delayed
hypersensitivity. Since a positive patch test reaction is not a histamine mediated process, there is no
pathophysiologic rationale to discontinue antihistamines prior to patch testing.
Effect of ultraviolet radiation — Patients should avoid irradiation from both

artificial and natural (sunlight) sources of ultraviolet (UV) radiation before patch testing. Irradiation
with UVB can reduce the number of antigen presenting cells in the skin and the intensity of patch
test reactions. Patch testing should be deferred in heavily tanned patients, and a minimum of four
weeks after significant sun exposure should be allowed before patch testing.
Patch test site — The optimal site for patch testing is the upper back. The outer
aspect of the upper arms is an alternative. Placing patches on other skin areas may result in a higher
degree of false-negative results. If the skin is oily, gentle degreasing can be performed with ethanol
or another mild solvent. The sites of patch application are then marked with a suitable marker to
identify the test sites.
Patch testing should be performed on intact skin without dermatitis to minimize the risk of
nonspecific inflammatory responses with numerous false-positive tests ("angry back" syndrome).
(See 'The "angry back"' below.)
Types of tests
Closed test — The most commonly accepted technique for patch testing involves the
application of test allergens under occlusion onto the skin of the upper back for two days. Allergens
are applied in standard amounts to aluminum or synthetic material chambers mounted on non-
occlusive tape strips. Commercially available patch test units are described in the table (table 1).
Open test — Open test may be used to test products with a potential to create irritation on
the skin, which include paints, soluble oils, soaps, glues, and other cleansing agents. Unlike
traditional patch testing, the area is kept open. After 30 minutes the materials are gently removed
and readings are performed in a delayed fashion similar to closed patch testing. If the reaction is
negative but contact allergy is still suspected, closed patch testing with single ingredients in
appropriate concentration and vehicle should be performed.
Semi-open test — The semi-open or semi-occlusive test is used for products with a
slight irritant potential, including [17,18]:
720
●Pharmaceutical products – Products containing antiseptic agents such as mercurial compounds
(eg, phenylmercuriborate), quaternary ammonium salts such as benzalkonium chloride and iodine;
antiseptics containing emulsifiers such as lauraminoxyde and nonoxynol; products containing
solvents such as propylene glycol in high concentrations; creams based on the emulsifier sodium
laurylsulfate.
●Cosmetic products – Products containing emulsifiers, solvents, or other potentially irritant

substances such as mascara, nail lacquers, hair dyes, shampoos, permanent-wave solutions, liquid
soaps, and peels.
●Household and industrial products – Paints, resins, varnish, glue, ink, wax, and soluble oils (after
having verified that the pH is >3 and <11 or that a corrosive material is not involved).
For a semi-open test, minute amounts of allergens (1 to 2 microL) are applied to the skin and allowed
to dry (water-soluble products can be tested as 1% or 2% solution). After complete drying, the test
site is covered with a non-occlusive tape for two days and read at two and four days in a fashion
similar to closed patch testing.
Repeated open application test — The repeated open application test

(ROAT) may be useful to evaluate the clinical relevance of doubtful positive patch test reaction to
preparations in which the putative allergen is present in a low concentration [19,20].
The ROAT is performed by applying 0.1 mL of the test substance to a specified area twice daily for
up to 28 days or until an eczematous reaction develops. The antecubital fossa and the outer aspect
of the upper arm are the most suitable areas for ROAT, as patients can easily perform the test and
observe any reactions. A positive reaction may establish the clinical relevance of the product for the
patient and confirm the source of the allergy.
Usage test — If a closed patch test or open test is negative despite a history suggestive of
allergic contact dermatitis (ACD), the patient is asked to use the product under real world conditions.
This method reproduces all the factors associated with the original dermatitis, for example sweating,
friction, or application of allergen on damaged or presensitized skin and is especially helpful in
suspected clothing and cosmetic dermatitis. However, usage tests may fail to differentiate irritative
from allergic dermatitis.
Patch test reading

Initial reading — The patches typically are left in place for a period of two days (48
hours), which allows adequate penetration of the allergen into the skin. To reduce the number of
false-positive readings, the initial evaluation is generally performed between 15 and 60 minutes after
the patches are removed, when the transient erythema has resolved. Patients should avoid removing
the skin marks before the second reading is performed.
721
Second reading — A second reading is critically important to distinguish irritant
reactions (which fade) from true allergic reactions (which persist) and to identify allergic reactions
that do not appear at the time of patch removal [21]. The time of the second reading varies among
different patch testing centers, but generally is on day four or five. Day four readings appear to be
associated with a low number of false-negative reactions [22]. Performing the second reading too
soon may miss some delayed reactions, whereas performing the second reading too late may result
in missing some positive reactions that fade rapidly, such as those due to fragrances. An additional
reading at day six or seven may be useful to identify a small number of late, positive reactions, in
particular to nickel, neomycin, and corticosteroids [23].
PATCH TEST
INTERPRETATION Correctreading and interpretation of patch test
reactions require the skills of a trained clinician. The International Contact Dermatitis Research
Group has developed a scoring system for evaluating patch test reactions that has been accepted by
the North American Contact Dermatitis Group (table 2) [24].
Strong positive allergic reactions are erythematous and infiltrated, often with minute papules or
vesicles that may coalesce into bullae (picture 1A-B). The reaction may extend beyond the margins
of the patch and is usually associated with pruritus. In all cases, positive reactions should be
evaluated within the clinical context to establish their relevance. (See 'Determining the clinical
relevance' below.)
It may be difficult to distinguish true-positive weak reactions from irritant (false-positive) reactions.
In addition, a variety of morphologic patterns can be seen in irritant patch test reactions, depending
upon the nature and/or concentration of irritants (table 3) [25].
DETERMINING THE CLINICAL

RELEVANCE The relevance of a positive reaction in the diagnosis of allergic
contact dermatitis (ACD) is established by examining the patient's clinical manifestations and
history. (See "Clinical features and diagnosis of allergic contact dermatitis", section on 'Diagnosis'.)
In many cases, relevance to the current problem can be clearly established and avoidance advice
given. In some cases the relevance is found to a past episode or may be uncertain. Some individuals
may have a positive patch test reaction but still tolerate the contact with the allergen.
If the relevance of the positive patch test is not easily apparent, it is important to reexamine in
greater detail the history of exposure to the allergen or cross-reacting substances, and evaluate the
outcome after the patient avoids the allergen.
722
A detailed exposure history must include occupational exposure, hobbies, personal care products,
topical medications, and protective measures (table 4). (See "Clinical features and diagnosis of
allergic contact dermatitis", section on 'History'.)
In some cases of occupational ACD, history must be supplemented with a detailed environmental
evaluation. This might include a workplace visit, assessment of materials contacted in the
workplace, evaluation of the physicochemical properties of a substance, and evaluating the
exposure parameters. The exposure parameters include the route and site of exposure, dose,
duration, frequency, and surrounding environmental conditions.
Sometimes provocation with the allergen in the form of a usage test or repeated open application
test (ROAT) may be required to determine the clinical relevance. (See 'Usage test' above and
'Repeated open application test' above.)
There is no consensus regarding the definition, scoring, and determination of clinical relevance
[26,27]. One set of criteria for scoring clinical relevance is provided in the table (table 5) [28]. The
most reliable "test" of relevance is the finding of clearance of the dermatitis with avoidance of
identified allergens.
COMPLICATIONS OF PATCH
TESTING Although generally safe, patch testing may cause adverse reactions (table
6).
Active sensitization — Patch testing is associated with a small risk of

sensitization. A late reaction appearing 10 to 20 days after the test may indicate active sensitization
from the patch test, although some "normal" patch test reactions may be observed at this late time.
However, the risk of active sensitization from patch testing appears to be very low [29-33].
The "angry back" — The "angry back" or "excited skin syndrome" occurs when a
few strong positive reactions cause a chain of multiple reactions to other patch tests that would
otherwise be negative [34]. In most cases, one or two strong reactions create an array of false-
positive reactions. The cause of this phenomenon is not known. One hypothesis is that some
individuals who have an active dermatitis at other body sites or exhibit a strong patch test reaction
develop a nonspecific hyperreactivity of the skin [34]. Another hypothesis is that placing substances
with a similar chemical affinity in the same area induces multiple positive reactions [35]. Patients
with the "angry back" should be retested with the positive allergens separately and sequentially.
Additional validation of positive reactions can be performed by using repeated open application
tests. (See 'Repeated open application test' above.)
723
Other — Patients undergoing patch testing may develop a flare of dermatitis, which provides
additional validation of a positive test result. Occasionally, a positive reaction may persist for several
weeks. Other uncommon adverse reactions are summarized in the table (table 6).

SUMMARY
●Patch testing is an essential investigation to identify specific allergens in allergic contact dermatitis
(ACD). (See 'Introduction' above.)
●Indications for patch testing include persistent eczematous dermatitis; chronic dermatitis,
especially of the hands, feet, face, or eyelids; eczematous dermatitis in individuals in high risk
occupations; and suspicion of ACD as a complication of other forms of dermatitis. (See 'Indications
for patch testing' above.)
●Standard series of contact allergens, which are designed to include the most common sensitizers
responsible for ACD in a given region, are recommended as the initial battery for patients undergoing
patch testing. Additional series may be used to complement the standard series (eg, hairdressers,
dental, or cosmetic series). (See 'Selection of allergens' above.)
●The most commonly accepted technique for patch testing involves the application of test allergens
to the skin of the upper back under occlusion for two days (closed test). Alternative methods,
including open or usage tests, may be useful for irritant allergens, pharmaceutical products, or
cosmetics. (See 'Types of tests' above.)
●Correct reading and interpretation of patch test reactions require the skills of a trained clinician
(table 2). Strong positive reactions are erythematous and infiltrated, often with minute papules or
vesicles (picture 1A-B). It may be difficult to distinguish true-positive weak reactions from irritant
reactions (table 3). (See 'Patch test interpretation' above.)
●The clinical relevance of a positive patch test is established by reexamining the patient's clinical
manifestations and history. (See 'Patch test interpretation' above.)
724
Management of allergic contact dermatitis
uptodate.com/contents/management-of-allergic-contact-dermatitis/print
INTRODUCTION Allergic contact dermatitis (ACD) is commonly

encountered by the practicing clinician. The most common clinical expression is an eczematous
dermatitis that can be mild to severe, acute and short lived, or chronic. The management of ACD is
based upon the identification of the offending allergen, avoidance of exposure, use of safe
alternatives, and treatment of symptoms.
This topic will discuss the management of ACD. The basic mechanisms, clinical manifestations, and
diagnosis of ACD are discussed separately. (See "Basic mechanisms and pathophysiology of
allergic contact dermatitis" and "Clinical features and diagnosis of allergic contact dermatitis" and
"Patch testing".)
OVERVIEW The optimal management of ACD requires a multipronged approach

[1]:
●Identification and avoidance of the offending allergen
●Alternatives to offending products
●Restoration of the skin barrier
●Skin protection
The identification of the offending allergen is a key step in the management of ACD. Although the
offending allergen is often identified through a detailed history, patch testing may be necessary to
identify specific antigens. (See "Clinical features and diagnosis of allergic contact dermatitis",
section on 'History' and "Patch testing".)
AVOIDANCE Education of patients on avoidance of offending substances and

recommendation of alternative, allergen-free products are a critical part of the management of
patients with ACD [2].
Common contact allergens
725
Plants — The avoidance measures for contact allergy to plants of the Toxicodendron genus
(poison ivy, oak, and sumac) are discussed separately. (See "Poison ivy (Toxicodendron) dermatitis",
section on 'Prevention'.)
Nickel — Nickel is found in alloys and plated objects, including jewelry, buttons, zippers, coins,
keys, scissors, children's toys [3], cell phones [4], handheld computers [5], and metal tools. Providing
nickel-sensitive patients with a list of objects that may contain nickel may be helpful. A nickel test kit
(eg, Spot Test for Nickel, Delasco) may also be useful for patients to identify nickel-releasing objects
at home or at work. These kits, which use dimethylglyoxime, do not harm the object being tested. In
one study, the nickel spot test had a sensitivity and specificity of 60 and 98 percent, respectively, in
detecting nickel released in amounts >0.5 microg/cm2 per week by a set of earrings [6]. This is the
threshold established by the European Union Nickel Directive for products intended to be in direct
and prolonged contact with the skin.
Since jewelry (including some yellow and white gold jewelry) and metal components of clothing are
the most common sources of nickel that are in prolonged contact with the skin, several avoidance
measures have been suggested to limit nickel exposure from these sources [7].
Coating a nickel object with a physical barrier may prevent the release of nickel ions. The application
of a clear barrier (eg, Nickel Guard) or clear nail polish to the buttons and rivets of jeans may prevent
nickel release through at least two wash and dry cycles [8]. As an alternative, iron-on patches may be
applied on clothes to cover metal parts that come in contact with the skin. Another physical barrier
is duct tape. This can adhere to the inside of buttons or snaps, is inexpensive, easy to apply, and
widely available.
Chemical barriers for nickel include chelating and nonchelating barrier creams. Barrier creams
containing agents such as disodium ethylenediamine tetra-acetate (EDTA) act by chelating the
positive ionic charge and rendering the metal inactive [9,10]. Nonchelating creams may prevent the
penetration of nickel through the skin.
Cosmetics and personal care products — Although cosmetics

and personal care products contain a high number of chemical ingredients, only a few of them are
responsible for most cases of ACD. These include [11-13]:
●Fragrances
●Preservatives (eg, quaternium-15, parabens, MI (methylisothiazolinone) or MCI/MI [the combination

of methylchloroisothiazolinone and methylisothiazolinone, which is marketed as Kathon CG or
Kathon WT], thimerosal)
●Excipients (eg, propylene glycol, lanolin, or colorants)
●Glues (eg, acrylates in nail products)
726
●Sunscreens
●Hair dyes (para-phenylenediamine and derivatives)
●Surfactants (cocamidopropyl betaine, decyl glucosides)
Learning to read the labels of cosmetic or personal care products is important for patients with ACD.
Information on specific ingredients in personal care or household products commercialized in the
United States can be found online at the Consumer Product Information Database.
Alternative products — Clinicians may obtain information on alternative

products for allergic patients from several sources. The Contact Allergen Management Program
(CAMP) of the American Contact Dermatitis Society (ACDS), which requires membership, allows the
clinician to create an individualized list of products, including gloves that are free of specific
allergens. SkinSAFE is another resource for alternative products [14].
The American Contact Alternative Group provides an extensive list of alternatives for the allergens
included in the 2018 American Contact Dermatitis Core Series [15]. Specific lists of alternatives for
facial cosmetics and hair products containing few or none of the allergens included in the core
allergen series of the American Contact Dermatitis Society are also available [16,17].
Patient education — It is helpful to provide patients with additional information

to help them understand the complex nature of their allergens. Most of the companies that
manufacture the allergens have information on their websites including Smart Practice
(www.truetest.com and www.allergeaze.com), Chemotechnique (www.dormer.com), as well as the
American Contact Dermatitis Society.
Occupational avoidance measures — Avoidance in the

workplace requires a more complex strategy. Several general measures may be adopted in the
workplace to reduce exposure to chemicals, including:
●Substitution of safer alternatives for allergenic materials
●Automation
●Process enclosure
●Use of equipment for handling substances [18]
●Keeping a safe working distance
●Washing promptly any chemical exposures from the skin
●Using protective clothing and gloves
727
Protective gloves can reduce or eliminate exposure of the hands to hazardous substances. Gloves
are ideally selected on the basis of the glove permeation and degradation properties and nature of
the compounds that are manipulated.
Multilayer laminate gloves, which incorporate a hydrophilic/polar layer between two

hydrophobic/nonpolar layers, usually provide a high level of protection against a wide range of
chemicals. Manufacturers of protective gloves provide lists of applications, hazards, and chemicals
for which their gloves have been tested (eg, www.bestglove.com or www.ansell.com).
However, gloves, particularly rubber gloves, contain allergens that may worsen hand dermatitis in
some patients. Education on the proper way to put on and take off gloves is required to minimize
exposures.
Skin protection — Irritant contact dermatitis is often associated with or precedes

the development of ACD. Prework (barrier) creams and after-work (emollients) creams appear to
confer some degree of protection against irritant contact dermatitis, although evidence from
randomized trials is limited [19]. The substitution of milder detergents for abrasive or irritating
cleansers and the application of allergen-free emollients (eg, petrolatum-based emollients) after
each hand washing may reduce the risk of hand dermatitis at the workplace [20].
The regular application of emollients to normal skin after repeated exposure to irritants may help to
maintain the skin barrier function [21]. Emollients may be liberally used as an adjunct to
corticosteroids in the treatment of ACD, particularly chronic, lichenified dermatitis.
ACTIVE TREATMENT
Therapeutic options — Although avoidance of the offending allergen is the
mainstay of management of ACD, treatment is required in most cases to achieve rapid control of
symptoms. The treatment of ACD follows the general principles of eczema treatment and includes:
●Topical corticosteroids – Topical corticosteroids are the first line treatment for localized ACD
[11,20]. Their efficacy in the treatment of ACD has not been evaluated in randomized trials. However,
their efficacy in other forms of eczematous dermatitis has been demonstrated in a systematic
review of randomized trials [22]. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical
corticosteroids'.)
●Topical calcineurin inhibitors – Topical tacrolimus or pimecrolimus may be an alternative to topical

corticosteroids in the management of chronic, localized ACD; localized ACD resistant to topical
corticosteroids; ACD involving the face or intertriginous areas; and ACD induced by topical
corticosteroids.
728
The efficacy of topical tacrolimus in ACD has been evaluated in randomized trials of experimentally
induced nickel contact dermatitis [23,24]. In one study, tacrolimus 0.1% ointment applied twice daily
was more effective than placebo in clearing the eruption over eight weeks of continued exposure to
the allergen [23].
There are no high quality studies comparing topical calcineurin inhibitors with topical
corticosteroids in ACD. The onset of action of tacrolimus is slower than for potent topical
corticosteroids. Local side effects of topical calcineurin inhibitors include burning and stinging at
the site of application. Additional side effects of topical calcineurin inhibitors are discussed
separately. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin
inhibitors'.)
●Other topical treatments – Soothing and drying agents may be useful for reduction of discomfort
and pruritus in acute ACD. These include aluminum acetate compresses, calamine lotion, and
colloidal oatmeal compresses or baths.
●Systemic corticosteroids – Oral corticosteroids are the first line treatment for ACD involving >20
percent of the body surface area or for acute ACD involving the face, hands, feet or genitalia if quick
relief is desired (eg, involvement of the eyelids) [11]. Oral corticosteroids for ACD have not been
studied in randomized trials. However, in clinical experience they are frequently beneficial in the
treatment of poison ivy dermatitis, a common form of ACD. (See "Poison ivy (Toxicodendron)
dermatitis", section on 'Systemic corticosteroids'.)
●Phototherapy – Phototherapy is a therapeutic option in patients with chronic ACD that is

unresponsive to topical or oral corticosteroids. Small observational studies of patients with chronic
hand eczema of various etiologies demonstrated clinical improvement with PUVA or narrowband
UVB [25-27]. Narrowband UVB is more convenient for the patient and associated with fewer side
effects than PUVA.
●Systemic immunosuppressive agents – Rarely, in cases of chronic ACD, azathioprine,

mycophenolate mofetil, and cyclosporine have been used. Situations such as airborne compositae
dermatitis or photodermatitis, where allergen avoidance is impossible, are examples.
Allergic contact dermatitis involving the face

or flexural areas — We suggest medium- or low-potency (groups 4 to 6 (table 1))
topical corticosteroids for mild to moderate ACD of the face and flexural areas. Topical
corticosteroids are applied once or twice daily for one to two weeks.
Systemic corticosteroids may be required for acute ACD involving the face if topical corticosteroids
are ineffective or if quick relief is desired (eg, for eyelid involvement). Treatment is started with
prednisone (or equivalent dose of other systemic corticosteroids (table 2)) at a dose of 0.5 to 1
mg/kg per day (maximum 60 mg/day) for seven days. The dose may be reduced by 50 percent in the
next five to seven days and then tapered and discontinued over the following two weeks.
729
Topical tacrolimus or pimecrolimus is an alternative to topical corticosteroids in the management of
ACD involving the face or intertriginous areas. Tacrolimus 0.1% ointment or pimecrolimus 1% cream
is applied twice daily until resolution.
Allergic contact dermatitis involving the

hands, feet, or nonflexural areas — We suggest high-potency
(groups 1 to 3 (table 1)) topical corticosteroids for treatment of ACD that does not involve the face or
flexural areas. Topical corticosteroids are applied once or twice daily for two to four weeks, or until
resolution of symptoms.
If the dermatitis is acute and weeping, topical corticosteroids may be used in combination with
drying agents (eg, aluminum acetate soaks).
We suggest oral corticosteroids as the first line treatment for ACD involving >20 percent of the body
surface area, or when localized ACD is disabling, as with ACD of the hands, feet or genitalia [11].
Treatment is started with prednisone (or equivalent dose of other systemic corticosteroids (table 2))
at a dose of 0.5 to 1 mg/kg per day (maximum 60 mg/day) for seven days. The dose may be reduced
by 50 percent in the next five to seven days and then tapered and discontinued over the following
two weeks.
Topical calcineurin inhibitors are an alternative to topical corticosteroids in the management of

localized ACD resistant to topical corticosteroids and ACD induced by topical corticosteroids.
Topical calcineurin inhibitors are applied twice daily until resolution.
Phototherapy and the other systemic agents mentioned above may also be useful. (See 'Therapeutic
options' above.)
Chronic allergic contact dermatitis — We suggest

intermittent high-potency (groups 1 to 3 (table 1)) topical corticosteroids for long-term control of
chronic ACD involving the hands, feet, or nonflexural areas. In a randomized trial, 120 patients with
chronic hand eczema initially treated with mometasone furoate 0.1% fatty cream for up to nine
weeks or until the dermatitis cleared, were randomly assigned to a 30-week maintenance period with
intermittent mometasone furoate (once daily on Sunday, Tuesday, and Thursday or on Saturday and
Sunday) or vehicle. Mometasone furoate applied three times weekly was more effective than vehicle
in preventing recurrence of dermatitis (83 versus 26 percent) [28].
Breakdown of the skin barrier (atrophy) is a complicating factor in many cases of chronic ACD,
which is exacerbated by overuse of topical corticosteroids. Every effort should be made to minimize
continuous use of these agents beyond two to four weeks.
Topical calcineurin inhibitors may be an alternative to topical corticosteroids in the management of

chronic localized ACD resistant to topical corticosteroids and ACD induced by topical
corticosteroids. They may be particularly useful in "sensitive-skin" locations (eg, the face or
730
intertriginous areas). However, topical calcineurin inhibitors are expensive and there is little evidence
to determine the optimal regimen. We suggest that calcineurin inhibitors (tacrolimus 0.1% ointment
or pimecrolimus 1% cream) be applied twice daily to affected areas until resolution. They can be
restarted if there is a recurrence. (See "Chronic hand eczema".)

SUMMARY AND
RECOMMENDATIONS
●The management of allergic contact dermatitis (ACD) consists of the identification of the offending
allergen, avoidance, and treatment of skin inflammation. (See 'Overview' above.)
●Education about avoidance of offending substances and recommendations for alternative,

allergen-free products are a critical part of the management of patients with ACD. (See 'Avoidance'
above.)
●We suggest medium- or low-potency (groups 4 to 6 (table 1)) topical corticosteroids for mild to
moderate ACD of the face and flexural areas (Grade 2C). Topical corticosteroids are applied once or
twice daily for one to two weeks. Topical calcineurin inhibitors are an alternative. Topical calcineurin
inhibitors are applied twice daily until resolution. (See 'Allergic contact dermatitis involving the face
or flexural areas' above.)
●We suggest high-potency (groups 1 to 3 (table 1)) topical corticosteroids for treatment of ACD that
involves <20 percent of the body surface area, does not involve the face or flexural areas, and is not
disabling (Grade 2C). Topical corticosteroids are applied once or twice daily for two to four weeks, or
until resolution of symptoms. Topical calcineurin inhibitors are an alternative. (See 'Allergic contact
dermatitis involving the hands, feet, or nonflexural areas' above.)
●We suggest systemic rather than topical corticosteroids for:
•Acute and extensive ACD involving the face if topical corticosteroids are ineffective or if quick relief
is desired (eg, for eyelid involvement) (Grade 2C).
•ACD that involves >20 percent of the body surface area (Grade 2C).
•ACD that involves <20 percent of the body surface area and is disabling or has not responded to
treatment with topical corticosteroids or calcineurin inhibitors (Grade 2C).
731
Treatment is started with prednisone (or equivalent dose of other systemic corticosteroids (table 2))
at a dose of 0.5 to 1 mg/kg (maximum 60 mg per day) per day for seven days. The dose may be
reduced by 50 percent in the next five to seven days and then tapered and discontinued over the
following two weeks.
●Phototherapy and systemic immunosuppressive medications are therapeutic options in patients

with chronic ACD that is unresponsive to topical or oral corticosteroids. Narrowband UVB is more
convenient for the patient and associated with fewer side effects than PUVA. (See 'Therapeutic
options' above.)
●We suggest intermittent high-potency (groups 1 to 3 (table 1)) topical corticosteroids rather than
emollients alone for long-term control of chronic ACD involving the hands, feet, or nonflexural areas
(Grade 2B). The topical steroid is applied once daily three times per week on alternate days. Topical
calcineurin inhibitors may be helpful in chronic localized ACD that is not responsive to topical
corticosteroids or that is induced by topical corticosteroids. (See 'Chronic allergic contact dermatitis'
above.)
732
Poison ivy (Toxicodendron) dermatitis - UpToDate
uptodate.com/contents/poison-ivy-toxicodendron-dermatitis/print
INTRODUCTION Exposure to plants of the Anacardiaceae family account

for more allergic contact dermatitis than all other plant families combined. In the United States, the
most important members of this family are those of the genus Toxicodendron (previously classified
as in the genus Rhus [1,2]), which include common or northern poison ivy (Toxicodendron radicans),
western poison ivy (Toxicodendron rydbergii), eastern poison oak (Toxicodendron toxicarium), western
poison oak (Toxicodendron diversilobum), and poison sumac (Toxicodendron vernix). Toxicodendron
means "poisonous tree," an appropriate choice for these dermatitis-provoking species. In contrast,
although they often have three-leaflet configurations similar to those of Toxicodendron, members of
the genus Rhus are nonallergenic [1,2]. Throughout this topic review, we refer to Toxicodendron
dermatitis by the common name "poison ivy dermatitis."
This topic reviews the epidemiology, prevention, and treatment of allergic contact dermatitis due to
these Toxicodendron species. The evaluation and management of contact dermatitis from other
causes is discussed separately (see "Overview of dermatitis (eczema)", section on 'Contact
dermatitis'). Despite the prevalence of poison ivy dermatitis in the United States, there are very few
well-designed, published studies examining the management of this condition.
733
EPIDEMIOLOGY Many people are sensitized to urushiol, the allergenic
compound found in poison ivy, poison oak, and poison sumac. Fifty percent of people will react to
poison ivy in nature, and approximately 75 percent will react to patch testing with urushiol. Annually,
an estimated 25 to 40 million Americans require medical treatment after exposure [3,4]. Firefighters,
forestry workers, and farmers constitute a large proportion of the victims affected through
occupational exposure, and this can have important occupational and economic impacts [4,5].
Poison ivy dermatitis affects all ethnicities and skin types, and most geographical regions in the
United States are at risk [6] (see 'Geography' below). Children are also affected; most children over
the age of eight years are sensitized [4]. Allergic responsiveness to poison ivy appears to wane with
age, especially in those with mild reactions and limited sensitizing exposures.
IDENTIFYING THE PLANT While the common phrase

"leaves of three, let them be" is a helpful reminder to avoid poison ivy and related plants, members of
the Toxicodendron genus have varied presentations based on the season, growth cycle, region, and
climate (figure 1 and picture 1A-C) [7].
Poison ivy and poison oak are often identified by three leaflets with flowering branches arising from
axillary positions on a single stem. Poison sumac more often forms leaflets of five, seven, or more
that angle upward toward the top of the stem. One may also find characteristic black dots on
Toxicodendron species; this black lacquer is oxidized urushiol (due to the enzyme laccase found in
the oleoresin) and can be found on plant leaves within 10 minutes of its exposure to oxygen.
Toxicodendron species also produce a green or off-white fruit in the autumn months [2]. Two species
of Rhus possess trifoliate leaves; however, the fruiting structures are red and terminal, not off-white
and axillary (figure 1).
GEOGRAPHY Toxicodendron species are ubiquitous in many environments,

particularly in the United States, and can be found in various forms or as cross-reacting allergenic
plants throughout the world. Northern poison ivy is more common east of the Rocky Mountains,
often growing as climbing vines. Poison ivy in and west of the Rocky Mountains is found as a low-
growing shrub. Poison oak is found primarily west of the Rocky Mountains, and poison sumac is
found in boggy, uninhabited areas of the southeastern part of the US. It is less common to find
Toxicodendron species above 4000 feet of elevation or in arid, desert climates (figure 2A-C) [4].
CROSS-REACTION Other members of Anacardiaceae and related

families contain allergenic catechols or noncatechol phenols that cross react with components of
urushiol found in Toxicodendron species. Mango rind, cashew nutshell, Japanese lacquer tree, Indian
marking nut tree (used for laundry marking in India), Brazilian pepper tree, and ginkgo tree can all
cause dermatitis in sensitized individuals.
734
PATHOGENESIS Urushiol is the allergenic substance in poison ivy and
related plants. It is a mixture of compounds that makes up 60 percent of the plant oleoresin. Those
compounds with zero, one, two, or three double bonds are allergenic; the diolefin (two double bonds)
is the most allergenic. The oleoresin also contains the enzyme laccase, gum, water, and water-
insoluble glycoproteins. It is a light, colorless oil present in the fruit, leaves, stem, and root of the
plant. Exposure to bruised or broken plant parts allows the toxic oil to contact skin, fingernails,
clothing, pets, tools, or other objects. Intact plant parts generally do not cause dermatitis. However,
plants are easily damaged by rubbing, rain, or dry fall weather.
Poison ivy dermatitis is a classic type IV hypersensitivity (cell-mediated) allergic reaction. The
allergens are low-molecular-weight haptens that easily and quickly penetrate the epidermis, where
they are taken up and processed by Langerhans cells. These antigen-presenting cells then travel to
regional lymph nodes where effector T lymphocytes are activated, expand, and circulate throughout
the body. Because urushiol is a powerful antigen, a single exposure can be adequate to cause
clinical symptoms. Once clonally expanded T lymphocytes exist, reexposure to poison ivy causes
cytokine release and clinical symptoms in 12 to 48 hours. Patients with a history of poison ivy
dermatitis may be at increased risk for dermatitis from cross-reaction with other urushiol-containing
plants such as mangoes [8].
CLINICAL PRESENTATION Intense pruritus and

erythema are the most common presenting signs of poison ivy dermatitis. Patients then develop
papules or plaques, vesicles, and/or bullae, often arranged in characteristic linear or streak-like
configurations where a portion of a plant has made contact with the skin (picture 2).
Involvement of the face and genitals may cause significant edema. Clinical presentations vary with
patient activity. One report found that children in New Zealand were more likely to present with facial
dermatitis reflective of play under Toxicodendron succedaneum trees, while adults more frequently
presented with upper limb symptoms acquired while gardening [9]. Urushiol contact has also caused
urticaria and erythema multiforme [10,11]. "Black spot" poison ivy dermatitis occurs when urushiol is
left on the skin and oxidizes, appearing as black spots that cannot be washed off (picture 2) [12].
The concentrated resin creates both an irritant dermatitis and an allergic dermatitis.
Symptoms of poison ivy dermatitis in sensitized individuals generally develop within 4 to 96 hours
after exposure and peak between 1 and 14 days after exposure [13]. New lesions can present up to
21 days after exposure in previously unexposed individuals. Lesions present in different locations at
different times after exposure based upon the amount of urushiol present and the stratum corneum
thickness of the involved areas. This can give the impression that the poison ivy is spreading from
one region to another. Blister fluid is not antigenic, however.
Occasionally, after the initial exposure, patients continue to come in contact with the dried, black
antigenic resin on contaminated clothing, pet fur or claws, gardening tools, or in crevices under the
fingernails. This perpetuates the patient's dermatitis and puts their contacts at risk for developing an
735
allergic reaction. (See 'Avoidance' below.)
Left untreated, the dermatitis usually resolves in one to three weeks. The most common
complication of poison ivy dermatitis is secondary bacterial infection of the skin with Staphylococcus
aureus or beta-hemolytic group A Streptococcus. Bacterial flora does vary somewhat by site and can
be polymicrobial [14].
Postinflammatory hyperpigmentation is more common in darker skin types and, while it can persist
for several months, usually resolves without treatment [6]. Renal and genitourinary complications
are rare, although urinary retention due to penile edema and nephrosis from immune complex
deposition in the kidney have both been reported [6,15].
DIAGNOSIS The diagnosis of poison ivy dermatitis is typically made based on a

history of exposure and a characteristic pattern of a well-demarcated contact dermatitis in areas of
skin that could have come in contact with plant parts, particularly when linear streaks are present
(picture 2). Atypical presentations may occur when patients are exposed secondarily, such as when
a pet gets urushiol on its fur and then brushes against the patient. It is impossible to diagnose
poison ivy as the cause of a rash based solely on the appearance of the rash.
The differential diagnosis of poison ivy dermatitis includes:
●A different plant-induced allergic contact dermatitis – Plants other than Toxicodendron can cause
dermatitis. (See "Overview of dermatitis (eczema)", section on 'Allergic contact dermatitis'.)
●Allergic contact dermatitis not from plants – Important allergens include nickel and topical
antibacterials. (See "Overview of dermatitis (eczema)", section on 'Allergic contact dermatitis'.)
●Irritant contact dermatitis – Many substances can produce a nonallergic inflammatory skin
reaction (picture 3). (See "Overview of dermatitis (eczema)", section on 'Irritant contact dermatitis'.)
●Nummular dermatitis – Nummular dermatitis consists of intensely pruritic, eczematous plaques.

Scale, crusting, or serous drainage may be evident. Patients can present with as few as one lesion or
as many as 20 to 50 lesions. Lesions tend to be circular and usually measure between 2 and 10 cm
in diameter. (See "Overview of dermatitis (eczema)", section on 'Nummular eczema'.)
●Phytophotodermatitis – Phytophotodermatitis is a phototoxic reaction with erythema with or

without blistering in response to ultraviolet exposure in patients exposed to photosensitizing plant
compounds. Unlike poison ivy dermatitis, lesions will only be seen on sun-exposed skin. Lesions
often resolve with significant hyperpigmentation. (See "Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and treatment", section on
'Phytophotodermatitis'.)
●Arthropod reactions – The pruritic burrows of scabies may be mistaken for poison ivy dermatitis,
but do not generally appear as vesicles (picture 4) (see "Scabies: Epidemiology, clinical features, and
diagnosis"). Bedbug bites can be linear and pruritic and may occasionally present as vesicles or
736
bullae. (See "Bedbugs".)
PREVENTION
Avoidance — The most important and effective treatment for poison ivy dermatitis is
identification and avoidance of toxic plants and related allergens. Sap-containing plant parts are
allergenic and irritant year round and cannot be safely handled during winter months. Allergenicity
can also persist years after the plant dies.
Protective clothing is useful, but patients should be reminded that clothing, pets, and fingernails can
harbor the allergenic resin for many days. The oleoresin can seep through clothing and can
penetrate rubber or latex gloves, but not heavy-duty vinyl gloves [13].
Burning poison ivy is not a safe way to dispose of the vegetation. Urushiol is stable at high
temperatures, and the plant particles dispersed in the smoke are allergenic and irritant.
Washing — After a known exposure, patients should remove any contaminated clothing
and wash the skin with mild soap and water as soon as possible. One study found that after
approximately 10 minutes on the skin, 50 percent of the urushiol can be removed; this number falls
to 10 percent after 30 minutes and zero after one hour [2]. Despite this, washing even two hours after
exposure significantly reduces the likelihood and severity of dermatitis [16]. Fingernails should be
washed carefully to remove resin that may remain under the nails.
Vigorous scrubbing is not useful and can exacerbate impending dermatitis. Washing the skin after
dermatitis has become clinically apparent is futile. A study that compared a chemical inactivator
intended to prevent poison ivy, an oil-removing compound, and a dishwashing soap found that all
three preparations significantly reduced dermatitis when used two hours after experimental
exposure to poison ivy [16]. Although the authors concluded that there was no significant difference
in the effectiveness of the three preparations, the point estimate of effectiveness was higher with
Tecnu than with the other two preparations, and the study was inadequately powered to detect
differences that patients would likely consider clinically important. Tecnu is significantly more
expensive than the other preparations, and it is reasonable to recommend to patients that they wash
with an inexpensive mild detergent.
Clothing, tools, or other items that may have come in contact with the oleoresin also should be
washed with warm, soapy water prior to reuse.
Barrier creams — The use of barrier creams to prevent contact dermatitis is

controversial. Barrier creams are topical preparations that are applied prior to exposure to a contact
allergen in an attempt to prevent the development of dermatitis. Organoclay compounds appear to
be more effective barriers than other preparations [17].
737
The barrier cream that has the best evidence for efficacy for the prevention of poison ivy dermatitis
is bentoquatam (5% quaternium-18 bentonite lotion), an organoclay compound. The efficacy of
bentoquatam is supported by a controlled trial in 211 subjects. Among the 144 subjects who
showed a reaction to urushiol, only 32 percent developed dermatitis at the site treated with
bentoquatam [18]. In addition, reactions that occurred at bentoquatam-treated sites were less severe
than those at untreated sites.
Bentoquatam must be reapplied every four hours and leaves a clay residue on the skin.
Other preparations that may be effective include [19]:
●Linoleic acid dimers. These do not prevent urushiol penetration of the skin and thus must be rinsed
off and reapplied after four to eight hours.
●Occlusive barrier ointments.
Other topical barrier creams may emerge as research continues for preparations effective in
preventing dermatitis from chemical warfare agents [20,21].
Desensitization — Reports of Native Americans achieving hyposensitivity to

poison ivy dermatitis by chewing the leaves, the lower prevalence of mango dermatitis in indigenous
Hawaiians compared with immigrants, and decreased poison ivy sensitivity of cashew nut shell oil
processing in factory workers have all prompted research into commercially available
hyposensitization kits [22-24].
These programs have generally not been effective [23]; require months of low-dose antigen ingestion
accompanied by side effects like pruritus ani, urticaria, and dermatitis [25]; and are neither practical
nor recommended.
Other — Pretreatment with oral pentoxifylline, a methylxanthine tumor necrosis factor (TNF)-
inhibitor, has been shown to diminish patch-test reactivity to nickel and other forms of allergic
contact dermatitis, but not to urushiol [26-28].
TREATMENT Few controlled trials of poison ivy dermatitis treatment have

been performed [29]. The information presented here is based mainly on clinical experience.
Topical symptomatic therapy — Soothing measures such as

oatmeal baths and cool, wet compresses are anecdotally helpful. Topical treatment with compounds
containing menthol and phenol (calamine lotion) may also provide symptomatic relief. Topical
astringents such as aluminum acetate (Burow's solution) or aluminum sulfate calcium acetate used
under occlusion may be useful to dry weeping lesions [3,24]. A soap mixture of ethoxylate and
sodium lauroyl sarcosinate surfactants may also be of benefit [30].
738
Topical antihistamines, anesthetics containing benzocaine, and antibiotics containing neomycin or
bacitracin should be avoided because of their own allergenic potential.
Pimecrolimus, a topical calcineurin inhibitor, is ineffective for the treatment of Toxicodendron-induced

allergic contact dermatitis [31].
Antihistamines — Although there is little to no evidence to support their use,

sedating and nonsedating oral antihistamines are commonly used to try to reduce pruritus [32].
However, the itching in poison ivy dermatitis is not caused by histamine release. Relief that patients
derive from oral antihistamines is primarily due to the sedating effects of certain antihistamines [33].
We do not use nonsedating antihistamines at all in the management of poison ivy dermatitis, but we
find sedating antihistamines occasionally beneficial for those who have difficulty sleeping due to
pruritus. (See "Pruritus: Overview of management", section on 'Antihistamines'.)
Topical corticosteroids — High-potency topical corticosteroids (table 1)

are most helpful early in allergic contact dermatitis. Once vesicles are established, they do little to
alter the natural course of the disease [34], but many clinicians believe they are helpful in relieving
symptoms. Clinical experience suggests that low-potency topical corticosteroids are of little use.
High-potency topical corticosteroids should generally not be used on thin skin such as the face,
genitals, or intertriginous areas, due to the potential for these agents to cause skin atrophy and other
adverse effects. However, the only topical corticosteroids that can influence the course of poison ivy
dermatitis are superpotent ones such as clobetasol propionate 0.05% cream. Use of superpotent
corticosteroids, even under occlusion, for up to a week on severely involved areas poses little threat
for permanent atrophy. (See "Topical corticosteroids: Use and adverse effects".)
Systemic corticosteroids — Patients with severe dermatitis, particularly

involving the face or genital region, may require systemic corticosteroids [35,36]. There are no well-
designed studies examining the proper dose and course of systemic corticosteroids for poison ivy
dermatitis; however, extensive clinical experience suggests that rebound dermatitis occurs
commonly if too short a course is used (such as the six-day course in a methylprednisolone dose
pack) [37]. As in other forms of allergic contact dermatitis, circulating T lymphocytes directed toward
urushiol are able to expand and activate cytokines for a significant period after exposure to antigen,
leading to rebound dermatitis when corticosteroids are stopped.
Oral prednisone started at a dose of approximately 1 mg/kg/day (maximum initial dose 60 mg/day)
can be dramatically beneficial for the miserable patient. The dose can then be tapered over two or
three weeks (for instance, 60 mg/day the first week, 40 mg/day the second week, 20 mg/day the
third week would be one possible taper for a 21-day course). There are no published studies
comparing 14- and 21-day courses of prednisone in poison ivy. We typically treat adults with a 21-
day total course, however. In clinical practice, however, 14-day courses only rarely result in rebound
dermatitis and may be appropriate if there are concerns about steroid toxicity. (See "Major side
effects of systemic glucocorticoids".)
739
Although oral administration of corticosteroids offers flexibility in daily dosing, intramuscular
injection of corticosteroids is a treatment option for patients who cannot tolerate or comply with
administration of oral corticosteroids [38]. In our clinical experience, we have found treatment with a
mixture of triamcinolone acetonide (1 mg/kg), a long-acting corticosteroid, and betamethasone (0.1
mg/kg), a short- to intermediate-acting corticosteroid, beneficial. However, published data are
lacking on the optimum regimen and dose of intramuscular corticosteroids for the treatment of
poison ivy.
Intralesional injection of triamcinolone acetonide (4 to 5 mg/mL) may be useful for treatment of

severe disease confined to small areas.
Antibiotics — If secondary bacterial infection is suspected, appropriate systemic

antibiotics (typically directed at gram-positive organisms) should be administered. Most patients
with secondary impetigo will be infected with S. aureus or group A Streptococcus. However, given
increasing rates of community-acquired methicillin-resistant S. aureus, performing a skin culture is
reasonable if pus is present. (See "Impetigo" and "Methicillin-resistant Staphylococcus aureus
(MRSA) in adults: Prevention and control" and "Cellulitis and skin abscess in adults: Treatment".)
Other — Jewelweed extract has been used for the treatment of poison ivy dermatitis, but does
not appear to be effective [39].


●Basics topics (see "Patient education: Dermatitis (The Basics)" and "Patient education: Poison ivy
(The Basics)")
740
(Beyond the Basics)" and "Patient education: Poison ivy (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Plants of the Anacardiaceae family account for more allergic contact dermatitis than all other plant
families combined. In the United States, the most important members of this family are those of the
genus Toxicodendron, which include poison ivy, poison oak, and poison sumac. (See 'Introduction'
above.)
●While the common phrase "leaves of three, let them be" is a helpful reminder to avoid poison ivy
and related plants, members of the Toxicodendron genus have varied presentations based on the
season, growth cycle, region, and climate (figure 1 and picture 1A-C). (See 'Identifying the plant'
above.)
●Urushiol is the allergenic substance in Toxicodendron. Exposure to urushiol can occur through
contact with parts of the plant (eg, roots, sap, leaves, or stems) or via contact with objects that have
been contaminated by the plant oleoresin. (See 'Pathogenesis' above.)
●Intense pruritus and erythema are the most common presenting signs of poison ivy dermatitis.
Patients then develop papules, vesicles, and/or bullae, often arranged in characteristic linear or
streak-like configurations where a portion of a plant has made contact with the skin (picture 2). (See
'Clinical presentation' above.)
●The diagnosis of poison ivy dermatitis is typically made based on a history of exposure and a
characteristic pattern of a well-demarcated contact dermatitis in areas of skin that could have come
in contact with plant parts, particularly when linear streaks are present. Atypical presentations may
occur when patients are exposed secondarily, such as when a pet gets urushiol on its fur and then
brushes against the patient. (See 'Diagnosis' above.)
●Poison ivy dermatitis is best prevented by avoiding exposure through the use of protective clothing
such as heavy-duty vinyl gloves. Washing with a detergent soap (or with special preparations
designed for poison ivy) as soon as possible after exposure can reduce the risk of dermatitis, but
washing even two hours after exposure can be beneficial (see 'Washing' above). Pretreatment of
exposed skin with topical bentoquatam is of some benefit in people who are at high risk for exposure
to poison ivy. (See 'Prevention' above.)
●Treatment for dermatitis can include topical symptomatic therapies such as oatmeal baths and
cool compresses (see 'Topical symptomatic therapy' above). High-potency topical corticosteroids
(table 1) do little to alter the natural course of poison ivy dermatitis once vesicles have developed,
but they may reduce itching, particularly if used under occlusion. (See 'Topical corticosteroids'
above.)
741
●Systemic corticosteroids, such as a course of oral prednisone tapered over 14 or 21 days, can be
dramatically effective in reducing symptoms and are the treatment of choice for extensive poison ivy
dermatitis and for significant dermatitis affecting the face or genital region. We typically use a 21-
day course to minimize the risk of rebound dermatitis, but a 14-day course may be appropriate when
there are concerns about steroid toxicity. Short courses of systemic corticosteroids (eg, a six-day
methylprednisolone dose pack) can result in rebound dermatitis and should be avoided. (See
'Systemic corticosteroids' above.)
742
Eyelid dermatitis (eczema) - UpToDate
uptodate.com/contents/eyelid-dermatitis-eczema/print
INTRODUCTION Eyelid dermatitis, also known as periocular dermatitis or

periorbital dermatitis, presents with a scaly, erythematous eruption of the upper and/or lower eyelids
and, possibly, the periorbital area [1,2]. Patients often report symptoms of itching, burning, and
stinging. Swelling may be present. Eyelid dermatitis may be caused by contact with irritants or
allergens, or it can be a manifestation of an underlying skin disease, such as atopic dermatitis or
seborrheic dermatitis. A periorbital dermatitis may also be a manifestation of rosacea or periorificial
(perioral) dermatitis.
This topic will discuss the clinical manifestations, differential diagnosis, evaluation, and treatment of
the most common types of eyelid dermatitis. Blepharitis, a chronic inflammation of the eyelid margin
associated with eye irritation, is discussed separately. Rosacea and periorificial dermatitis are also
743
●(See "Blepharitis".)
●(See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
●(See "Perioral (periorificial) dermatitis".)
EPIDEMIOLOGY Eyelid dermatitis is usually seen in adults and teens and

is less common in children, unless associated with atopic dermatitis (AD). The exact prevalence of
eyelid dermatitis in the general population is unknown, but it is commonly encountered in clinical
practice. Both men and women can manifest eyelid dermatitis, but women greatly outnumber men in
most patch test studies of patients presenting with eyelid dermatitis [3-8].
Allergic contact dermatitis (ACD) is the most common type of eyelid dermatitis, accounting for
approximately 50 percent of cases, followed by irritant contact dermatitis (ICD) and atopic eyelid
dermatitis [3,4,9,10]:
●A 10-year retrospective review from a single institution of 105 patch test patients with eyelid
dermatitis found that 43.8 percent of patients had ACD, 38 percent had seborrheic dermatitis, and
7.6 percent had ICD [4].
●A study of 362 females with eyelid dermatitis found that 50.1 percent had ACD, 20.9 percent had
ICD, 13.5 percent had AD, 6.5 percent had an unspecified dermatitis, 6.3 percent had seborrheic
dermatitis, and 2.9 percent were diagnosed with psoriasis [9]. Involvement of all four lids was
strongly associated with ACD.
●A study of 609 patients with periorbital dermatitis who underwent patch testing found that 52
percent had underlying ACD with common allergens, including nickel, benzoyl peroxide, fragrances,
and antimicrobials [3]. Allergic eyelid dermatitis patients had an increased rate of allergies to topical
antimicrobials and antibiotics, which may reflect exposure to topical eye medicaments [3].
ETIOLOGY The cause of eyelid dermatitis is often multifactorial. It may result from
contact with irritants or allergens, or it can be a manifestation of an underlying skin disease, such as
atopic dermatitis (AD) or seborrheic dermatitis [1].
Contact dermatitis — The eyelids are a sensitive site due to the thinness of the
skin and the potential increased penetration of allergens and irritants. Frequently, eyelids may be the
only site affected by contact dermatitis. For example, eyelid dermatitis may be the only
manifestation of contact dermatitis to hair care products, in the absence of a coexisting eruption on
the scalp. Nail products and other allergens may be transported from the hand to the eyelid area and
may cause isolated eyelid dermatitis in the absence of hand dermatitis.
744
Allergic contact dermatitis — Allergens found to cause allergic contact
dermatitis (ACD) on the eyelids include metals (eg, nickel, gold), fragrances, preservatives, and
topical antibiotics [4-8]. In one study of 1247 patients referred for patch testing, including 266
patients with periorbital dermatitis and 981 without periorbital dermatitis, the sensitization pattern
was not different in the two groups, with nickel and fragrance mix being the most frequently involved
sensitizers [7]:
●Fragrance is commonly found to cause allergic eyelid dermatitis. In a study of 100 patients with
eyelid dermatitis who underwent patch testing, 42 were found to be positive to a fragrance or
fragrance marker. However, 15 of the 42 patients (36 percent) only reacted to a fragrance chemical
on a supplemental fragrance tray, suggesting that fragrance-allergic patients may be missed by only
testing for fragrance screeners on a standard patch test tray [11].
●Gold remains another cause of eyelid dermatitis. Exposure to gold occurs from jewelry on the
hands or ears and perhaps is worsened by concurrent use of mineral-based cosmetics or
sunscreens. Gold was the most commonly relevant positive reaction in a study of 268 patients with
eyelid ACD who had undergone patch testing [6].
●Nail polish, particularly those made from acrylates, can also cause ACD on the face and eyelids
[12].
Topical ophthalmic preparations may cause irritant contact dermatitis (ICD) or ACD. In a study of
4779 European patients with periorbital dermatitis who underwent patch testing over a 10-year
period, two distinct populations with allergic eyelid dermatitis were identified: younger patients with
a history of AD and frequent use of cosmetics, and older patients with allergies to topical ophthalmic
preparations [5]. Allergens found in topical ophthalmic preparations included phenylmercuric
acetate, topical antibiotics (including gentamycin and neomycin), and phenylephrine. Eight percent
were found to have ICD [5]. In this series, thimerosal was positive in 9.3 percent of patch test
patients with eyelid dermatitis. This antimicrobial has been historically used in eye drop preparations
but is now infrequently found in such products, despite being present as a preservative in some
adult vaccines [5]. Many positive patch test reactions to this chemical are likely due to past
relevance. A study of 118 patients with ACD due to topical ophthalmic preparations found that the
active ingredient (antibiotics or steroids) was the culprit 59 percent of the time. The vehicle (wool
alcohol, preservatives) was the source of ACD in 29 percent of patients, with 12 percent of patients
reacting to both the active drug and a component of the vehicle [13].
Airborne contact dermatitis — Airborne contact dermatitis of the eyelids is

caused by exposure to antigen or irritant particles suspended in air. These include plant antigens,
wood allergens, plastics, rubber, glues, metal, industrial and agricultural dusts, pesticides, and drugs
[1]. Plants of the Compositae family (eg, parthenium, ragweed, aster, sunflower, chrysanthemum,
artichoke) are among the most frequent causes of airborne contact dermatitis of the eyelids.
745
Protein contact dermatitis — Protein contact dermatitis is an
immunoglobulin E (IgE)-mediated ACD due to sensitization to plant or animal proteins [14]. These
include foods, pollen, animal hair, and latex.
Irritant contact dermatitis — Irritants known to cause or exacerbate eyelid

dermatitis include soaps, preservatives, and fragrances. The use of antiaging products on the face
can cause eyelid dermatitis in the absence of other sites involved, even if the product is not being
directly used on the eyelids. Patients with eyelid dermatitis should be specifically asked about the
use of topical retinoid derivatives on the face.
Atopic dermatitis — Eyelid dermatitis may occur in patients with a history of

childhood-onset atopic dermatitis (AD) and/or other atopic diseases, including asthma and seasonal
allergies. Irritants often play a role in the development of eyelid dermatitis in patients with atopic
disease. Additionally, patients with AD may develop superimposed ACD and protein contact
dermatitis involving the eyelids.
Seborrheic dermatitis — Seborrheic dermatitis is a chronic, relapsing form

of dermatitis that has a predilection for nasolabial creases, eyelids, ears, scalp, chest, and
intertriginous sites. Less commonly, it may involve the eyelid skin and/or the eyelid margin
(seborrheic blepharitis). In a series of 447 patients with eyelid dermatitis, 6 percent were diagnosed
with seborrheic dermatitis [9]. (See "Seborrheic dermatitis in adolescents and adults" and
"Blepharitis".)
CLINICAL MANIFESTATIONS Eyelid dermatitis

generally presents as an erythematous, scaly, pruritic rash on the upper and/or lower eyelids. It may
occur in isolation or be associated with dermatitis of other body sites. Dermatitis is in most cases
bilateral, but may be unilateral and affect the upper or lower eyelids, or both. Clinical findings may
vary according to the etiology.
Patients with contact eyelid dermatitis present with unilateral or bilateral eyelid dermatitis
associated with itching, scaling, burning, and pain (picture 1A-C) [15]. Pruritus is often a prominent
symptom of allergic contact dermatitis (ACD), and there may be features of lichenification from
chronic rubbing and scratching. In a series of 264 patients with eyelid dermatitis referred to a
specialty patch test clinic in France, common symptoms included erythema, pruritus, edema, and
scaling [16]. Eyelids may appear fissured, and crusting may occur on the lashes. Approximately 25
percent of patients with eyelid contact dermatitis have an associated conjunctivitis [16]. Dermatitis
is often present elsewhere on the body, including the face, neck, and periauricular skin.
Atopic eyelid dermatitis often develops in teenage years and adulthood but may also occur in older
individuals. Occasionally, it can be the only manifestation of atopic dermatitis (AD). The upper
eyelids may appear scaly and fissured (picture 2A-B). The so-called "allergic shiners" (symmetric,
746
dark circles beneath the lower eyelid) and Dennie-Morgan lines (extra skin folds under the lower
eyelid) are often present (picture 2C) [17].
However, atopic eyelid dermatitis and contact eyelid dermatitis can be clinically indistinguishable,
and patch testing is often necessary for the correct diagnosis (see 'Patch testing' below).
Additionally, patients with AD may develop superimposed ACD. (See "Atopic dermatitis (eczema):
Seborrheic dermatitis on the eyelids may appear scaly and waxier than contact dermatitis or AD
(picture 2D); itching is less common than other symptoms, such as flaking or burning.
CLINICAL COURSE Clinical course often varies with etiology. Eyelid

dermatitis may wax and wane and sometimes exhibits seasonal variation. For example, eyelid
dermatitis associated with underlying atopic dermatitis may be chronic and flare with seasons and
exposure to environmental allergens. Patients may notice that airborne irritants, including plants,
pollens, dust, and dander, may trigger or worsen the disease. Eyelid dermatitis may also flare with
hay fever, allergic rhinitis, or conjunctivitis, possibly related to chronic tearing or mechanical rubbing.
Occupational eyelid dermatitis may worsen with workplace exposures and improve with time off
from work.
DIAGNOSIS
Clinical — The diagnosis of eyelid dermatitis is made in most cases clinically, based on the
characteristic appearance of the eruption, associated symptoms, and clinical history. A full skin
examination for other areas of dermatitis should be performed in all patients.
A careful clinical history may provide clues to the etiology. As an example, the presence of bilateral
eyelid dermatitis, prominent itch, involvement of other sites on the face, lack of seasonal variation of
symptoms, and a history of temporary or inadequate improvement with standard treatment suggest
the diagnosis of allergic contact dermatitis (ACD). A careful history of exposure to potential
allergens should be elicited in patients with suspected eyelid ACD. Patch testing may be needed to
confirm the diagnosis. (See 'Patch testing' below.)
Atopic eyelid dermatitis is suspected in adolescents and young adults with a history of childhood-
onset atopic dermatitis (AD) and/or other atopic diseases, including asthma and seasonal allergies.
The presence of an associated flexural dermatitis supports the diagnosis. However, exposure to
irritants or contact sensitization may have a role in the development of eyelid dermatitis in patients
with atopic disease.
747
Patch testing — Atopic eyelid dermatitis and contact eyelid dermatitis can
sometimes be clinically indistinguishable. Any patient with eyelid dermatitis requiring ongoing
treatment beyond four to eight weeks should be strongly considered for patch testing to ensure the
correct diagnosis. In a study of 401 patients with eyelid dermatitis who were patch tested, contact
hypersensitivity was detected in 34 percent of patients; the most frequent sensitizers were nickel
sulphate, fragrance mix, balsam of Peru, paraphenylenediamine, and thiomersal [18].
If patch testing is negative or positive reactions are deemed not to be relevant to the current
dermatitis, the diagnosis of irritant contact dermatitis (ICD) should be considered. In a series of 609
patients with eyelid dermatitis, 21 percent had negative patch testing and were subsequently
diagnosed with ICD [3]. (See "Clinical features and diagnosis of allergic contact dermatitis", section
on 'Diagnosis' and "Patch testing".)
Skin biopsy — A skin biopsy is generally not helpful for the diagnosis of eyelid
dermatitis. Histopathologic examination would show nonspecific changes that are common to all
types of eczematous dermatitis (eg, spongiosis [epidermal edema], lymphohistiocytic infiltrate in the
dermis) and, therefore, would not help identify the specific cause of eyelid dermatitis. However, a
skin biopsy can be performed if the diagnosis is uncertain and, in particular, to rule out connective
tissue disease and dermatomyositis. A biopsy showing interface dermatitis would suggest
connective tissue disease and prompt further evaluation for autoimmune disease.
ASSOCIATED OCULAR DISEASE Most

patients with eyelid dermatitis do not have associated eye disease. However, patients with atopic
dermatitis have an increased risk of comorbid eye diseases, including keratitis, conjunctivitis, and
keratoconus [19]. A careful clinical examination for associated erythema, crusting, and blepharitis
many prompt referral to an ophthalmologist.

of eyelid dermatitis is ample and includes common and less common skin diseases:
●Psoriasis – Psoriasis on the eyelids tends to be nonpruritic. Patients may manifest the typical
scaly plaques of psoriasis on the body and scalp, and a full skin examination is essential for the
diagnosis. Nail or joint disease may also be present, aiding in diagnosis. (See "Psoriasis:
●Ocular rosacea – Ocular rosacea typically presents with lid margin telangiectasias and
conjunctival injection. Crusted papules may be present on the eyelid margin (picture 3). The
concurrent presence of acneiform papules and pustules, face flushing, and/or telangiectasias are a
clue for the diagnosis of rosacea. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
748
●Periorificial periocular dermatitis – Periorificial periocular dermatitis presents with patchy
erythema and numerous tiny papules involving the eyelids and the periocular area (picture 4). A
history of recent use of topical, nasal, or inhaled corticosteroids may be a clue to the diagnosis. (See
"Perioral (periorificial) dermatitis".)
●Dermatomyositis – Dermatomyositis involving the eyelids tends to present with the classic
"heliotrope rash" characterized by violaceous erythema (picture 5A-B). A biopsy shows interface
dermatitis and not spongiosis. Pruritus is usually absent, and patients may have other symptoms of
dermatomyositis, including scalp rash, extensor erythema, photosensitivity, characteristic nail
changes, and muscle weakness, among others. Eyelid edema alone can be an early presenting sign.
(See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
●Newborns and infants may have asymptomatic, pink patches on the upper eyelids consistent with
nevus simplex, which is a benign vascular birthmark (picture 6). Commonly called "stork bite" or
"angel kiss," nevus simplex typically fades with aging. (See "Vascular lesions in the newborn", section
on 'Nevus simplex (macular stain)'.)
In infants, a rare cause of periocular dermatitis is neonatal lupus, which typically occurs in the first
few weeks of life and can be associated with cardiovascular disease. A history of maternal lupus will
aid in diagnosis. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and
diagnosis".)
MANAGEMENT The management of eyelid dermatitis involves ongoing

avoidance of exposure to irritants and allergens for patients with contact dermatitis and the use of
topical anti-inflammatory agents, including topical corticosteroids and topical calcineurin inhibitors.
There are no randomized trials assessing the efficacy and safety of these agents for eyelid eczema,
and their use is based on limited evidence from small observational studies, indirect evidence based
on their use in other types of eczema, and clinical experience [20-23].
Skin care — Conservative initial management of eyelid dermatitis includes gentle skin
care and avoidance of fragrance and other known irritants in personal care, hair, and facial skin care
products. Bland, fragrance-free emollients, such as petrolatum, may be applied directly to the
eyelids.
Avoidance of irritants and allergens — For patients with a

confirmed diagnosis of irritant or allergic contact eyelid dermatitis, ongoing avoidance of irritants
and allergens is the mainstay of treatment. Petrolatum or other ointment-based emollients that are
free of fragrance and other common allergens may be used. The use of perfume and aerosol hair
sprays should be avoided.
749
Topical corticosteroids — We suggest topical corticosteroids rather than
topical calcineurin inhibitors as the first-line therapy for eyelid dermatitis. As the eyelids exhibit the
highest percutaneous absorption on the body (and in the setting of active dermatitis, where the skin
barrier is broken, the absorption may be even higher), only low-potency topical corticosteroids
(groups 6 and 7 (table 1)) are safe for short-term use on the eyelids. We typically use low- potency
topical corticosteroids twice daily for up to two to four weeks. If needed, treatment with topical
corticosteroids can be repeated after a "steroid holiday" of one to two weeks before application is
resumed.
However, patients requiring continued treatment for more than four weeks should be switched to a
topical calcineurin inhibitor. (See 'Topical calcineurin inhibitors' below.)
In a small comparative study, 20 patients with moderate eyelid eczema and atopic
keratoconjunctivitis were treated for three weeks with tacrolimus 0.1% ointment or clobetasone
butyrate (a mid-potency topical corticosteroid) [21]. Both treatments were equally effective in
reducing eyelid eczema and blepharitis signs and symptoms. No increase in the mean intraocular
pressure (defined as an increase ≥2 mmHg) was noted in either group. However, one patient in the
clobetasone butyrate group and one in the tacrolimus group developed an increase in the intraocular
pressure of 5 mmHg that normalized in both cases after washout.
Prolonged use of topical corticosteroids in the periorbital area may induce a number of adverse
effects (see "Topical corticosteroids: Use and adverse effects"). Even with low-potency topical
corticosteroids, the eyelids remain vulnerable to thinning and atrophy. Long-term use of topical
steroids on the eyelids can also lead to the development of a periorbital dermatitis, a rosacea-like
eruption (picture 4). (See "Perioral (periorificial) dermatitis".)
Ocular complications may rarely occur with inappropriate use of topical corticosteroids in the
periocular area [24]. Glaucoma has been reported from periorbital use of topical corticosteroids in
case reports and small case series [25-29]; however, in those cases, the corticosteroid strength was
higher than what would be typically recommended for use on the eyelids and/or the topical
corticosteroid was used for a prolonged period. In a retrospective review of 88 patients with atopic
dermatitis (AD), 37 patients had used topical corticosteroids (groups 3 and 4) on the eyelids and
periorbital region, with an average frequency of 3.9 days per week and 6.4 months per year for 4.8
years. One patient had transient intraocular hypertension without glaucomatous changes, and two
patients developed corticosteroid-induced cataract [25].
Topical calcineurin inhibitors — Topical calcineurin inhibitors

(tacrolimus and pimecrolimus) can be used as an alternative to topical corticosteroids for the
treatment of eyelid dermatitis in patients who require prolonged treatment (beyond four weeks).
Topical calcineurin inhibitors are applied twice daily for two to four weeks or until improvement is
noted, and then tapered. Treatment can be resumed if flares occur. The use of topical calcineurin
inhibitors can initially be limited by a burning sensation when applied to inflamed skin, which
improves with ongoing use.
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The use of calcineurin inhibitors for eyelid dermatitis is supported by a few observational studies:
●In one study, 20 adult patients with moderate to severe AD of the eyelids and no pre-existing
glaucoma, cataract, or elevated intraocular pressure were treated with tacrolimus 0.1% ointment
twice daily for eight weeks and followed for two additional weeks after the last day of treatment [20].
Of the 16 patients who completed the treatment, 12 patients were clear or showed excellent
improvement based on the physician global assessment score. None of the patients developed
cataract, glaucoma, or increased intraocular pressure during the course of the study.
●In another study, 20 adult patients with long-standing allergic contact eyelid dermatitis were treated
with tacrolimus 0.1% ointment twice daily for 15 days, followed by once-daily application for an
additional 15 days [23]. Patients were then allowed to use topical tacrolimus once daily as needed
for one month. Improvement from baseline was observed for multiple dermatitis parameters
(erythema, edema, scaling, lichenification, itching, and burning). Treatment was well tolerated.
Transient skin burning and itching was the only adverse effect reported by 12 of 20 patients.
●In a small comparative study, 20 patients with moderate eyelid eczema and atopic
keratoconjunctivitis were treated for three weeks with tacrolimus 0.1% ointment or clobetasone
butyrate (a mid-potency topical corticosteroid) [21]. Both treatments were equally effective in
reducing eyelid eczema and blepharitis signs and symptoms.

SUMMARY AND
RECOMMENDATIONS
●Eyelid dermatitis or eczema is a relatively common condition presenting with a scaly, erythematous
eruption of the upper and/or lower eyelids and periorbital area. It is more commonly seen in adults
and teens, predominantly in women. (See 'Introduction' above and 'Epidemiology' above.)
●The cause of eyelid dermatitis is often multifactorial. It may result from contact with irritants or
allergens, or can be a manifestation of an underlying skin disease, such as atopic dermatitis or
seborrheic dermatitis. Allergens most commonly found to cause allergic contact dermatitis (ACD) of
the eyelids include metals (eg, nickel, gold), fragrances and preservatives contained in cosmetics,
and topical agents in prescription eye preparations. (See 'Etiology' above.)
●Eyelid dermatitis generally presents as an erythematous, scaly, pruritic rash on the upper and/or
lower eyelids (picture 2A, 2C-D). It is in most cases bilateral, but may be unilateral and affect the
upper or lower eyelids, or both. Clinical findings may vary according to the etiology. Itching, burning,
751
and pain are common symptoms. Lichenification from chronic rubbing and scratching may be also
seen. (See 'Clinical manifestations' above.)
The diagnosis of eyelid dermatitis is made in most cases clinically, based on the characteristic
appearance of the eruption, associated symptoms, and clinical history. Patch testing may be needed
to identify patients with ACD. (See 'Diagnosis' above.)
●The initial management of eyelid dermatitis involves ongoing avoidance of exposure to irritants and
allergens and the use of topical anti-inflammatory agents. We suggest low-potency topical
corticosteroids (groups 6 and 7 (table 1)) rather than topical calcineurin inhibitors as first-line
therapy for eyelid dermatitis (Grade 2C). Topical corticosteroids are applied twice daily for up to two
to four weeks. For patients requiring prolonged treatment for eyelid dermatitis (beyond four weeks),
we suggest topical calcineurin inhibitors (ie, topical tacrolimus, pimecrolimus) (Grade 2C). Topical
calcineurin inhibitors are applied twice daily until improvement is noted, and then tapered. (See
752
Keratosis pilaris - UpToDate
uptodate.com/contents/keratosis-pilaris/print
INTRODUCTION Keratosis pilaris (KP) is a common disorder of follicular

keratinization characterized by keratotic follicular papules with variable perifollicular erythema.
Lesions involve predominantly the extensor aspects of proximal arms, thighs, and cheeks (picture
1A-C). KP is often seen in association with atopic dermatitis and ichthyosis vulgaris [1].
This topic will review KP. Other follicular keratotic syndromes are discussed separately. (See "Lichen
planopilaris" and "Pityriasis rubra pilaris" and "Darier disease".)
753
EPIDEMIOLOGY Onset of KP typically occurs in children or adolescents
without sex predilection. It is seen in all ethnic groups, with an estimated prevalence of 2 to 12
percent in pediatric populations [2-4].
ETIOLOGY AND PATHOGENESIS The cause

of KP is not fully understood but has been associated with filaggrin mutations [5,6]. It is thought to
be a genetic disorder of keratinization that results in the formation of horny plugs in the hair follicle
orifices. The mode of inheritance has not been determined, although in many cases it fits into an
autosomal dominant pattern with incomplete penetrance. Patients with a generalized form of KP
have been found to have a chromosome 18p deletion [7,8]. There are a few reports of KP induced by
nilotinib, a second-generation tyrosine kinase inhibitor approved for the treatment of imatinib-
resistant chronic myeloid leukemia [9-11].
PATHOLOGY An orthokeratotic keratin plug, which may contain one or more

twisted hairs, fills and dilates the infundibulum of the hair follicle and protrudes above the skin
surface (picture 2). There may be a mild perivascular lymphocytic infiltrate in the upper dermis [12].
CLINICAL MANIFESTATIONS KP typically

manifests during childhood or adolescence but may also occur in infants (picture 3) [13]. It presents
with spiny keratotic papules predominantly involving the extensor aspects of proximal arms and
thighs. The face, trunk, buttocks, and distal extremities may also be affected (picture 1A-D). The
papules may be grouped or scattered, and there is often an associated mild perifollicular erythema.
KP is usually asymptomatic and may be an incidental finding during physical examination. Some
patients report a rough texture and an unsightly appearance of their skin. Since KP is associated
with other skin conditions, such as atopic dermatitis or ichthyosis vulgaris, these conditions may
also be seen on the patient's skin.
Exacerbation during the winter months is common, likely due to xerosis or friction from thick
clothing [14]. Worsening during pregnancy has also been reported (picture 4) [15]. KP usually
improves with age but may persist into adult life [14].
Clinical variants — In some patients, perifollicular erythema may be prominent,

particularly on the cheeks, forehead, and neck (picture 5). This form of KP is called "keratosis pilaris
rubra" [16].
"Erythromelanosis follicularis faciei et colli" is another variant of KP, primarily seen in adolescents
and young adults. It presents with erythema, hyperpigmentation, and follicular papules involving the
temples and cheeks with extension to the preauricular areas and sides of the neck (picture 6)
754
[17,18]. Follicular keratotic papules, similar to simple KP, are often found on the extensor aspects of
the arms.
Associated conditions — KP is commonly seen in patients with ichthyosis

vulgaris and atopic dermatitis [19]. It is also reported in association with type 1 diabetes mellitus [20]
and obesity [21,22]. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and
diagnosis" and "Ichthyosis vulgaris".)
DIAGNOSIS The diagnosis of KP is clinical, based upon the finding of spiny

keratotic papules with variable erythema involving the extensor aspects of proximal arms and thighs
(picture 1A-C). Involvement of the eyebrows, marked inflammation, and atrophic scarring with
alopecia suggest the diagnosis of KP atrophicans.
Biopsy is usually not necessary; if performed, it reveals a dilated follicular infundibulum and an
orthokeratotic keratin plug. (See 'Pathology' above.)

of KP includes:
●Lichen spinulosus – Lichen spinulosus is typically only seen in pediatric patients and is
characterized by small, follicular papules with keratotic spines that coalesce into larger patches
distributed symmetrically on the trunk and extremities (picture 7). Lichen spinulosus typically
spontaneously remits [23].
●Phrynoderma – Phrynoderma is characterized by follicular hyperkeratosis, with papules first

appearing on the extensor surfaces on the extremities, shoulders, and buttocks (picture 8). It is
caused by vitamin A deficiency or general malnutrition [24]. (See "Overview of vitamin A", section on
'Deficiency'.)
●Keratosis pilaris atrophicans – Keratosis pilaris atrophicans is a group of rare genodermatoses

characterized by follicular keratosis, a variable degree of inflammation and secondary scarring,
and/or alopecia [25]. They include keratosis pilaris atrophicans faciei (also called ulerythema
ophryogenes), atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans. The face
and in particular the lateral eyebrows and cheeks are typically involved (picture 9A-C) [26]. (See
"Keratosis pilaris atrophicans".)
Follicular keratosis is also seen in Darier disease (picture 10A-B) and perforating dermatoses
(picture 11) disease. However, their clinical presentation is remarkably different from KP [1]. (See
"Darier disease".)
755
TREATMENT KP may improve with age without treatment; however, it very
commonly waxes and wanes throughout one's lifetime into early and middle adulthood. It is,
however, less commonly seen in older patients. However, patients with widespread KP and/or
intense erythema who have cosmetic concerns may request treatment to reduce skin roughness and
erythema. Improvement is usually temporary; responsive patients should be educated to maintain
therapy to achieve continued remission.
All patients with KP may benefit from skin care measures aimed at preventing excessive skin
dryness, including using mild soaps or soap-free cleansers and avoiding hot baths or showers [27].
Emollients and topical keratolytics are the first-line therapy for KP. Preparations containing lactic
acid, salicylic acid, or topical urea are helpful in softening and flattening the keratotic papules, but do
not reduce or relieve the associated erythema [28]. In a series of 30 patients with widespread KP, a
preparation of salicylic acid 2% in topical urea cream 20% applied to the involved skin for several
weeks was effective in improving the skin texture and appearance [29].
Topical retinoids (eg, tretinoin 0.05% cream, adapalene 0.1% cream, or tazarotene 0.05% cream) may
be used as a second-line therapy for patients who fail to respond to emollients and keratolytics.
Topical retinoids are applied once a day for 8 to 12 weeks. In a small, randomized trial, tazarotene
0.05% cream was more effective than placebo in reducing itching, roughness, and redness in
patients with more than 20 hyperkeratotic papules on the posterior upper arms [30]. In a small, open
study, tazarotene 0.01% emulsion reduced or resolved KP lesions in four to eight weeks [31].
Short courses of low- to medium-potency topical corticosteroids (groups 4 to 6 (table 1)) may be
used in conjunction with other topical agents if there is prominent inflammation [29]. Topical
corticosteroids are applied to the involved areas once or twice daily for one to two weeks.
Third-line therapies include systemic retinoids, laser therapy, or other ablative procedures.
Combination treatments with lasers (eg, pulsed-dye laser, long-pulsed 755-nm alexandrite laser, 810-
nm long-pulsed diode laser, long-pulsed 1064-nm Nd:YAG laser) and microdermabrasion have been
tried in a few patients with temporary reduction of perifollicular erythema and skin roughness [32-
35]. (See "Light-based, adjunctive, and other therapies for acne vulgaris", section on
'Microdermabrasion'.)
Treatment is not well defined for erythromelanosis follicularis faciei et colli, with anecdotal reports of
similar treatments as for KP.
SUMMARY AND
RECOMMENDATIONS
756
●Keratosis pilaris (KP) is a common disorder of follicular keratinization characterized by keratotic
follicular papules and variable perifollicular erythema. It is often seen in association with atopic
dermatitis and ichthyosis vulgaris. (See 'Introduction' above and "Atopic dermatitis (eczema):
Pathogenesis, clinical manifestations, and diagnosis" and "Ichthyosis vulgaris".)
●KP typically appears during childhood or adolescence with spiny keratotic papules predominantly
involving the extensor aspects of proximal arms and thighs (picture 1A-C). The face, trunk, buttocks,
and distal extremities may also be affected. (See 'Clinical manifestations' above.)
●The diagnosis of KP is clinical, based upon the finding of spiny keratotic papules with variable
erythema involving the extensor aspects of proximal arms and thighs (picture 1A-C). Involvement of
the eyebrows, marked inflammation, and atrophic scarring with alopecia suggest the diagnosis of
KP atrophicans (picture 9A-C). (See 'Diagnosis' above and "Keratosis pilaris atrophicans".)
●KP typically improves with age without treatment. However, for patients with widespread KP and/or
intense erythema who have cosmetic concerns, treatment can provide partial, temporary
symptomatic relief. The initial treatment of KP includes general skin care measures, emollients, and
topical keratolytics. For patients who fail to respond to initial therapy, topical retinoids may be a
treatment option. (See 'Treatment' above.)

to acknowledge Jennifer Perryman, MD, who contributed to an earlier version of this topic review.
757
Keratosis pilaris atrophicans - UpToDate
uptodate.com/contents/keratosis-pilaris-atrophicans/print
INTRODUCTION Keratosis pilaris atrophicans is a group of related

disorders characterized by inflammatory keratotic papules that may result in alopecia and scarring.
They include keratosis pilaris atrophicans faciei (also called ulerythema ophryogenes),
atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans [1].
This topic will review the clinical presentation and management of keratosis pilaris atrophicans.
Keratosis pilaris is discussed separately. (See "Keratosis pilaris".)
PATHOGENESIS Keratosis pilaris atrophicans is caused by abnormal

keratinization of the follicular infundibulum, resulting in obstruction of the growing hair shaft and
inflammation. Chronic inflammation leads to fibrosis, atrophy, shrinkage of the hair bulb, and
758
alopecia. The association with several congenital syndromes due to partial monosomy or deletion in
chromosome arm 18p suggests that the genes regulating the follicular keratinization may be located
on chromosome 18p. (See 'Associated syndromes' below.)
Autosomal recessive keratosis pilaris atrophicans has been shown to be due to a mutation in the
desmoglein 4 gene [2].
PATHOLOGY The histopathologic features of keratosis pilaris atrophicans are

nonspecific. In the early stages, there is an orthokeratotic keratin plug that blocks and dilates the
orifice and upper portion of the follicular infundibulum (picture 1) [3]. A twisted hair shaft may be
trapped within this keratotic material, and a mild perivascular mononuclear cell infiltrate is usually
present in the adjacent dermis. In later stages, dermal fibrosis and loss of hair follicles may be seen.
CLINICAL VARIANTS There are three clinical variants of

keratosis pilaris atrophicans: ulerythema ophryogenes (also called keratosis pilaris atrophicans
faciei), atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans (KFSD) [4].
Clinical features common to all forms include involvement of the face, in particular of the lateral
eyebrows and cheeks; prominent erythema; and progression to an atrophic stage with loss of hairs
in the involved areas [5].
Ulerythema ophryogenes — Ulerythema ophryogenes (the prefix

"ophryo-" refers to the eyebrow), also called "keratosis pilaris atrophicans faciei," primarily involves
the eyebrow areas, resulting in atrophy and permanent loss of the involved hairs [5,6]. It usually
occurs as a sporadic disease, but an autosomal dominant pattern of inheritance has been also
reported [1].
Ulerythema ophryogenes typically begins in the first months of life, with erythema and tiny keratotic
follicular papules involving the lateral one-third of the eyebrows (picture 2B). Over time, atrophy and
loss of the eyebrows occur. The disorder may extend to the temples, cheeks, and forehead, resulting
in a persistent facial erythema (picture 2A). The affected areas may feel rough on gentle palpation.
The condition typically improves after puberty, but the loss of the lateral eyebrows and resultant
scarring is often permanent. Simple keratosis pilaris is often present on the extensor aspects of the
limbs. (See "Keratosis pilaris".)
Associated syndromes — Ulerythema ophryogenes is considered a marker of

several congenital syndromes, such as Noonan syndrome, Rubinstein-Taybi syndrome, Cornelia de
Lange syndrome, cardiofaciocutaneous syndrome, and chromosome 18p deletion [7-12]. (See
"Noonan syndrome" and "Microdeletion syndromes (chromosomes 12 to 22)", section on '16p13.3
deletion syndrome (Rubinstein-Taybi syndrome)' and "Microdeletion syndromes (chromosomes 12
to 22)", section on '18p deletion syndrome'.)
759
An association has also been reported with woolly hair (MIM #194300), a group of autosomal
dominant hair shaft disorders characterized by fine and tightly curly hair [13].
Atrophoderma vermiculatum — Atrophoderma vermiculatum is a

rare form of keratosis pilaris atrophicans, characterized by hyperkeratotic follicular papules with
surrounding erythema on the cheeks, which evolve into coalescent follicular depressions in a
honeycomb or worm-eaten pattern (picture 3) [14]. It usually begins during childhood and
progresses until puberty. The cheeks and preauricular regions are predominantly involved, with
sparing of the eyebrows, eyelashes, and scalp.
Atrophoderma vermiculatum is a feature of Rombo syndrome, a genetic syndrome characterized by

facial follicular atrophy, multiple milia, hypotrichosis, peripheral vasodilation with cyanosis,
trichoepitheliomas, and predisposition to develop basal cell carcinomas [15,16]. Atrophoderma
vermiculatum has also been associated with Loeys-Dietz syndrome, a rare autosomal aortic
aneurysm syndrome with multiple skeletal abnormalities and dysmorphic facial features, caused by
mutations in the transforming growth factor-beta receptor gene (TGFBR) [17].
Keratosis follicularis spinulosa

decalvans — Keratosis follicularis spinulosa decalvans (KFSD, MIM #308800) is an
exceedingly rare variant of keratosis pilaris atrophicans characterized by follicular keratosis and
progressive cicatricial alopecia involving the scalp, eyebrows, and eyelashes (picture 4A-B) [4]. KFSD
affects predominantly males, suggesting an X-linked mode of inheritance [18]. Mutations in the
membrane-bound transcription factor protease site 2 (MBTPS2) gene on Xp22.12-p22.11 have
been found in patients from several families with KFSD [19-21]. However, autosomal dominant forms
have also been reported [18,22].
KFSD presents with facial erythema and extensive keratosis pilaris of the face, scalp, extremities,
and trunk during early childhood (picture 4B). Cicatricial alopecia of the scalp and eyebrows begins
around puberty and slowly progresses with follicular inflammation and fibrosis.
Associated features include palmoplantar keratoderma, photophobia, blepharitis, and corneal

dystrophy. Acne keloidalis nuchae and tufted hair folliculitis have been described in several patients
with KFSD [23-25]. (See "Evaluation and diagnosis of hair loss", section on 'Cicatricial alopecia'.)
KFSD shares many clinical features with ichthyosis follicularis, congenital atrichia, and
photophobia (IFAP) syndrome (MIM #308205), an X-linked condition caused by mutations in the
MBTPS2 gene, in which affected neonates show widespread keratotic follicular papules with a
sandpapery feel to the skin, atrichia or severe hypotrichosis, and photophobia [4,26].
DIAGNOSIS The diagnosis of keratosis pilaris atrophicans is clinical. A skin

biopsy is usually not necessary for the diagnosis. If performed, it shows nonspecific features
including keratotic plugs in the pilosebaceous units and a mild perifollicular inflammatory infiltrate
760
[6]. (See 'Pathogenesis' above.)
The differential diagnosis of keratosis pilaris atrophicans includes:
●Keratosis pilaris rubra faciei, a clinical variant of the common keratosis pilaris characterized by
marked perifollicular erythema on the cheeks, forehead, and neck (picture 5). (See "Keratosis pilaris",
section on 'Clinical variants'.)
●Erythromelanosis follicularis faciei et colli, another variant of keratosis pilaris presenting with
erythema, hyperpigmentation, and follicular papules involving the cheeks, preauricular areas, and
sides of the neck (picture 6). (See "Keratosis pilaris", section on 'Clinical variants'.)
TREATMENT There are no effective therapies for keratosis pilaris atrophicans.

The condition often improves with age. Ultraviolet (UV) protection is encouraged, since the condition
is often photoexacerbated [6]. Topical corticosteroids, keratolytics, and topical retinoids are of
limited benefit [27]. There are isolated reports of successful use of systemic retinoids for
atrophoderma vermiculatum and keratosis follicularis spinulosa decalvans [28,29].
Pulsed dye laser and intense pulsed light have been reported as effective in reducing erythema in
small series of patients [30,31]. Hair transplant surgery has been reported for dormant keratosis
pilaris atrophicans [32].
SUMMARY AND
RECOMMENDATIONS
●Keratosis pilaris atrophicans is a group of rare conditions characterized by follicular keratosis,
chronic inflammation, and secondary scarring and alopecia. (See 'Introduction' above.)
●Keratosis pilaris atrophicans comprises three distinct entities: ulerythema ophryogenes (picture
2A-B) (also called keratosis pilaris atrophicans faciei), atrophoderma vermiculatum (picture 3), and
keratosis follicularis spinulosa decalvans (picture 4A-B). Clinical features common to all forms
include involvement of the face, in particular of the lateral eyebrows and cheeks; prominent
erythema; and progression to an atrophic stage with loss of hairs in the involved areas. (See 'Clinical
variants' above.)
●Keratosis pilaris atrophicans often improves with age, but the loss of eyebrows and scarring are
typically permanent. Ultraviolet (UV) protection is encouraged. Topical treatments may include
corticosteroids, keratolytics, and topical or systemic retinoids. Surgical interventions, including laser
treatment and hair transplantation, have also been described. (See 'Treatment' above.)
761
to acknowledge Jennifer Perryman, MD, who contributed to an earlier version of this topic review.
762
Cheilitis - UpToDate
uptodate.com/contents/cheilitis/print
INTRODUCTION Cheilitis is an acute or chronic inflammation of the lips.

It usually involves the lip vermilion and the vermilion border, but the surrounding skin and the oral
mucosa may also be affected [1]. Common symptoms include erythema, dryness, scaling, fissuring,
edema, itching, and burning.
Cheilitis may be caused by a multiplicity of endogenous or exogenous factors, the most common of
which are atopic dermatitis, contact irritants or allergens, chronic sun exposure, and infection [2].
Secondary involvement of the lips can occur in many cutaneous and systemic disorders, such as
lichen planus, lupus erythematosus, autoimmune bullous diseases, Crohn disease, sarcoidosis, and
nutritional deficiencies.
This topic will review the clinical manifestation, diagnosis, and treatment of primary lip diseases. An
overview of oral lesions in adults and children and the oral manifestations of cutaneous and
systemic diseases are discussed separately.
●(See "Oral lesions".)
●(See "Soft tissue lesions of the oral cavity in children".)
763
●(See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".)
●(See "Overview of cutaneous lupus erythematosus", section on 'Mucosal manifestations'.)
●(See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
●(See "Clinical manifestations, diagnosis, and prognosis of Crohn’s disease in adults".)
●(See "Cutaneous manifestations of sarcoidosis".)
ECZEMATOUS CHEILITIS Eczematous cheilitis is the

most common type of lip disease. It presents with dryness, scaling, erythema, and fissuring of the
lips. The inflammation may extend to the perioral skin or, less frequently, to the oral mucosa. Pruritus
and burning are frequent symptoms.
Eczematous cheilitis may be due to endogenous factors (eg, atopic dermatitis) or may be caused by
exogenous factors, such as contact irritants or allergens [3]. Multiple contributing factors may
coexist in some patients.
Irritant contact cheilitis — Irritant contact cheilitis is the most common

inflammatory lip disorder, typically affects the upper and lower lip, and can extend onto the
cutaneous lip [1,4,5]. Chronic lip licking is a major cause, particularly in young children (picture 1D).
Other causes include environmental factors (eg, cold, low humidity, wind, occupational exposure to
irritants), irritants in lip cosmetics or oral hygiene products, or foods.
Allergic contact cheilitis — Allergic contact cheilitis is a delayed-type

hypersensitivity reaction to allergens that come in contact with the lips. Women are more commonly
affected than men, likely due to a heavier exposure to allergens from lipsticks, lip balms, sunscreens,
makeup products, or nail polish [3-10]. Other causes of allergic contact cheilitis include oral hygiene
products, such as toothpastes and mouthwash, and certain foods, such as mango, citrus fruit, and
cinnamon [3-5,8,9].
Although fragrances, Myroxylon pereirae, and nickel are the most frequent cosmetic sensitizers
identified by patch testing in patients with lip dermatitis, many other ingredients that are unique to
lipsticks can also cause allergic cheilitis [11]. Examples are ricinoleic acid, also known as castor oil,
found in most lipsticks for its ability to dissolve pigments; resins (eg, colophony, shellac); drug and
cosmetic dyes; preservatives; ozonated olive oil; propolis (a bee product found in many lip-care
products); and copolymers [4,12-15]. (See "Common allergens in allergic contact dermatitis".)
Patients typically present with an erythematous, scaly eruption that involves both lips and often
extends beyond the vermilion border to involve the perioral skin (picture 1A) [4]. Edema, fissuring,
vesiculation, and superficial ulceration can also be seen (picture 1B).
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Symptoms include pruritus, burning, and tenderness. Depending upon the allergen source and
exposure patterns, eczematous lesions may also be present in other body areas, providing a clue to
the diagnosis.
Atopic cheilitis — Cheilitis is common in patients with atopic dermatitis or a history

of atopic disease. The clinical manifestations include erythema, dryness, scaling, and fissuring
(picture 1C). The clinical appearance may be indistinguishable from irritant or allergic cheilitis.
Diagnosis — The evaluation of the patient presenting with eczematous cheilitis involves
the following:
●A general skin examination that includes the oral mucosa for signs of atopic dermatitis or other
skin diseases that may involve the lips.
●Assessment of personal or family history of atopic disease (atopic dermatitis, allergic rhinitis,
asthma).
●A detailed history that reviews the exposure to irritants or allergens (eg, cosmetics, sunscreens,
foods, hobbies, instruments, dental hygiene products).
●Patch testing.
●Biopsy should be considered when standard treatments are not effective or in patients with
persistent, painful, bleeding, hyperkeratotic, or eroded findings.
Patch testing is an essential investigation in patients with suspected allergic contact cheilitis.
Testing should include standard series of allergens, as well as extended series for cosmetics and
possibly the patient's personal products. (See "Patch testing", section on 'Selection of allergens'.)
The diagnosis of allergic contact cheilitis is based upon a relevant patch test reaction (see "Patch
testing", section on 'Determining the clinical relevance'). Relevant patch test reactions are detected
in 30 to 65 percent of patients tested with standard and supplementary series of allergens [4,5,10].
Patients with negative patch tests are diagnosed with irritant contact cheilitis or atopic cheilitis.
However, since multiple factors can be responsible for lip inflammation, the differentiation between
the various types of eczematous cheilitis may be difficult in many cases. In a series of 75 patients
with lip dermatitis, 49 patients had a sole diagnosis of allergic contact cheilitis and 26 had at least
one additional diagnosis, with irritant contact cheilitis being the second most common diagnosis [4].
Treatment — Removal of the causative irritant or allergen from the patient's environment
is the mainstay of treatment of irritant or allergic contact cheilitis. Patients should be advised to
avoid lip balms containing flavors, preservatives, propolis, lanolin, and other potential allergens. (See
"Management of allergic contact dermatitis", section on 'Avoidance'.)
765
Topical corticosteroids are helpful in reducing inflammation and pruritus. Low- to medium-potency
corticosteroids (groups 4 to 6 (table 1)) can be applied twice a day for one to two weeks. Simple
emollients, such as petrolatum, can be liberally used in combination with topical corticosteroids.
Prolonged use of topical corticosteroids, however, may cause atrophy, which can exacerbate irritant
cheilitis. Off-label use of topical calcineurin inhibitors (pimecrolimus or tacrolimus) may be used as
an alternative to topical corticosteroids for long-term use.
ORAL RETINOID-ASSOCIATED
CHEILITIS Systemic retinoids, such as etretinate and isotretinoin, cause dryness,
scaling, erythema, and fissuring of the lips in nearly all patients [16,17]. The mouth commissures can
also be involved. The severity of cheilitis is dose dependent. Any other medication that produces dry
mouth can result in drying of the lips as well. Treatment is symptomatic and consists of bland lip
moisturizers and emollients. Complete remission occurs shortly after drug discontinuation.
ACTINIC CHEILITIS Actinic or solar cheilitis is a premalignant

disorder of the lip caused by chronic sun exposure [1,18-20]. It is most common in geographic areas
with a hot, dry climate, in outdoor workers, and in light-skinned individuals [1,20-24]. The clinical
features, diagnosis, and management of actinic cheilitis are discussed separately. (See "Actinic
cheilitis".)
ANGULAR CHEILITIS Angular cheilitis, also known as perlèche,

is an acute or chronic inflammation of the skin and contiguous labial mucosa located at the lateral
commissures of the mouth. It typically presents with erythema, maceration, scaling, and fissuring at
the corners of the mouth (picture 2A-B). Lesions are most often bilateral and may be painful.
Angular cheilitis is caused by excessive moisture and maceration from saliva and secondary
infection with Candida albicans or, less commonly, Staphylococcus aureus [25-27]. Angular cheilitis
may occur at any age without sex predilection but is especially common in older individuals wearing
dentures. Predisposing local factors include wearing orthodontic appliances or ill-fitting dentures,
sicca symptoms (dry mouth), intraoral fungal infection, poor oral hygiene, and age-related anatomic
changes of the mouth due to reduced vertical facial dimensions [25,28-30].
In older individuals, the loss of vertical dimension of the mouth due to recession of the alveolar
ridges or edentulous state leads to drooping of the corners of the mouth, drooling, and retention of
saliva in the creases [1,25,29]. Drooling, thumb sucking, and lip licking are frequent causes of
angular cheilitis in young children [25,28-30].
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Less common causes in both adults and children include nutritional deficiencies, such as B9 (folic
acid), zinc, B6 (pyridoxine), B2 (riboflavin), or B3 (niacin) deficiency. Other causes include type 2
diabetes, Sjögren syndrome, immunodeficiency, irritant or allergic reactions to oral hygiene products
or denture materials, and medications causing dryness and xerostomia (eg, isotretinoin, acitretin)
[16,26,31,32].
Diagnosis — The diagnosis of angular cheilitis is usually straightforward. A potassium

hydroxide (KOH) preparation from lesions and oral mucosa may be needed to confirm or rule out
Candida infection. In patients with recalcitrant cheilitis, a lesion swab for bacterial and fungal culture
should be obtained.
Treatment — The management of angular cheilitis involves the control of local

predisposing factors and treatment of fungal or bacterial superinfection. General measures to
reduce moisture pooling at the corners of the mouth include:
●Improving denture fit and cleaning
●Maintaining optimal oral hygiene
●Treating sicca symptoms (dry mouth) (see "Treatment of dry mouth and other non-ocular sicca
symptoms in Sjögren's syndrome", section on 'Treatment of dry mouth')
●Use of barrier creams (eg, zinc oxide paste) or petrolatum
For patients with positive KOH preparation, we suggest topical antifungal therapy with azole (eg,
miconazole, clotrimazole) ointment. The topical antifungal is applied two times per day for one to
three weeks and repeated as necessary. For patients with associated Candida stomatitis,
clotrimazole troches (one 10 mg troche dissolved slowly five times daily for two weeks) or oral
fluconazole (100 mg per day for one to two weeks) may be beneficial. (See "Treatment of
oropharyngeal and esophageal candidiasis".)
Staphylococcal infection can be treated with topical mupirocin ointment. Topical mupirocin is
applied two times a day for 7 to 14 days.
Once cleared, a barrier cream or petrolatum applied nightly can help protect the skin from moisture.
However, recurrence of angular cheilitis is common [33].
EXFOLIATIVE CHEILITIS Exfoliative cheilitis is an

uncommon, chronic, superficial, inflammatory disorder of the lips characterized by hyperkeratosis,
desquamation, and crusting of the lips [34]. Some patients describe this condition as chronic
chapped lips. The etiology is unknown, although cases due to repeated licking or biting of the lips
have been reported.
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Exfoliative cheilitis is an exclusion diagnosis after other types of cheilitis with similar clinical
appearance, such as eczematous or actinic cheilitis, have been ruled out. Treatment is difficult.
There are isolated reports of successful treatment with topical corticosteroids or topical tacrolimus
in combination with lip moisturizers [34,35]. Antidepressants have been reported as beneficial in a
few cases associated with a habit tic [36,37]. A case report has shown that excimer laser therapy
and narrowband ultraviolet B (NBUVB) phototherapy were effective in two patients with recalcitrant
disease [38].
PLASMA CELL CHEILITIS Plasma cell cheilitis is a rare,

benign, inflammatory condition presenting with a well-defined, indurated, or eroded erythematous
plaque most often located on the lower lip [1,39-42]. It shares clinical and histopathologic features
with Zoon balanitis and similar lesions affecting other mucosal sites, such as the vulva (Zoon
vulvitis), gingiva, oral mucosa, and upper respiratory tract [41,43-45]. (See "Vulvar lesions:
Differential diagnosis based on morphology" and "Balanitis in adults".)
Diagnosis and differential diagnosis — The diagnosis of

plasma cell cheilitis is based upon the examination of a lip biopsy. Histology shows in the upper
dermis a dense, band-like lichenoid infiltrate predominantly composed of mature plasma cells
(picture 3) [41,42,46]. Associated findings include capillary dilation, erythrocyte extravasation,
hemosiderin deposits, and mild epidermal spongiosis.
The differential diagnosis includes [39-41] (see 'Actinic cheilitis' above and 'Allergic contact cheilitis'
above and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Cutaneous
squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Cutaneous squamous
cell carcinoma of the lip'):
●Allergic contact cheilitis (picture 1A-B)
●Actinic cheilitis (picture 4A-C)
●Lichen planus (picture 5)
●Squamous cell carcinoma (picture 6)
●Syphilis (picture 7)
Treatment — Treatment of plasma cell cheilitis is difficult. Potent topical corticosteroids

and intralesional corticosteroids have been used in a few patients with variable results [42,47,48].
Other treatments that have been reported as beneficial in individual patients include topical
calcineurin inhibitors [40,41], topical cyclosporine [49], oral griseofulvin [46], topical antibiotics [50],
and excimer laser therapy [51].
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CHEILITIS GLANDULARIS Cheilitis glandularis is a rare,
chronic, inflammatory disease involving the minor salivary glands of the lower lip [52-54]. It is
usually seen in older males, but young individuals and women also may be affected. The cause is
unknown, but several factors appear to play a role, including chronic sun exposure, factitial cheilitis,
atopy, infection, and tobacco use [1,53,55].
Cheilitis glandularis typically presents with enlargement and eversion of the lower lip, which shows
numerous pin-sized orifices from which mucous saliva can be easily squeezed. Patients describe
tenderness and bumpiness of the lip as well as the presence of a sticky substance that dries on the
lips.
In the more severe suppurative form, the dilated ostia of the minor salivary glands on the vermilion
area exude a mucopurulent fluid; superficial ulceration and crusting may also be present [56].
Secondary infection can lead to ulceration, abscess, and drainage [53]. Squamous cell carcinoma
arising in the context of cheilitis glandularis has been reported in a few patients [52,53,56,57].
Diagnosis — The diagnosis of cheilitis glandularis is made clinically, based upon the
clinical finding of a swollen lip with dilated salivary gland ostia exuding a mucous substance.
Papules and nodules can be felt upon palpation.
The histopathology is nonspecific and may reveal salivary gland hyperplasia, duct ectasia, and a
dermal inflammatory infiltrate composed of lymphocytes, plasma cells, and histiocytes [57].
However, a biopsy may be helpful in ruling out other types of cheilitis and squamous cell carcinoma.
Treatment — Numerous therapies have been used for cheilitis glandularis, including
systemic antibiotics and topical, intralesional, or systemic corticosteroids, and surgical excision of
the vermilion [1,52-55,58,59]. However, evidence of efficacy is limited to individual case reports and
small case series.
For patients with mild disease, topical corticosteroids and sunscreen products may be helpful [60].
Vermilionectomy with dissection of the enlarged minor salivary glands may be required for patients
with severe disease [1,52-55,58,60].
CHEILITIS GRANULOMATOSA Cheilitis

granulomatosa, also known as Miescher's cheilitis, is a persistent, idiopathic, nontender swelling of
one or both lips [61]. It is considered a manifestation of orofacial granulomatosis (OFG), a non-
necrotizing granulomatous inflammatory disorder characterized by persistent or recurrent soft
tissue enlargement, oral ulceration, and a variety of orofacial features, in the absence of systemic
granulomatous disorders such as Crohn disease or sarcoidosis [62-65].
769
Cheilitis granulomatosa is rare. It primarily affects young adults but can occur at any age, without
sex predilection [62,66]. The etiology is unknown. Many factors, including allergy to foods, genetic
predisposition, infection, and atopy, have been implicated [62,67].
Clinical manifestations — The first manifestation of disease is often an

intermittent swelling of the upper lip that mimics angioedema [68]. The initial episodes typically
resolve in hours to days. As the disease progresses, the episodes increase in duration and lead to
persistent swelling that may involve both lips, resulting in functional disability and cosmetic
disfigurement (picture 8A-C).
Cheilitis granulomatosa is in most cases an isolated finding. When associated with recurrent facial
palsy and/or lingua plicata (fissured tongue), it is referred to as Melkersson-Rosenthal syndrome
(picture 9) [65,69]. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults" and
"Salivary gland swelling: Evaluation and diagnostic approach", section on 'Processes that may mimic
salivary gland enlargement'.)
Diagnosis and differential diagnosis — The examination

of a lip biopsy is necessary for the diagnosis. However, granulomatous inflammation is not
invariably present, especially in the early stages of the disease, and histology may only show edema,
a perivascular infiltrate of lymphocytes and plasma cells, and lymphangiectasia [70]. Granulomas, if
present, are noncaseating, small, and scattered; contain Langerhans giant cells (picture 10); and are
indistinguishable from those seen in sarcoidosis or orofacial manifestations of Crohn disease.
The diagnosis of cheilitis granulomatosa is thus frequently one of exclusion. Other diseases with
oral or facial involvement that must be ruled out include:
●Angioedema – In the early stage of disease characterized by intermittent lip swelling, cheilitis
granulomatosa should be differentiated from angioedema. A history of atopy or current therapy with
an angiotensin-converting enzyme (ACE) inhibitor or calcium channel blocker should alert the
practitioner to the possibility of angioedema. (See "An overview of angioedema: Clinical features,
diagnosis, and management".)
●Crohn disease – Oral localizations of Crohn disease, including labial, intraoral, or gingival swelling
(picture 11), cobblestoning of the oral mucosa, oral ulcers, and tag-like mucosal lesions, are
uncommon. In exceedingly rare cases, they can be the initial manifestation of the disease [71,72].
(See "Clinical manifestations, diagnosis, and prognosis of Crohn’s disease in adults" and "Clinical
presentation and diagnosis of inflammatory bowel disease in children".)
●Sarcoidosis – Sarcoidosis involving the lips (picture 12) may be clinically and histologically
indistinguishable from cheilitis granulomatosa. However, in sarcoidosis, ACE levels are often
elevated, and bilateral hilar lymphadenopathy may be present. (See "Clinical manifestations and
diagnosis of pulmonary sarcoidosis".)
770
●Foreign body reaction – A foreign body reaction to injectable dermal fillers should also be
considered in the differential diagnosis of cheilitis granulomatosa. The foreign material can be
identified on histologic examination, based upon the unique host response induced by each material
[73]. (See "Injectable soft tissue fillers: Overview of clinical use".)
●Infection – In rare cases, tuberculosis or histoplasmosis may present with orofacial localization
[74-76]. Cutaneous leishmaniasis and leprosy have also been reported to mimic granulomatous
cheilitis [77]. (See "Cutaneous manifestations of tuberculosis", section on 'Tuberculosis cutis
orificialis' and "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients"
and "Pathogenesis and clinical manifestations of disseminated histoplasmosis".)
Treatment — Treatment of cheilitis granulomatosa is difficult, with complete remission

uncommon [78]. Multiple therapies, alone or in combination, have been reported as successful in
individual patients. Examples include topical, intralesional, and systemic corticosteroids [79-83];
antibiotics, such as minocycline [84], roxithromycin [85], and metronidazole [86]; clofazimine [87];
dapsone [88]; thalidomide [89]; anti-tumor necrosis factor (TNF) agents [90-92]; methotrexate [93];
and surgery [94].
Topical or intralesional corticosteroids are used in most cases as first-line therapy [63]. Intralesional
corticosteroids have been reported as effective in reducing lip swelling in several case reports and
case series [79-83]. In a retrospective study of 22 patients with orofacial granulomatosis,
intralesional injections of triamcinolone acetonide 40 mg/mL once a week for three consecutive
weeks was effective in reducing lip swelling at up to 48 months after treatment [82].
Patients with persistent and disfiguring lip swelling that is unresponsive to conservative treatment
may benefit from reduction cheiloplasty, consisting of surgical excision of excess tissue [94].
LEISHMANIAL CHEILITIS Primary mucocutaneous

leishmaniasis may uncommonly present as cheilitis [95,96]. The initial presentation may be an
erythematosus papule that gradually enlarges and then ulcerates or a persistent lip enlargement
(macrocheilia). The diagnosis is often delayed and requires a high index of suspicion, as lesions can
mimic a variety of infectious and noninfectious diseases, including herpes labialis, primary syphilis,
cheilitis granulomatosa, basal cell carcinoma, and squamous cell carcinoma. Skin scraping or
biopsy stained with Giemsa, culture, and polymerase chain reaction are used for diagnosis. (See
"Cutaneous leishmaniasis: Clinical manifestations and diagnosis", section on 'Mucosal
leishmaniasis'.)
SUMMARY AND
RECOMMENDATIONS
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●Cheilitis is an acute or chronic inflammation of the lips. It may be caused by a multiplicity of
exogenous or endogenous factors, the most common of which are contact irritants or allergens,
chronic sun exposure, infection, or atopic disease. (See 'Introduction' above.)
●Eczematous cheilitis is the most common type of lip disease. It may be due to endogenous factors
(eg, atopic dermatitis) or may be caused by exogenous factors, such as contact irritants or allergens.
Symptoms include dryness, scaling, erythema, and fissuring that may involve also the perioral skin
(picture 1A, 1C-D). Treatment involves removal of irritants or allergens, mild to mid-potency topical
corticosteroids, and lip emollients. (See 'Eczematous cheilitis' above.)
●Actinic or solar cheilitis is a premalignant keratosis of the lip caused by chronic sun exposure. It
presents as a persistent area of dryness and scaling on the lower lip that progresses to atrophy,
edema, erythema, ulceration, and crusting in more advanced lesions (picture 4A-C). Actinic cheilitis
is discussed separately. (See "Actinic cheilitis".)
●Angular cheilitis, also known as perlèche, is an acute or chronic inflammation of the skin and
contiguous labial mucosa located at the lateral commissures of the mouth caused by excessive
moisture and maceration from saliva and secondary infection with Candida albicans or, less
commonly, Staphylococcus aureus (picture 2A-B). Predisposing factors include loss of vertical
dimension of the mouth, wearing ill-fitting dentures, sicca syndrome, and poor oral hygiene.
Treatment involves removal of predisposing factors, topical antifungals or antibiotics, and use of
barrier creams. (See 'Angular cheilitis' above.)
●Plasma cell cheilitis is a rare, benign, inflammatory condition characterized by dense plasma cell
infiltrates in the lips. It shares clinical and histopathologic features with similar conditions affecting
other mucosal sites, such as Zoon balanitis and vulvitis. It presents with a well-defined, indurated, or
eroded erythematous plaque most often located on the lower lip. Treatment is difficult. Topical or
intralesional corticosteroids may be of some benefit. (See 'Plasma cell cheilitis' above.)
●Cheilitis glandularis is a rare, chronic, inflammatory disease involving the minor salivary glands of
the lower lip. It typically presents with enlargement and eversion of the lower lip, which shows
numerous pin-sized orifices exuding a viscous or mucopurulent fluid. Topical corticosteroids and
sunscreen products may be beneficial in patients with mild disease. Vermilionectomy with
dissection of the enlarged minor salivary glands may be required in severe cases. (See 'Cheilitis
glandularis' above.)
●Cheilitis granulomatosa, also known as Miescher's cheilitis, is characterized by a persistent,

nontender swelling of the lips (picture 8A-C). It is in most cases an isolated finding; when associated
with facial palsy and/or plicated tongue, it is referred to as Melkersson-Rosenthal syndrome (picture
9). Cheilitis granulomatosa must be differentiated from oral or facial localizations of other
granulomatous diseases, including Crohn disease and sarcoidosis. Treatment is difficult. Topical or
intralesional corticosteroids may be beneficial in reducing lip swelling. (See 'Cheilitis granulomatosa'
above.)
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Acute palmoplantar eczema (dyshidrotic eczema)
uptodate.com/contents/acute-palmoplantar-eczema-dyshidrotic-eczema/print
INTRODUCTION Acute palmoplantar eczema (more popularly known as

dyshidrotic eczema or pompholyx) is an intensely pruritic, vesicular eruption affecting the palms,
soles, or both [1,2]. It is characterized by deep-seated lesions ranging from small vesicles to large
tense bullae clinically and by spongiotic vesicles histologically. Recurrence is common and patients
typically experience frequent episodes for months or years.
This topic will discuss the pathogenesis, clinical presentation, diagnosis, and management of
dyshidrotic eczema. Other forms of eczema involving the hands, including irritant and allergic
contact dermatitis and atopic dermatitis, are discussed separately. (See "Irritant contact dermatitis
in adults" and "Clinical features and diagnosis of allergic contact dermatitis" and "Management of
allergic contact dermatitis" and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations,
and diagnosis" and "Treatment of atopic dermatitis (eczema)".)
TERMINOLOGY The terminology for acute palmoplantar eczema is

confusing. The term "dyshidrosis" was coined in 1873 to describe a blistering disease of the palms
and soles that was believed to be a disorder of the sweat glands [3]. It is now accepted that the
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sweat glands are not involved in the pathogenesis [4,5]. However, the term "dyshidrotic eczema"
continues to be used.
Other terms for acute palmoplantar eczema include pompholyx, dyshidrosis, vesicular palmoplantar
eczema, acute and recurrent vesicular hand dermatitis, cheiropompholyx (affecting the hands), or
podopompholyx (affecting the feet). These terms do not represent a specific diagnosis, but rather a
morphologic pattern of hand/foot eczema that can occur with irritant contact, allergic contact, or
endogenous eczema.
EPIDEMIOLOGY The prevalence of dyshidrotic eczema, including mild

and severe forms of dyshidrotic eczema, in the general population is unknown. Among patients with
hand dermatitis, dyshidrotic eczema accounts for 5 to 20 percent of cases [6-8]. It occurs most
commonly in young adults and equally among males and females. Risk factors for dyshidrotic
eczema include history of atopic dermatitis and exposure to contact allergens or irritants [9-11]. A
rare autosomal dominant form of dyshidrotic eczema has been described [12].
ETIOLOGY AND PATHOGENESIS The cause

of dyshidrotic eczema is unknown, but it is probably multifactorial. Although in most cases, a
causative or predisposing factor cannot be identified, factors that have been associated with the
development of dyshidrotic eczema include:
●History of atopic dermatitis [11,13]
●Exposure to contact allergens, particularly metals [10,11,14]
●Exposure to contact irritants (eg, metalworking fluids) [9]
●Systemic exposure to contact allergens (eg, ingestion of nickel or cobalt) [15]
●Dermatophyte infection at a distant site (id reaction) [13]
●Intravenous immune globulin [14,16-20]
●Hyperhidrosis [11]
●Smoking [21]
●Exposure to ultraviolet (UV) radiation [22]
CLINICAL PRESENTATION Episodes of dyshidrotic

eczema often start with pruritus followed by a sudden symmetric eruption of intensely pruritic
vesicles on the palms, lateral and dorsal aspects of the fingers (picture 1A-C), or soles. In 70 to 80
percent of patients, only the hands are involved [14]. In mild cases, vesicles develop only on the
775
lateral aspect of fingers (picture 1B, 1D). The vesicles are typically deep-seated and multilocular
("tapioca or sago pudding" lesions); they may coalesce into large bullae (picture 2A). In some
patients, symptoms may be severe enough to interfere with occupational duties and daily activities
(picture 2B).
Vesicles and bullae persist for several weeks, desiccate, and resolve with desquamation (picture 3)
[1,3]. Frequent relapses may result in chronic hand dermatitis, characterized by red, lichenified, and
scaling patches or plaques with fissures (picture 1E). Severe episodes can affect the nail matrix and
produce dystrophic nail changes such as horizontal ridging and color changes (picture 1E).
Secondary infection, usually with Staphylococcus aureus, may occur.
Episodes may recur at intervals of three to four weeks for months or years and are more common in
warm weather. In some patients, flares may be associated with emotional or physical stress but
most often they occur in the absence of an identifiable trigger.
DIAGNOSIS
Clinical diagnosis — The diagnosis of dyshidrotic dermatitis is usually made
based upon clinical findings, symptoms, and history:
●Tense, deep-seated vesicles or bullae localized on the palms and soles and often on the lateral
aspect of the fingers (picture 1A-B)
●Intense pruritus
●Acute onset
●History of recurrence
In mild cases, tiny vesicles may be seen only on the lateral aspect of fingers (picture 1D).
Histopathology — A skin biopsy for histopathologic examination is rarely needed.

Potential indications for skin biopsy include lack of response to treatment and exclusion of other
conditions in the differential diagnosis (eg, psoriasis or palmoplantar pustulosis). If a skin biopsy is
performed, periodic acid-Schiff (PAS) staining for fungal elements may be useful in excluding a
fungal infection. (See 'Differential diagnosis' below.)
The histologic features of dyshidrotic eczema depend upon the stage (acute or chronic) of the
disease:
●The acute form is characterized by intraepidermal spongiotic vesicles or bullae that do not involve
the intraepidermal portion of the eccrine sweat duct (acrosyringium). A sparse, superficial
perivascular infiltrate of lymphocytes is usually present. The epidermal thickness is normal and the
thick stratum corneum of acral skin is intact.
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●In chronic cases, there is a predominance of parakeratosis and acanthosis with minimal or no
spongiosis and a dermal lymphocytic infiltrate.
Patch testing — Patch testing is not helpful in making the diagnosis of dyshidrotic
eczema. However, it is often performed by dermatologists to determine whether there is a
component of allergic contact dermatitis, in which case avoidance of the allergen is an important
part of management, and may be warranted in patients who do not respond to initial therapy [1,3].
(See "Patch testing" and "Management of allergic contact dermatitis", section on 'Avoidance'.)

of dyshidrotic eczema includes the following inflammatory and infectious vesicobullous skin
diseases [1,3]:
●Allergic contact dermatitis – Allergic contact dermatitis may be clinically indistinguishable from
dyshidrotic eczema (picture 4A-B). The correct diagnosis is based upon the assessment of allergen
exposure and results of patch testing. (See "Clinical features and diagnosis of allergic contact
dermatitis", section on 'Diagnosis'.)
●Bullous tinea – Bullous tinea occurs more often on the feet than on the hands and is usually
unilateral (picture 5A-B). Potassium hydroxide (KOH) microscopic examination of scrapings from the
lesions reveals fungal elements. (See "Dermatophyte (tinea) infections", section on 'Tinea pedis'.)
●Irritant contact dermatitis – Irritant contact dermatitis usually involves the dorsal aspect of the
hands and web spaces (picture 6A-B). Patients often report a history of irritant exposure. (See
"Irritant contact dermatitis in adults".)
●Atopic hand dermatitis – Atopic hand dermatitis commonly involves the dorsum of the hands.
Patients report a history of atopic dermatitis, seasonal allergies, or asthma and may present with
eczema lesions or lichenification involving flexural areas (ie, antecubital and popliteal fossae)
(picture 7). (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis",
●Dermatophytid (id) reaction – A dermatophytid reaction is a secondary pruritic, papulovesicular

eruption that may occur on the palms in association with a dermatophyte infection at a distant site
(eg, on the scalp or foot) (picture 8). A complete skin examination and a KOH preparation of
scrapings from suspicious lesions are necessary to confirm the diagnosis. (See "Dermatophyte
(tinea) infections", section on 'Dermatophytid (id) reactions'.)
●Herpetic infection – Herpetic lesions present as grouped vesicles on a red base, are more often
painful than pruritic, and usually unilateral (picture 9). The diagnosis can be made by viral culture,
immunofluorescence staining, polymerase chain reaction, or Tzanck smear. (See "Epidemiology,
clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on
'Diagnosis'.)
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●Palmoplantar pustulosis – Palmoplantar pustulosis may have an early vesicular stage, but
pustules usually develop in a few days (picture 10A-B). In 8 to 10 days the pustules change their
color to dark brown, become dry, and desquamate (picture 11). (See "Palmoplantar pustulosis:
Epidemiology, clinical features, and diagnosis".)
●Autoimmune bullous diseases – Bullous pemphigoid and pemphigus vulgaris may rarely present
as localized disease involving the hands or feet (picture 12). The history reflects a longer and
unremitting course. Biopsy for routine histology, direct immunofluorescence, and serologic testing
for specific autoantibodies provide the correct diagnosis. (See "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Diagnosis' and "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus", section on 'Diagnosis'.)
CLINICAL COURSE Dyshidrotic eczema is a recurrent disease.

Patients typically experience frequent attacks of vesicular dermatitis for many years. Episodes tend
to occur less frequently with age and most patients eventually go into complete remission [23].
MANAGEMENT The management of dyshidrotic eczema involves the

following:
●Identification and avoidance of causative or exacerbating factors
●Adoption of skin care measures to reduce skin irritation
Dyshidrotic eczema has a tendency to spontaneously resolve over several weeks. However,
treatment is required for most patients who present with complaints of pruritus or other symptoms.
The approach to treatment is guided by the severity of the disease.
Assessment of severity — The severity of dyshidrotic eczema is

generally assessed subjectively. A scoring tool called the dyshidrotic eczema area and severity index
(DASI), based upon the number of vesicles, intensity of erythema, desquamation, and itch, was
designed for use in clinical trials but is not routinely used in clinical practice [24].
We consider dyshidrotic eczema to be mild to moderate if it does not involve the entire palmar or
plantar surface, presents as a few crops of vesicles or scattered small vesicles with absent or
modest erythema (picture 1A, 1E-G), and the patient does not complain of intolerable pruritus,
burning, or pain.
We consider dyshidrotic eczema to be severe if it involves the entire palmar or plantar surface and
presents with large vesicles or bullae that are disabling (picture 2A-C) (ie, prevent walking or use of
the hands), or if it is intensely painful or pruritic (regardless of the size of the lesions).
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General measures — In clinical experience, avoidance of irritants or
exacerbating factors is beneficial for most patients with dyshidrotic eczema. General skin care
measures aimed at reducing skin irritation and restoring the skin barrier include [25]:
●Using lukewarm water and soap-free cleansers to wash hands
●Drying hands thoroughly after washing
●Applying emollients (eg, petroleum jelly) immediately after hand drying and as often as possible
●Wearing cotton gloves under vinyl or other nonlatex gloves when performing wet work
●Removing rings and watches and bracelets before wet work
●Wearing protective gloves in cold weather
●Wearing task-specific gloves for frictional exposures (eg, gardening, carpentry)
●Avoiding exposure to irritants (eg, detergents, solvents, hair lotions or dyes, acidic foods [eg, citrus
fruit])
In clinical practice, astringent solutions such as aluminum subacetate (Burow's solution) or witch
hazel are used for wet, weeping skin. Hands or feet are soaked in the solution for 15 minutes two to
four times per day. Large bullae may be drained or aspirated using a sterile syringe to reduce pain
and prevent spontaneous rupture with risk of local infection.
Mild to moderate disease

Topical corticosteroids — For patients with mild to moderate dyshidrotic
eczema (picture 1A, 1E-G) that has not responded to general measures, we suggest super high
potency or high potency topical corticosteroids (group one to three (table 1)) rather than calcineurin
inhibitors, which are approximately equivalent to moderate potency corticosteroids. (See
'Assessment of severity' above and 'General measures' above.)
Topical corticosteroids are applied twice daily for two to four weeks. Ointments generally are
preferred to other vehicles (creams, solutions, or foams) because they contain fewer potential
irritants such as additives or preservatives [1,3,25]. However, some patients prefer other vehicles
because ointments make their hands too greasy for performing tasks.
The efficacy of topical corticosteroids versus placebo or no treatment for dyshidrotic eczema has
not been adequately evaluated in randomized trials. However, they are used in clinical practice
because of their antiinflammatory properties and their efficacy in other forms of hand eczema. (See
"Treatment of atopic dermatitis (eczema)", section on 'Topical corticosteroids'.)
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The long-term use of topical corticosteroids is limited by their side effects, which include skin
atrophy, striae, and telangiectasia. (See "Topical corticosteroids: Use and adverse effects", section
on 'Adverse effects'.)
Topical calcineurin inhibitors — We generally do not suggest topical

calcineurin inhibitors as the first-line antiinflammatory treatment for dyshidrotic eczema. The
antiinflammatory effect of topical calcineurin inhibitors is approximately equivalent to moderate
potency topical corticosteroids [26]. In addition, topical calcineurin inhibitors are more expensive
than many topical corticosteroids.
However, when patients and/or clinicians prefer to avoid long-term use of topical corticosteroids for
the treatment of mild to moderate dyshidrotic eczema (picture 1A, 1D, 1F), the topical calcineurin
inhibitor tacrolimus is an alternative [27,28]. Tacrolimus 0.1% ointment is applied twice daily until
resolution.
In a randomized trial including 16 patients with moderate to severe dyshidrotic eczema, topical
tacrolimus was compared with mometasone furoate, a high-potency (group three) topical
corticosteroid [29]. After four weeks of treatment with either topical tacrolimus 0.1% or mometasone
furoate 0.1% ointment, the dyshidrotic eczema area and severity index (DASI) was reduced by more
than 50 percent.
Severe disease
Systemic corticosteroids — In addition to the general measures described
above, we suggest oral rather than topical corticosteroids for the treatment of severe dyshidrotic
eczema (picture 2A-C). (See 'Assessment of severity' above and 'General measures' above.)
We generally start with prednisone 40 to 60 mg once per day in the morning for one week. If there is
an adequate response, the dose is then reduced by 50 percent in the next five to seven days and
finally tapered and discontinued over the following two weeks.
Oral corticosteroids for dyshidrotic eczema have not been evaluated in clinical trials. However, in
clinical experience they have been beneficial for the short-term treatment of dyshidrotic eczema and
other forms of severe eczematous dermatitis. (See "Management of severe atopic dermatitis
(eczema) in children", section on 'Systemic corticosteroids'.)
Topical corticosteroids — Superpotent topical corticosteroids (group one, (table

1)) are a treatment option for severe dyshidrotic eczema in patients for whom systemic
glucocorticoids are contraindicated or patients who prefer to avoid systemic corticosteroids.
Topical corticosteroids are applied twice daily for two to four weeks. Ointments generally are
preferred to other vehicles (creams, solutions, or foams) because they contain fewer potential
irritants such as additives or preservatives [1,3,25]. However, some patients prefer other vehicles
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because ointments make their hands too greasy for performing tasks.
Application of topical corticosteroids under occlusive dressings (eg, polyethylene gloves for the
hands or plastic wrap for the feet) may be helpful in patients with severe disease. Occlusive
dressings enhance the corticosteroid penetration into the skin and may lead to a more rapid
response. To limit the inconvenience of occlusive dressings, they are usually used at nighttime for
three to seven days. However, some patients prefer open application of topical corticosteroids
because they find occlusive dressings uncomfortable.
The risk of systemic absorption of topical corticosteroids applied on palms or soles is low because
of the limited area involved and greater thickness of volar skin [30]. However, a prolonged use of
superpotent topical corticosteroids is associated with cutaneous side effects including skin atrophy,
striae, and telangiectasia. (See "Topical corticosteroids: Use and adverse effects", section on
'Adverse effects'.)
Treatment response — Clinical criteria to evaluate the response to treatment

include cessation of vesiculation, clearance of preexisting vesicles, and reduction of erythema,
pruritus, and pain. Resolution is usually associated with increased skin dryness and desquamation.
Emollients can be liberally used multiple times per day to reduce dryness and scaling.
If there is no improvement/resolution in two to four weeks, additional evaluation is necessary. (See

'Refractory disease' below.)
Refractory disease
Evaluation — Patients with clinical features of dyshidrotic eczema who do not respond or
are not adequately controlled after two to four weeks of topical or systemic corticosteroids or topical
tacrolimus may need further evaluation to confirm or rule out the diagnosis.
Additional testing may include (see 'Differential diagnosis' above):
●Potassium hydroxide (KOH) preparation to rule out a fungal infection.
●Bacterial culture to rule out bacterial superinfection – Superinfection with S. aureus is a common
cause of inadequate response to treatment in patients with hand eczema, especially with severe
disease and wet, weeping lesions. Bacterial superinfection is treated with oral antibiotics. (See
"Impetigo", section on 'Systemic antibiotics'.)
●Skin biopsy and histopathologic examination to confirm the diagnosis of dyshidrotic eczema and
exclude other conditions. Periodic acid-Schiff (PAS) staining for fungal elements should be included.
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●Patch testing and detailed history of household- or work-related exposures to exclude an allergic or
irritant contact dermatitis. (See "Patch testing" and "Clinical features and diagnosis of allergic
Treatment — We suggest oral or topical psoralen plus ultraviolet A therapy (PUVA) for
patients with confirmed diagnosis of dyshidrotic eczema who have frequent or severe episodes that
are not adequately controlled with topical or systemic corticosteroids or topical tacrolimus.
The use of PUVA for patients with dyshidrotic eczema is largely supported by its use in the
treatment of other inflammatory dermatoses, as only a few small clinical trials have demonstrated
clinical improvement with PUVA in patients with dyshidrotic eczema [31-34].
Phototherapy may not be available in all communities. Phototherapy treatments are usually
delivered two or three times per week. Several weeks of treatment are required to induce clinical
improvement and several months are required for resolution. Thus, the potential benefits of
phototherapy should be weighed against the inconvenience of prolonged therapy on a case by case
basis. Phototherapy that is limited to the palms and soles has few adverse effects. (See "Psoralen
plus ultraviolet A (PUVA) photochemotherapy", section on 'Topical PUVA'.)
Systemic immunosuppressive agents such as low-dose methotrexate, mycophenolate mofetil, and

cyclosporine, have been occasionally used in the management of patients with severe dyshidrotic
eczema [35,36]. Their use has not been evaluated in randomized trials and there is insufficient
evidence of benefit to suggest their use in refractory cases.
SUMMARY AND
RECOMMENDATIONS
●Acute palmoplantar eczema (also known as dyshidrotic eczema or pompholyx) is a recurrent,
pruritic vesicular eruption affecting the palms, soles, or both. It occurs most commonly in young
adults with equal frequency in males and females. (See 'Introduction' above and 'Epidemiology'
above.)
●Dyshidrotic eczema is characterized by the sudden eruption of intensely pruritic vesicles on the
palms (picture 1G), soles, or lateral aspects of the fingers (picture 1B). The vesicles persist for
several weeks, desiccate, and resolve with desquamation. Episodes may recur at intervals of three to
four weeks for months or years. (See 'Clinical presentation' above.)
●The diagnosis of dyshidrotic eczema is usually based upon the clinical appearance and location of
lesions, symptoms, and history. In most patients, patch testing is useful to determine whether there
is a component of allergic contact dermatitis. (See 'Diagnosis' above.)
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●The differential diagnosis of dyshidrotic eczema includes bullous tinea (picture 5B), dermatophytid
reaction (picture 8), bullous impetigo, herpes simplex infection (picture 9), allergic contact dermatitis
(picture 4A), and palmoplantar pustulosis (picture 10A-B). (See 'Differential diagnosis' above.)
●Avoidance of irritants or exacerbating factors is important for most patients with dyshidrotic
eczema. (See 'General measures' above.)
●For patients with mild to moderate dyshidrotic eczema (picture 1A, 1E-G) that has not responded to
general measures, we suggest super high potency or high potency topical corticosteroids (group
one to three (table 1)) rather than calcineurin inhibitors (Grade 2C). Topical corticosteroids are
applied twice daily for two to four weeks. Ointments are preferred to other vehicles. (See 'Topical
corticosteroids' above.)
●We suggest oral corticosteroids for the treatment of severe dyshidrotic eczema (Grade 2C). For
patients in whom oral corticosteroids are contraindicated or who prefer to avoid systemic
corticosteroids, superpotent topical corticosteroids (group one, (table 1)) are an alternative.
Treatment is started with prednisone 40 to 60 mg per day for one week. The dose may be reduced by
50 percent in the next five to seven days and then tapered and discontinued over the following two
weeks. (See 'Systemic corticosteroids' above and 'Topical corticosteroids' above.)
●Patients with clinical features of dyshidrotic eczema who do not respond or are not adequately
controlled after two to four weeks of topical or systemic corticosteroids may need further evaluation
to confirm or rule out the diagnosis. (See 'Evaluation' above.)
●We suggest phototherapy with oral or topical psoralen plus ultraviolet A (PUVA) for patients with
confirmed diagnosis of dyshidrotic eczema who have frequent or severe episodes that are not
adequately controlled with topical or systemic corticosteroids or topical tacrolimus (Grade 2B). (See
'Refractory disease' above.)
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Cradle cap and seborrheic dermatitis in infants
uptodate.com/contents/cradle-cap-and-seborrheic-dermatitis-in-infants/print
INTRODUCTION Seborrheic dermatitis is a self-limiting eruption

consisting of erythematous plaques with greasy-looking, yellowish scales distributed on areas rich
in sebaceous glands such as the scalp, the external ear, the center of the face, and the intertriginous
areas.
This topic will discuss cradle cap and seborrheic dermatitis in infants. Seborrheic dermatitis in
adolescents and adults is discussed separately. (See "Seborrheic dermatitis in adolescents and
adults".)
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EPIDEMIOLOGY Seborrheic dermatitis occurs in infants between the
ages of 3 weeks and 12 months. It has been reported in about 10 percent of infants younger than
one month [1]. The prevalence peaks at the age of three months (about 70 percent) and decreases
steadily in the following months, affecting about 7 percent of children aged one to two years [2].
PATHOGENESIS The pathogenesis of infantile seborrheic dermatitis is

not known. Transplacental transfer of maternal androgens stimulates the growth of the infant's
sebaceous glands, which are necessary but not sufficient for the development of seborrheic
dermatitis. The role of Malassezia, a lipid-dependent yeast, is not clear; Malassezia colonization has
been reported in infants with seborrheic dermatitis, infants with other dermatologic conditions, and
in normal infants [3-5].
CLINICAL MANIFESTATIONS The most common

manifestation of seborrheic dermatitis in newborns and infants is "cradle cap," an asymptomatic and
non-inflammatory accumulation of yellowish, greasy scales on the scalp (picture 1A-B). The vertex
and the frontal area are commonly involved. Sometimes the eruption starts on the face, with
erythematous, scaly, salmon-colored plaques (picture 2). The forehead, the retroauricular areas,
eyebrows and eyelids, cheeks, and nasolabial folds are commonly affected (picture 3). Seborrheic
dermatitis may also occur in the napkin (diaper) area (picture 4), on the trunk, with a predilection for
the umbilical area, or in the intertriginous areas. It also may occur simultaneously at multiple sites
(picture 5).
In the folds around the neck, in the axillae, and the crural region, the lesions have a moist, glistening,
nonscaly aspect and tend to be confluent. In more widespread forms, large areas of the trunk may
become involved with sharply marginated plaques of erythema and scaling that cover the lower
abdomen, pubic and groin area, as well as the buttocks. Rarely, seborrheic dermatitis may present as
an erythrodermic eruption in infants [6,7].
The infant is generally well; feeding and sleep are not disturbed. The pruritus is mild in most cases.
The clinical manifestations fluctuate, but most cases eventually resolve spontaneously within weeks
to a few months. Cases persisting beyond the age of 12 months are rare, and require the diagnosis
to be reconsidered. (See 'Differential diagnosis' below.)

of infantile seborrheic dermatitis includes:
●Atopic dermatitis – Atopic dermatitis is the other major dermatitis of infancy. It is characterized by
severe pruritus that interferes with feeding and sleep. The erythematous, scaly, and crusted lesions
of atopic dermatitis are generally poorly demarcated, and commonly involve the cheeks, scalp, and
extensor surfaces of the limbs (picture 6A-C). The diaper area is usually spared (picture 7). A
785
positive family history of eczema, asthma, and allergic rhinitis is often present. (See "Atopic
dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical
manifestations'.)
●Diaper dermatitis – Irritant diaper dermatitis is caused by the moist environment and friction of the
diaper. In contrast to seborrheic dermatitis, it usually spares the skin folds. However, diaper
dermatitis with superimposed Candida infection has a beefy red, glistening appearance, sometimes
with superficial erosions, and involves the skin folds. Transient pustules may be seen at the
advancing borders, and satellite lesions are common (picture 8). Infrequently, diaper dermatitis may
spread beyond the diaper area and become disseminated, with a pattern resembling seborrheic
dermatitis.
●Psoriasis – Psoriasis is uncommon in infants, but can mimic seborrheic dermatitis, especially
when it involves the flexures or the diaper area. The psoriatic plaques are sharply defined, shiny and
bright red in color, with the typical large, silvery scales of psoriasis usually seen in nonintertriginous
areas (picture 9). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on
●Pityriasis (tinea) amiantacea – In older children, pityriasis amiantacea (tinea amiantacea) may be
an infrequent scalp reaction caused by psoriasis or seborrheic dermatitis. It presents with a thick
accumulation of whitish hard scales on the scalp (picture 10). The scales are adherent to the scalp
and cement the proximal part of the hair. Forcefully removing the scales pulls the hair with them.
Treatment of pityriasis amiantacea involves frequent shampooing, repeated overnight application of
emollients, and combing to remove scales.
●Langerhans cell histiocytosis – Langerhans cell histiocytosis may present in infancy as a

refractory seborrheic dermatitis or as diaper dermatitis with ulceration and erosion. Sometimes,
papules and brownish-red or purpuric nodules can be seen on the scalp, retroauricular areas, axillae,
and inguinocrural folds (picture 11A-B). A skin biopsy will confirm the diagnosis.
●Tinea capitis – In infants, tinea capitis may present as a scaly scalp dermatitis with moderate or
minimal inflammation (picture 12). Hair loss generally is present but is not always easy to detect.
KOH examination of the hair shaft and fungal cultures will confirm the diagnosis. Tinea is rare in
infants.
TREATMENT
Cradle cap — In infants, seborrheic dermatitis has a self-limited course and resolves
spontaneously in weeks to several months. Therefore, we suggest that initial treatment should be
conservative, including education and reassurance of parents, and simple skin care measures.
Conservative measures for scalp seborrheic dermatitis may include:
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●Application of an emollient (white petrolatum, vegetable oil, mineral oil, baby oil) to the scalp
(overnight, if necessary) to loosen the scales, followed by removal of scales with a soft brush (eg, a
soft toothbrush) or fine-tooth comb
●Frequent shampooing with mild, non-medicated baby shampoo followed by removal of scales with
a soft brush (eg, a soft toothbrush) or fine-tooth comb
In more extensive or persistent cases, we suggest either a short course of low-potency topical
corticosteroids (group seven (table 1)) applied once per day for one week or ketoconazole 2% cream
or shampoo twice per week for two weeks. Corticosteroids are preferred if there is a predominant
inflammatory component; ketoconazole 2% cream or shampoo is an alternative in diffuse cases or if
the use of topical corticosteroids is a concern for the parents [8].
Ketoconazole shampoo may cause eye irritation. The use of lower-potency topical corticosteroids in
children is generally safe when used for short durations. (See "Topical corticosteroids: Use and
adverse effects".)
There are no randomized trials of antifungal agents or topical corticosteroids for the treatment of
cradle cap in infants. In a nonrandomized study of 48 children aged two weeks to two years,
ketoconazole 2% cream was equivalent to 1% hydrocortisone cream in clearing the lesions in two
weeks [9].
Due to the scarcity of data concerning the safety of topical ketoconazole in the pediatric population,
the manufacturer of ketoconazole shampoo and cream recommends to limit its use to individuals
older than 12 years of age, except under the advice of a clinician. In clinical practice, topical
ketoconazole has been used in infants and children without adverse effects. Systemic absorption of
topical ketoconazole in infants has been evaluated in two studies. In one, ketoconazole 2% shampoo
used twice a week for four weeks in 13 infants (<12 months) produced no detectable serum
ketoconazole levels and no abnormalities of liver function tests [10]. In the other, ketoconazole 2%
cream was used once daily for 10 days to treat 19 children with seborrheic dermatitis of the scalp
and diaper area. Peak plasma levels of ketoconazole detected one to three hours after topical
treatment were 1 to 2 percent of those measured after systemic administration [11].
Other antiseborrheic shampoos (eg, selenium sulfide 2.5%, zinc pyrithione, salicylic acid) have been
used in the treatment of infantile seborrheic dermatitis. However, there are no clinical trials
evaluating their efficacy and safety in infants. Observational studies in adults suggest that
shampoos and ointments containing salicylic acid may result in systemic toxicity because of
transcutaneous absorption [12].
Nonscalp, nonintertriginous seborrheic

dermatitis — We suggest that seborrheic dermatitis involving body areas other than the
scalp in infants be treated with ketoconazole 2% cream (once a day for one to two weeks) or a low-
787
potency topical corticosteroid (eg, hydrocortisone 1% cream once a day). The use of topical
corticosteroids should be limited to the time needed to achieve the clearing of the lesions, but no
longer than one week (see 'Response to therapy' below). Emollients can be used liberally.
There are no randomized trials evaluating the treatment of nonscalp seborrheic dermatitis in infants.
A single randomized trial in adults suggested that ketoconazole 2% cream and mid-potency
corticosteroids are equally effective. We generally use only low-potency topical corticosteroids for
seborrheic dermatitis in infants given the natural history of spontaneous resolution and the potential
for systemic absorption of topical corticosteroids. (See "Topical corticosteroids: Use and adverse
effects", section on 'Use in children'.)
Neck folds and other intertriginous areas — We

suggest that infants with seborrheic dermatitis of the intertriginous areas be treated with a topical
azole (ketoconazole 2% cream or other azole preparation, once a day for one to two weeks). In
addition, topical creams or ointments containing zinc oxide and/or petrolatum may be applied
liberally. Although there are no randomized trials evaluating this therapy, seborrheic dermatitis
involving the intertriginous areas is frequently superinfected with Candida albicans. The topical
barrier helps to limit skin maceration.
Response to therapy — If the rash does not improve after one week of
corticosteroid therapy or two weeks of antifungal therapy as described above, the diagnosis should
be reconsidered. (See 'Differential diagnosis' above.)
If the diagnosis of infantile seborrheic dermatitis is confirmed, intermittent courses of treatment may
be needed, since the disease may recur for weeks to months before disappearing.

provided separately. (See "Society guideline links: Seborrheic dermatitis".)

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●Basics topics (see "Patient education: Seborrheic dermatitis (The Basics)")
●Beyond the Basics topics (see "Patient education: Seborrheic dermatitis (including dandruff and
cradle cap) (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Seborrheic dermatitis in infants is a common and self-limited condition most frequently involving
the scalp (cradle cap (picture 13)). (See 'Clinical manifestations' above.)
●The initial treatment of scalp seborrheic dermatitis includes education, reassurance, and
conservative measures (emollients and frequent shampooing) to soften and remove the scales. If
conservative measures fail, we suggest either topical low-potency corticosteroids (group seven
(table 1)) or ketoconazole 2% shampoo or cream (Grade 2C). Topical corticosteroid is applied once
per day for one week. Ketoconazole 2% shampoo or cream is used twice per week for two weeks.
(See 'Cradle cap' above.)
●For seborrheic dermatitis of areas other than the scalp, we suggest ketoconazole 2% cream or a
low-potency corticosteroid cream (table 1) (Grade 2C). Ketoconazole 2% cream should be applied
once a day for one to two weeks. Topical corticosteroid is applied once a day for up to one week.
(See 'Nonscalp, nonintertriginous seborrheic dermatitis' above.)
●For seborrheic dermatitis of the intertriginous areas, we suggest ketoconazole 2% cream or other
azole cream (Grade 2C). The azole cream is applied once a day for one to two weeks. In addition,
topical creams or ointments containing zinc oxide and/or petrolatum may be applied liberally. (See
'Neck folds and other intertriginous areas' above.)
●If the rash does not resolve or improve considerably after one week of corticosteroid therapy or two
weeks of antifungal therapy as described above, the diagnosis should be reconsidered (see
'Differential diagnosis' above). If the diagnosis of infantile seborrheic dermatitis is confirmed,
intermittent courses of treatment may be needed, since the disease may recur for weeks to months
before disappearing.
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Intertrigo - UpToDate
uptodate.com/contents/intertrigo/print
790
INTRODUCTION Intertrigo, or intertriginous dermatitis, is a common
inflammatory condition of skin folds characterized by moist erythema, malodor, weeping, pruritus,
and tenderness (picture 1A-D). Initiating factors include moisture and friction associated with an
absence of air circulation in deep skin folds. In addition, candidal or bacterial infection may initiate
or aggravate intertrigo.
The diagnosis is usually straightforward and based upon the clinical findings. Treatment is rapidly
effective in the majority of patients. However, the disease typically recurs if initiating and
exacerbating factors are not eliminated.
The clinical features, diagnosis, and management of intertrigo will be reviewed here. Intertrigo
involving the diaper area of young children and other forms of diaper dermatitis are reviewed in
detail separately. (See "Diaper dermatitis".)

FACTORS Intertrigo can affect individuals of all ages, sexes, and socioeconomic
backgrounds and is predisposed by the chronic presence of moisture within deep skin folds. It is
most common in bedridden or debilitated older adults and infants because of immobility and
minimal aeration of intertriginous areas. Cutaneous infections, particularly Candida infection, may
initiate or exacerbate intertrigo.
Additional risk factors include obesity, incontinence, poor hygiene, hyperhidrosis, and immune
deficiencies that increase risk for skin infections (particularly Candida infection), such as in diabetes
mellitus, HIV infection, and malnutrition. Erosio interdigitalis blastomycetica, a variant of candidal
intertrigo that occurs in web spaces of the digits, typically occurs in association with frequent wet
work involving the hands (eg, dishwashing) or hyperhidrosis. (See "Susceptibility to infections in
persons with diabetes mellitus".)
PATHOGENESIS The pathophysiologic basis of intertrigo is

characterized by a variety of predisposing factors that often coincide to promote inflammation
within deep skin folds, including humidity, friction, and infection. Rubbing of moist skin against
moist skin leads to maceration and denudes the stratum corneum, exposing Langerhans cells to
environmental pathogens that stimulate an immune reaction.
Fungal or bacterial infection or colonization of the skin may contribute to intertrigo through the
initiation of innate or acquired immunity-mediated inflammatory cascades. Candidal infection is
common in intertrigo and may exacerbate or induce its development. Secondary bacterial infection
may also occur, particularly in areas of excoriated skin. Seborrheic dermatitis, an inflammatory
disorder in which fungi in the genus Malassezia are thought to play a role, may present with findings
consistent with intertrigo. (See "Susceptibility to infections in persons with diabetes mellitus".)
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Additional exacerbating factors for intertrigo include irritant and allergic contact dermatitis. The
chronically irritated skin of intertrigo increases susceptibility for these disorders. Common causes of
allergic contact dermatitis include fragrances in perfumes, colognes, and moisturizers; preservatives
in moisturizers and diaper wipes (eg, methylchloroisothiazolinone [MCI] and methylisothiazolinone
[MI]); and topical medications (including topical corticosteroids). Irritant contact dermatitis may
result from urine, feces, soaps, detergents, and other irritants that are not thoroughly rinsed from
skin in involved areas. (See "Common allergens in allergic contact dermatitis".)
CLINICAL PRESENTATION Intertrigo can occur in any

area where skin opposes skin. The hallmark clinical finding is a moist, red or red-brown, beefy,
homogenous patch within skin folds (picture 1A-D). Most cases of intertrigo occur in the deep folds
of the groin, though it is also common in the axillary area, inframammary area, umbilicus, and under
the panniculus. Neck fold involvement is common in infants and may also occur in individuals with
torticollis (picture 2). The antecubital fossae and popliteal fossae can be involved in patients with
limb contractures. Erythematous satellite papules and pustules suggest candidal involvement
(picture 3).
Patients with intertrigo may complain of burning, tenderness, pruritus, and/or a malodorous
discharge within affected areas. When fissuring is present, the involved areas can be especially
painful. Scratching can lead to excoriations and bruising.
Erosio interdigitalis blastomycetica (candidal intertrigo of the finger or toe web spaces) presents
with moist erythema and fissuring in the deepest part of the web space (picture 1D). On the feet, it
usually involves thethird and fourth or fourth and fifth web spaces. Despite the name, there is no
relationship to infection with the Blastomycetes fungal organism.
Intertrigo may occur in association with seborrheic dermatitis in infants and adults (picture 4A-B).
These patients usually exhibit erythema and scale in other areas characteristic for seborrheic
dermatitis, such as the face, retroauricular skin, and scalp. (See "Seborrheic dermatitis in
adolescents and adults", section on 'Clinical manifestations' and "Cradle cap and seborrheic
dermatitis in infants", section on 'Clinical manifestations'.)
CLINICAL COURSE Intertrigo typically persists if measures are not

taken to eliminate contributory factors. With appropriate management, intertrigo usually clears
rapidly. Secondary infection and cellulitis are potential complications of persistent intertrigo. (See
'Treatment' below.)
DIAGNOSIS Intertrigo typically can be diagnosed based upon the physical

examination. Supportive findings include erythematous, moist patches limited to intertriginous skin.
Findings that should prompt consideration of other disorders include vesicles, bullae, extensive
erosions, and vegetative plaques. (See 'Differential diagnosis' below.)
792
A full skin examination is helpful for identifying other sites of involvement as well as detecting
abnormalities on nonintertriginous skin or nails that suggest other disorders. Examination with a
Wood's lamp is helpful for distinguishing intertrigo from erythrasma (picture 5). (See 'Differential
diagnosis' below.)
Although not required in patients who have a clinical picture consistent with intertrigo, candidal
involvement (suggested by the presence of satellite papules and pustules) may be confirmed with a
potassium hydroxide (KOH) preparation of skin scrapings from a satellite pustule or skin fold
(picture 6). A KOH preparation is also helpful for identifying patients with tinea cruris (caused by
dermatophyte fungi) rather than intertrigo; suggestive findings for tinea cruris are erythematous
patches with partial central clearing and a slightly elevated, erythematous border. An alternative to a
KOH preparation is a fungal culture. (See "Office-based dermatologic diagnostic procedures", section
on 'Potassium hydroxide preparation' and "Dermatophyte (tinea) infections", section on 'Tinea cruris'
and 'Differential diagnosis' below.)
A bacterial culture should be obtained for patients with signs of secondary bacterial infection
(purulence, crusting, pain). Perianal involvement in children should raise concern for perianal
streptococcal infection.
Skin biopsies are not usually indicated and are reserved for patients in whom the diagnosis is
uncertain and a disorder requiring a biopsy diagnosis is in the differential diagnosis (eg, Hailey-
Hailey disease or pemphigus vegetans). (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS A variety of other

inflammatory disorders can present with intertriginous erythema. Disorders commonly in the
differential diagnosis include psoriasis, tinea cruris, erythrasma, and contact dermatitis:
●Inverse psoriasis – Inverse psoriasis is a variant of psoriasis characterized by the development of

well-demarcated, shiny plaques on intertriginous skin (picture 7) [1,2]. There is minimal to no
overlying scale. Common sites include the groin, axillae, and inframammary skin. Friction and
maceration are postulated to contribute to the development of intertriginous manifestations in
patients with psoriasis through the Koebner phenomenon (development of new skin disease lesions
in sites of cutaneous trauma) [1]. The identification of other cutaneous or nail manifestations of
psoriasis (eg, psoriatic plaques, nail pits, onychomycosis) aids in distinguishing inverse psoriasis
from intertrigo. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on
'Inverse (intertriginous) psoriasis'.)
●Tinea cruris – Tinea cruris is a dermatophyte infection involving the groin, proximal medial thighs,
perineum, or buttocks. The classic presentation consists of a centrifugally expanding, erythematous
patch with partial central clearing and a slightly elevated, sharply demarcated border (picture 8).
Concomitant tinea pedis is common. A potassium hydroxide preparation demonstrating septate
hyphae characteristic of dermatophytes confirms the diagnosis (picture 9). (See "Dermatophyte
(tinea) infections", section on 'Tinea cruris'.)
793
●Erythrasma – Erythrasma is a cutaneous corynebacterial infection that typically presents as
macerated, scaly plaques between the toes or as an intertriginous eruption of erythematous to
brown patches or thin plaques with fine scale (picture 10A-C). The moist maceration of intertrigo is
typically absent in areas other than the feet. Examination of erythrasma with a Wood's lamp
demonstrates coral-red fluorescence and is useful for distinguishing erythrasma from intertrigo.
(See "Erythrasma".)
●Allergic contact dermatitis – Allergic contact dermatitis to substances that come in contact with
intertriginous skin, such as methylisothiazolinone used as a preservative in diaper "wet" wipes, can
mimic intertrigo or represent a secondary complicating factor in patients with intertrigo (picture 11A-
C). Elimination of the allergen is required for resolution [3]. The patient history is helpful for
diagnosis. In addition, unlike intertrigo, the dermatitis usually extends out beyond the intertriginous
skin. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Common allergens in
allergic contact dermatitis".)
Less common disorders in the differential diagnosis are Hailey-Hailey disease, pemphigus vegetans,
and malignant intertrigo:
●Hailey-Hailey disease – Hailey-Hailey disease, also known as benign familial pemphigus, is a rare
genetic disorder that presents with blistering, erosions, maceration, and frequent secondary
infection primarily on flexural skin. Patients often present with large, macerated, exudative plaques
with superficial erosions and crusting (picture 12A-C). Vegetative, malodorous plaques with painful
fissures may also occur. Many patients also have longitudinal white bands on the nails. A skin
biopsy is needed to confirm the diagnosis. (See "Hailey-Hailey disease (benign familial
pemphigus)".)
●Pemphigus vegetans of Hallopeau – Pemphigus vegetans of Hallopeau is a variant of pemphigus

that presents with vegetating plaques on intertriginous skin (picture 13A-B) [4]. Skin biopsies for
routine histologic examination and direct immunofluorescence are necessary to confirm the
diagnosis. Direct immunofluorescence testing reveals intercellular deposition of immunoglobulin G
(IgG) in the epidermis. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus",
section on 'Pemphigus vulgaris'.)
●Malignant intertrigo – Malignant intertrigo is a distinct subset of toxic erythema of chemotherapy

affecting the intertriginous area [5]. Malignant intertrigo is more painful and tender than classic
intertrigo and is not associated with satellite papules or pustules at the periphery. It has been
described in association with a variety of chemotherapies.
The differential diagnosis of intertrigo in the diaper area of infants is reviewed separately. (See
"Diaper dermatitis", section on 'Differential diagnosis'.)
TREATMENT Treatment of intertrigo is advised to improve symptoms and

minimize risk for complications related to secondary infection. Although intertrigo is common, data
on treatment are limited. The few randomized trials performed have methodologic flaws and
794
considerable risk of bias [6]. A systematic review found insufficient evidence to confirm efficacy of
any particular approach to treatment [6].
Practices aimed at minimizing moisture and friction in the involved area and reducing susceptibility
to intertrigo are the mainstays of treatment. Typical beneficial practices include:
●Daily cleansing of intertriginous skin with a mild cleanser followed by drying of affected area with a
hair dryer on a cool setting
●Aeration of affected area when feasible
●Daily application of drying powders
●Use of absorbent material or clothing, such as cotton or merino wool, to separate skin in folds
●Application of barrier creams in areas that may come in contact with urine or feces
●Treatment of hyperhidrosis in the affected area
●Weight loss in overweight or obese patients
●Appropriate treatment of coexisting diabetes mellitus
In addition to these measures, we routinely prescribe a topical azole antifungal cream (eg,
ketoconazole, clotrimazole, miconazole, econazole) given the common presence of candidal
infection and the additional antibacterial and anti-inflammatory effects of these drugs [7,8].
Benzylamines, such as butenafine 1% cream, and allylamines, such as naftifine 2% cream and
terbinafine 1% cream, also have anti-inflammatory properties and are additional treatment options
[9]. Once- or twice-daily application of the antifungal drug for two to four weeks is usually sufficient.
Although nystatin is an option for treating candidal involvement in intertrigo, we favor other
antifungal agents because of their anti-inflammatory and antibacterial effects. In addition, azole,
benzylamine, and allylamine antifungal drugs are also effective for tinea cruris, a common condition
that may be mistaken for intertrigo. (See 'Differential diagnosis' above.)
We usually reserve topical corticosteroid therapy for patients with marked pruritus given that the
measures above are usually effective and the risk of skin atrophy associated with long-term topical
corticosteroid use in intertriginous areas. We typically prescribe a low-potency (ie, group 7 (table 1))
topical corticosteroid, such as hydrocortisone 2.5%, applied twice daily for one week, once daily for
one week, and every other day for one week. Pramoxine 1% is an alternative noncorticosteroid
topical agent that may reduce pruritus. Use of combination antifungal/corticosteroid creams, such
as betamethasone-clotrimazole and nystatin-triamcinolone, should be avoided because the
corticosteroid is excessively potent, increasing the likelihood of local adverse effects. (See "Topical
corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
795
This combination of skin care measures and topical therapy usually leads to marked improvement in
both signs and symptoms of intertrigo within a few weeks. The same regimen can be repeated for
recurrences.
Alternative, less commonly used treatments include topical tacrolimus, iodochlorhydroxyquin (with
or without hydrocortisone), and Castellani's paint. In one series, 10 adults with intertrigo (without
associated infection) applied tacrolimus 0.1% ointment twice daily for six weeks. It is unclear
whether local skin care measures were also incorporated. After one week, seven patients were clear
or at least 75 percent clear; after six weeks, eight patients were clear. Burning at the site of
application was the most common adverse effect. One patient withdrew from the study after two
days due to burning and discomfort associated with drug application. A disadvantage of topical
tacrolimus is higher cost compared with topical antifungal or corticosteroid therapy.
Iodochlorhydroxyquin ointment has both antifungal and antibacterial actions and is available in a
combination with hydrocortisone 1% cream [10]. Castellani's paint is a topical antifungal agent; its
use is limited by purple staining of skin and clothing.
Oral antifungal therapy can be effective for candidal intertrigo and is typically reserved for disease
that fails to respond to topical therapy. Fluconazole is commonly used. A wide variety of dose
regimens for fluconazole have been reported in the literature [11-15]. In a trial in which patients with
cutaneous dermatophyte or candidal infections were randomly assigned to fluconazole 150 mg per
week or 50 mg per day for up to four weeks, 10 of 11 and 12 of 13 patients treated for candidal
infections with weekly or daily dosing, respectively, achieved clinical or mycologic cure by the end of
treatment [12]. Our preferred regimen for fluconazole therapy for adults is 150 mg once weekly for
four weeks. Oral ketoconazole should not be used for the treatment of intertrigo because of risk for
hepatotoxicity and adrenal insufficiency.
Although typically not the sole indication for this intervention, surgical reduction of skin folds may
lead to improvement in intertrigo. Reduction mammoplasty has been associated with reduced
intertrigo in women with macromastia in uncontrolled studies [6].
PREVENTION OF RECURRENCE Data on the

efficacy of preventive interventions for intertrigo are lacking. In general, measures to minimize
moisture within skin folds should be continued after successful treatment to minimize risk for
recurrence. (See 'Treatment' above.)
We typically instruct patients to cleanse intertriginous areas daily with mild soap followed by drying
with a hair dryer on a cool setting. Subsequently, a drying powder can be applied. In our experience,
some patients with frequent recurrences may benefit from indefinite, once-weekly application of a
topical azole antifungal medication.
796
SUMMARY AND
RECOMMENDATIONS
●Intertrigo is a common cutaneous disorder characterized by inflammation of intertriginous skin.
Moisture and friction within skin folds are important contributors to the development of this
condition. (See 'Introduction' above.)
●Intertrigo may occur at any age but most often occurs in debilitated older adults and infants.
Obesity, incontinence, poor hygiene, hyperhidrosis, and immune deficiencies are additional risk
factors. (See 'Epidemiology and risk factors' above.)
●Fungal or bacterial infection or colonization of skin folds may initiate or exacerbate intertrigo.
Allergic and irritant contact dermatitis are additional exacerbating factors. (See 'Pathogenesis'
above.)
●The classic clinical findings of intertrigo are moist, red or red-brown patches within skin folds
(picture 1A-D). The groin is the most common site of involvement. Examples of other sites are the
axilla, inframammary skin, umbilicus, neck folds in infants, under the panniculus, and finger and toe
web spaces (erosio interdigitalis blastomycetica). Burning, tenderness, pruritus, and malodor may
accompany the physical manifestations. (See 'Clinical presentation' above.)
●Candidal skin infection commonly coexists with intertrigo. Satellite papules and pustules suggest
candidal infection. (See 'Pathogenesis' above and 'Clinical presentation' above.)
●Intertrigo usually can be diagnosed based upon recognition of the classic clinical findings. When
the diagnosis is uncertain, a Wood's lamp examination, potassium hydroxide preparation, or skin
biopsy can aid with differentiating intertrigo from other conditions. A bacterial culture should be
obtained if there are signs of secondary bacterial infection. (See 'Diagnosis' above and 'Differential
diagnosis' above.)
●High-quality data on the efficacy of treatments for intertrigo are lacking. Implementation of
measures to minimize moisture and friction in skin folds and reduce susceptibility to intertrigo is the
mainstay of treatment. In addition, we suggest application of a topical antifungal drug with
anticandidal activity (Grade 2C). We typically use an azole because of the antifungal, anti-
inflammatory, and antibacterial effects of azole antifungal drugs. A low-potency topical
corticosteroid may be helpful for patients with significant pruritus. (See 'Treatment' above.)
●Intertrigo may recur after treatment. Measures to minimize moisture within skin folds should be
continued after treatment to minimize risk for recurrence. (See 'Prevention of recurrence' above.)
797
Nummular eczema - UpToDate
uptodate.com/contents/nummular-eczema/print
INTRODUCTION Nummular eczema, also called discoid eczema or

nummular dermatitis, is a chronic inflammatory skin disease characterized by multiple pruritic, coin-
shaped eczematous lesions involving the extremities and, less commonly, the trunk (picture 1A) [1].
Nummular eczema is regarded as a distinctive form of endogenous (idiopathic) eczema.
798
This topic will discuss the clinical features, diagnosis, and treatment of nummular eczema. Atopic
dermatitis, allergic contact dermatitis, and other types of eczematous dermatitis are discussed
separately.
●(See "Stasis dermatitis".)
●(See "Urticarial dermatitis".)
EPIDEMIOLOGY Nummular eczema affects men more frequently than

women. Most patients are over the age of 50, although individuals of any age can be affected [2].
PATHOGENESIS The pathogenesis of nummular eczema is incompletely

understood. Numerous factors have been implicated as causal, including xerosis and decreased
cutaneous lipid production, Staphylococcus aureus colonization, contact allergy to metals, and
sensitization to environmental aeroallergens such as Candida albicans or house dust mites [1,3-8].
Nummular eczema has been reported in patients treated with isotretinoin and in patients with
hepatitis C infection treated with interferon-alpha-2b and ribavirin [9-11]. In a study of 1662 patients
undergoing breast reconstruction, approximately 3 percent developed nummular eczema in the area
of reconstruction [12]. In nearly two-thirds of cases, nummular eczema developed after the
implantation of tissue expanders or silicone implants, suggesting that stretching or tension applied
to the skin may be a trigger for this type of dermatitis. A report of nummular eczema developing
after initiating the interleukin (IL) 23 inhibitor guselkumab for psoriasis treatment suggests that the
balance of Th1 and Th2 cytokines may play a role in the pathogenesis of some cases [13].
PATHOLOGY The pathologic features of nummular eczema are

indistinguishable from other forms of eczema, showing primarily spongiosis, superficial perivascular
lymphocytic infiltrates, with some eosinophils and occasional neutrophils and plasma cells (picture
2) [14]. Mild papillary edema and vascular dilation may be present.
CLINICAL MANIFESTATIONS Nummular eczema

typically presents with highly pruritic, round, coin-shaped patches of eczematous dermatitis ranging
in diameter from 1 to 10 cm (picture 1A-C). In the acute phase, lesions are dull red, exudative, and
799
crusted. Over time, they become more dry and scaly, occasionally with central clearing leading to
annular lesions.
The legs and the upper extremities are the sites most frequently involved. Involvement of the trunk is
less common, but when present, the lower trunk is more likely to be involved than the upper trunk. If
the face or neck is involved, alternative diagnoses should be considered.
Nummular eczema is a chronic and relapsing disease. Days to months after resolution, apparently
dormant lesions may become active again or new lesions may occur in adjacent areas.
DIAGNOSIS The diagnosis of nummular eczema is usually clinical, based upon

the typical finding of round, coin-shaped, and highly pruritic lesions in a patient with diffusely dry
skin. Biopsy or laboratory tests are generally not necessary for diagnosis. However, a skin swab for
bacterial culture may be performed in patients with exudative or crusted lesions if infection with
unusual organisms is suspected. Patch testing may be helpful in patients with recalcitrant disease
and/or a history suggesting allergic contact dermatitis [6,15]. (See "Patch testing".)
Differential diagnosis — The differential diagnosis of nummular eczema

includes:
●Atopic dermatitis – Nummular lesions may be an atypical clinical presentation of atopic dermatitis
in both adults and children [16,17]. A history of atopic disease, including reactions to aeroallergens,
asthma, and atopic dermatitis in typical flexural locations supports the diagnosis of atopic
dermatitis. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)
●Allergic contact dermatitis – Allergic contact dermatitis may rarely present with lesions
indistinguishable from nummular eczema. Comprehensive patch testing to contact sensitizers
based upon the patient's history of exposure can clarify the diagnosis. (See "Clinical features and
diagnosis of allergic contact dermatitis" and "Patch testing".)
●Tinea corporis – Early lesions of tinea corporis may mimic nummular eczema (picture 3A-B). A
potassium hydroxide (KOH) preparation will show the segmented hyphae and arthrospores
characteristic of all dermatophyte infections. (See "Dermatophyte (tinea) infections".)
●Stasis dermatitis – Early lesions of stasis dermatitis may present as erythematous, scaly, and itchy
patches (picture 4). A history of venous insufficiency and/or the presence of other signs of chronic
venous insufficiency such as varicosities, pitting edema, and hyperpigmentation support the
diagnosis of stasis dermatitis. (See "Stasis dermatitis".)
●Psoriasis – Psoriatic lesions are usually dry, with more prominent scaling, and asymptomatic,
although some patients may complain of pruritus. (See "Psoriasis: Epidemiology, clinical
800
●Prodromal bullous pemphigoid – Bullous pemphigoid can present with nonspecific, pruritic,
eczematous lesions for a prolonged period prior to the appearance of classic blisters. In one case
report, lesions typical of nummular eczema developed into classic, immunopathologically confirmed
bullous pemphigoid [18]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid".)
MANAGEMENT The management of nummular eczema involves general

measures aimed at reducing skin dryness and exposure to irritants and treatment of skin
inflammation.
General measures — General measures to reduce skin dryness and exposure

to skin irritants may include:
●Limit bathing to once daily with lukewarm water using mild, nonsoap cleansers.
●Apply a moisturizer at least twice a day and immediately after bathing. The author prefers cream
preparations that contain ceramides.
●Use a laundry detergent that is based primarily on nonionic surfactants and/or double-rinse the
laundry.
●Consider oral supplementation with L-histidine. L-histidine has been shown to increase filaggrin
levels in keratinocytes and improve xerosis [19].
●Consider obtaining a whole house humidifier or a room humidifier for the bedroom.
First-line therapy — High- or ultra-high potency topical corticosteroids (groups 1

to 3 (table 1)) are first-line therapy for nummular eczema. Topical corticosteroids are applied once or
twice daily for two to four weeks or until resolution of the lesions. The use of occlusive dressings
may enhance the corticosteroid penetration into the skin and may lead to a more rapid response.
For isolated recalcitrant lesions, intralesional triamcinolone may be a treatment option. The author
injects 0.5 to 1 mL of 4 to 5 mg/mL triamcinolone per lesion. Patients should be warned about the
possibility of temporary atrophy or dyspigmentation.
The efficacy of topical corticosteroids for the treatment of nummular eczema has not been
evaluated in randomized trials. Their use is based upon indirect evidence of efficacy in other
eczematous skin diseases (eg, atopic dermatitis, allergic contact dermatitis) and clinical experience.
Severe or refractory disease
801
Phototherapy — Patients with extensive disease that does not respond to topical
corticosteroids may be treated with narrowband ultraviolet B (NBUVB) therapy. Typically, 10 to 30
treatments, given two to three times per week, are necessary before a response is noted. Once all
lesions are cleared, the frequency may be reduced to once weekly for a month, then to every other
week for two months, as needed and tolerated. (See "UVB therapy (broadband and narrowband)".)
If NBUVB therapy is not available or not possible for logistic reasons, commercial tanning beds or
natural sunlight during the summer may be alternative options. If natural sunlight is utilized, patients
should be instructed to start by obtaining 10 minutes of direct, unprotected sunlight between 10 AM
and 2 PM and increasing the duration by several minutes daily, up to a maximum of 30 minutes
daily. Lightly pigmented patients and those with red or blond hair may need to start with 5 minutes
and limit the exposure time to a maximum of 20 minutes. Unaffected areas of the skin should be
covered to limit unnecessary solar exposure.
The potential increased risk of skin cancer should be weighed against the benefits of avoiding the
use of systemic immunosuppressants in the individual patient.
Systemic therapies — For patients with recalcitrant disease, a short course of

systemic corticosteroids is an alternative treatment option if phototherapy is not available or not
possible for logistic reasons. The author's preference is to use intramuscular triamcinolone at a
dose of 40 mg given up to once every three months. For clinicians who prefer oral corticosteroids,
prednisone can be initiated at 40 mg per day, with the dose reduced by 10 mg every 5 days and then
discontinued.
Methotrexate 10 to 25 mg per week or cyclosporine 3 to 5 mg/kg per day are alternative therapies for
patients in whom systemic corticosteroids are contraindicated or in whom the disease recurs
shortly after corticosteroid discontinuation. The author initiates methotrexate therapy with 10 mg
weekly for six weeks. If the response is inadequate and laboratory monitoring has not shown any
abnormalities, the dose is increased to 15 mg weekly for another four to six weeks, and this pattern
is continued up to a maximum dosage of 25 mg weekly if needed to achieve clearance. Once an
adequate response is achieved, the dose is maintained for three to six months and then tapered by
2.5 mg monthly until the medication is stopped or until the minimum dose necessary for disease
control is achieved.
Cyclosporine is initiated at a dose of 4 mg/kg per day (based upon ideal body weight). This dose is
maintained until the disease is controlled, typically two to six weeks. The dose is then reduced by
100 mg/day every one to two months until discontinuation.
Systemic corticosteroids, methotrexate, or cyclosporine for the treatment of nummular eczema have
not been evaluated in clinical trials. Their use is based upon evidence of efficacy in the treatment of
other forms of severe dermatitis. The use of methotrexate for nummular eczema has been reported
in two series of 25 and 28 pediatric patients [20,21]. Complete clearance was observed in 16 and 10
children, respectively, after an average treatment time of 10.5 months.
802
Dupilumab, an interleukin (IL) 4 and IL-13 inhibitor approved for the treatment of moderate to severe
atopic dermatitis, has been reported as effective in a small series of patients with nummular
eczema, with five out of six patients having excellent response [22]. However, the author has used
dupilumab in several patients with nummular eczema refractory to multiple treatments, including
systemic corticosteroids, methotrexate, and cyclosporine, with disappointing results. Due to cost
and limited evidence of efficacy, a trial of dupilumab may only be considered in patients who have
failed phototherapy and systemic immunosuppressants.
PROGNOSIS Prognosis is excellent, with disease control achieved in nearly all

patients and eventual long-term remission achieved in the majority.
SUMMARY AND
RECOMMENDATIONS
●Nummular eczema, also called discoid eczema, is a chronic inflammatory skin disease
characterized by multiple coin-shaped eczematous lesions (picture 1A). (See 'Introduction' above.)
●Nummular eczema typically presents with highly pruritic, round, coin-shaped patches of
eczematous dermatitis ranging in diameter from 1 to 10 cm (picture 1B-C). The legs and the upper
extremities are the sites most frequently involved. (See 'Clinical manifestations' above.)
●The diagnosis of nummular eczema is clinical. Patch testing may be helpful in patients with
recalcitrant disease and/or a history suggesting allergic contact dermatitis. (See 'Diagnosis' above.)
●High- or ultra-high potency topical corticosteroids (groups 1 to 3 (table 1)) are the first-line therapy
for nummular eczema. Topical corticosteroids are applied twice daily for two to four weeks or until
resolution of the lesions. (See 'First-line therapy' above.)
●For patients with extensive or recalcitrant disease that does not respond to topical corticosteroids,
narrowband ultraviolet B (NBUVB) phototherapy, systemic immunosuppressants, and dupilumab are
alternative treatments. (See 'Severe or refractory disease' above.)
803
Overview of dermatitis (eczema) - UpToDate
uptodate.com/contents/overview-of-dermatitis-eczema/print
Overview of dermatitis (eczema)
Authors:
William L Weston, MD
William Howe, MD
Section Editor:
Deputy Editor:
INTRODUCTION The terms "dermatitis" and "eczema" are frequently used

interchangeably. When the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic
eczema). "Eczematous" also connotes some scaling, crusting, or serous oozing as opposed to mere
erythema. The term "dermatitis" is typically used with qualifiers (eg, "contact dermatitis") to describe
several different skin disorders.
Eczematous dermatoses are common, representing approximately 10 to 30 percent of dermatologic

consultations across different populations and ethnic groups [1-3]. Specific types of eczematous
dermatitis are more common in some age groups. As an example, atopic dermatitis is far more
common in children than in adults, whereas asteatotic eczema and nummular eczema are typically
seen in older adults.
A brief overview of the clinical features of the most common types of eczematous dermatoses is
provided here. Additional information on diagnosis and treatment of individual types of dermatitis is
provided separately.
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SEBORRHEIC DERMATITIS Seborrheic dermatitis is a

common, relapsing skin disorder that affects approximately 1 to 3 percent of adults [4,5]. In infants,
seborrheic dermatitis of the scalp is often called "cradle cap." (See "Cradle cap and seborrheic
dermatitis in infants", section on 'Clinical manifestations'.)
Seborrheic dermatitis presents with erythematous, scaly patches located in areas with a high
density of sebaceous glands, such as the lateral sides of the nose and the nasolabial folds,
eyebrows and glabella, retroauricular folds, and scalp (picture 1A-I). Less commonly involved are the
chest (picture 1J), upper back, and axillae (picture 2). Dandruff of the scalp is a mild form of
seborrheic dermatitis characterized by scaling with minimal inflammation (picture 3).
Seborrheic dermatitis is common in HIV infection and can be a presenting finding. It is clinically
atypical, however, with greater severity (picture 4) and characteristically distinct histologic findings
[6]. Before the introduction of effective antiretroviral therapies (ARTs), up to 40 percent of HIV
seropositive individuals and 80 percent of those with AIDS had seborrheic dermatitis [7,8]. However,
seborrheic dermatitis may also be a cutaneous manifestation of the immune reconstitution
inflammatory syndrome in patients on ART [9]. (See "Immune reconstitution inflammatory
syndrome".)
Seborrheic dermatitis is a common finding in Parkinson disease and in neuroleptic-induced

parkinsonism, although the pathogenetic mechanisms underlying these associations are unclear
[10]. Other neurologic disorders, including mood disorders and tardive dyskinesia, are also frequently
associated with seborrheic dermatitis [4,11]. (See "Clinical manifestations of Parkinson disease",
section on 'Nonmotor symptoms' and "Diagnosis and differential diagnosis of Parkinson disease",
section on 'Drug-induced parkinsonism'.)
The clinical manifestations, diagnosis, differential diagnosis, and management of seborrheic

dermatitis in adolescents and adults are discussed in detail separately. (See "Seborrheic dermatitis
in adolescents and adults".)
ATOPIC DERMATITIS Atopic dermatitis (AD, eczema) is a

chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects
adults. The hallmarks of AD are dry skin, severe pruritus, and cutaneous hyperreactivity to various
environmental stimuli. The clinical presentation varies with age:
●In infants and toddlers (<2 years), AD presents with pruritic, red, weeping or scaly, and crusted
lesions on the extensor surfaces of limbs and on the trunk, face, and scalp (picture 5A-G).
●In older children and adolescents, AD typically presents with lichenified plaques in a flexural
distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and
neck (picture 6A-D).
805
●In adults, AD is usually more localized, with predominant lichenification (picture 7A-E), but
exudative forms can also be seen (picture 8); chronic hand eczema, facial dermatitis, and eyelid
eczema are also frequently seen in adults (picture 9A-D).
Patients with AD often present a variety of minor cutaneous findings, the so-called atopic stigmata,
which include keratosis pilaris (picture 10A-C), palmar hyperlinearity (picture 11A-B), pityriasis alba
(picture 12A-B), periorbital darkening (picture 13), Dennie-Morgan infraorbital folds (picture 14A-B),
and nipple eczema.
The clinical manifestations, diagnosis, and management of AD are discussed separately.
CONTACT DERMATITIS Contact dermatitis refers to any

dermatitis arising from direct skin exposure to a substance. The dermatitis may either be allergic or
irritant-induced; the latter accounts for 80 percent of cases of contact dermatitis. In allergic contact
dermatitis (ACD), an allergen induces an immune response, while in irritant contact dermatitis (ICD),
the trigger substance itself directly damages the skin.
Allergic contact dermatitis — Allergic contact dermatitis (ACD)

occurs when contact with a particular substance elicits a delayed (type IV) hypersensitivity reaction.
The most common sensitizer in North America is the plant oleoresin urushiol found in poison ivy,
poison oak, and poison sumac (figure 1 and picture 15A-C) (see "Poison ivy (Toxicodendron)
dermatitis"). Ginkgo fruit and the skin of mangoes also contain urushiol and can produce ACD. Other
common sensitizers in the United States include metals (eg, nickel in jewelry), preservatives (eg,
formaldehyde and quaternium-15 in cosmetics and personal care products), fragrances (perfumes,
cosmetics), topical antibiotics, and paraphenylenediamine (commonly used in hair dyes) [12]. (See
ACD usually presents a well-demarcated, intensely pruritic, eczematous eruption localized to the
area of skin that comes in contact with the allergen, for example, cosmetics on the face (picture 16A-
B), nickel where jewelry is worn (picture 17C) or metal buttons in garments that are in contact with
the skin (picture 17D), rubber and latex where gloves are worn (picture 17E) or elastic bands that
contact the skin (picture 17F), and points of shoe that contact the feet (picture 17A-B). Allergens
applied to the scalp, including hair dyes and shampoos, may elicit dermatitis in adjacent areas, such
as the neck, retroauricular folds, or eyelids (picture 18A-B). A diffuse or patchy dermatitis of the
trunk, often with accentuation in the axillary folds, may be caused by cloth dyes or textiles (picture
17G).
806
Poison ivy, poison oak, and poison sumac typically cause an acute, eczematous reaction, with linear
lesions representing the areas of contact with the plant leaves or stems (picture 19A-B). However,
lesions can occur at other body sites due to transfer of the plant resin by the hands (picture 20). (See
"Poison ivy (Toxicodendron) dermatitis".)
ACD, most frequently induced by fragrances, lanolin, preservatives, and topical antibiotics, is
common in patients with stasis dermatitis [13]. ACD should be suspected in patients with
recalcitrant stasis dermatitis that fails to improve or worsens despite appropriate skin care and
topical therapy. (See "Stasis dermatitis", section on 'Contact sensitization'.)
The diagnosis and treatment of ACD and poison ivy dermatitis are discussed separately. (See
"Clinical features and diagnosis of allergic contact dermatitis" and "Management of allergic contact
dermatitis" and "Poison ivy (Toxicodendron) dermatitis", section on 'Treatment'.)
Irritant contact dermatitis — Irritant contact dermatitis (ICD) is the

most common form of contact dermatitis. It results from exposure to substances that cause
physical, mechanical, or chemical irritation of the skin [14]. Common irritants include water and wet
work, soaps and cleansers, bleach, solvents, acids and alkalis, plant parts, paper, and dust or soil.
ICD of the hands is the most common type of occupational dermatitis, particularly among food
handlers, health care workers, mechanical industry workers, cleaners, and housekeepers (table 1).
(See "Irritant contact dermatitis in adults" and "Contact dermatitis in children", section on 'Irritant
contact dermatitis'.)
Acute ICD presents with erythema, edema, vesicles and bullae, and oozing (picture 21A-C). In
chronic ICD, lichenification, hyperkeratosis, and fissuring predominate. Mild irritants produce
erythema, chapped skin, dryness, and fissuring (picture 21C). Pruritus and pain are accompanying
symptoms. The hands are the usual site for ICD; the web spaces of the fingers trap irritating
substances and may be the first area of involvement.
Rubber gloves may also induce an ICD, which is distinct from latex allergy. Friction, as well as
irritation from repeated moisture build-up under gloves, and the drying after the removal of the
gloves can be contributing factors.
JUVENILE PLANTAR
DERMATOSIS Juvenile plantar dermatosis (JPD), also called dermatitis
plantaris sicca, is an eczematous disorder involving the soles that typically occurs in children aged 3
to 14 years, more often in those with an atopic diathesis [15,16]. Its pathogenesis is unknown,
although irritation from synthetic shoe materials, synthetic fabrics, friction, and sweating are thought
to have a role. Histologically, JPD is characterized by subacute or chronic, spongiotic dermatitis with
the distinctive finding of a lymphocytic infiltrate surrounding the eccrine sweat ducts [17].
807
Clinical presentation and diagnosis — JPD presents with
redness and soreness of the plantar surface of the foot, which assumes a shiny, glazed, and cracked
appearance (picture 22A-C). The web spaces between the toes and the dorsal aspect of the feet are
typically spared.
The diagnosis of JPD is usually clinical. Skin scraping for a potassium hydroxide (KOH) preparation
and patch testing can be performed to rule out a fungal infection or allergic contact dermatitis (ACD)
from leather shoe chemicals or rubber.
Treatment — JPD is a self-limiting condition and usually resolves spontaneously over a

few years. Avoidance of synthetic socks and shoes and frequent use of emollients are the mainstay
of treatment.
STASIS DERMATITIS Stasis dermatitis, or stasis eczema, is a

common inflammatory dermatosis of the lower extremities occurring in patients with chronic
venous insufficiency. It typically presents with erythematous, scaling, and eczematous patches or
plaques on chronically edematous legs. Acute forms may present with severely inflamed, weeping
plaques, vesiculation, and crusting, often with bacterial superinfection (picture 23).
Allergic contact dermatitis (ACD) due to sensitization to topical preparations, dressings, and topical
antibiotics is a frequent complication. Hyperpigmentation, due to dermal hemosiderin deposition,
scaling, and potential development of lipodermatosclerosis occur in chronic forms (picture 24A-B).
Lipodermatosclerosis is a chronic form of panniculitis resulting from chronic inflammation, fat

degeneration, and fibrosis, resulting in a constriction of the ankle region that gives the legs the
appearance of an inverted champagne bottle (picture 25). (See "Stasis dermatitis" and "Clinical
manifestations of lower extremity chronic venous disease".)
ASTEATOTIC ECZEMA Asteatotic eczema, also called eczema

craquelé, is a common type of pruritic dermatitis that typically occurs on the lower extremities of
older individuals with dry skin. Its incidence peaks during cold winter months. Water loss from the
stratum corneum due to age-related skin barrier impairment is believed to be a key pathogenetic
factor. Low environmental humidity (eg, cold and dry weather, central heating) and exposure to harsh
detergents or irritants are well-known exacerbating factors.
In the vast majority of cases, asteatotic eczema is an isolated finding. Rarely, it may occur in
association with an underlying condition, such as malnutrition, hypothyroidism, and malignancy, or
as an adverse effect of certain drugs (eg, retinoids, diuretics, antineoplastic agents) [18-22].
808
Clinical features and diagnosis — Asteatotic eczema typically
presents with scaling and superficial fissuring of the skin resulting in the so-called "dried river bed"
appearance, with varying degrees of inflammation (picture 26A-C). In severe cases, the fissures can
be hemorrhagic. Pruritus is usually present.
The upper and lower extremities are the sites most commonly involved. Generalized forms have
been rarely described in patients with cancer [18-20].
The diagnosis of asteatotic eczema is usually clinical. If performed, a skin biopsy usually shows a
subacute, eczematous pattern with acanthosis, hyperkeratosis, mild spongiosis, and a superficial,
perivascular, lymphocytic infiltrate.
Treatment — Asteatotic eczema usually responds promptly to treatment with topical

corticosteroids. Emollients should be used liberally multiple times per day to avoid recurrence.
DYSHIDROTIC ECZEMA Dyshidrotic eczema, also called

acute palmoplantar eczema, pompholyx, or dyshidrosis, is an intensely pruritic, chronic and
recurrent, vesicular dermatitis of unknown etiology that typically involves the palms and soles and
lateral aspects of the fingers [23]. It occurs most commonly in young adults of both sexes.
The typical physical finding is the presence of multiple small, deep-seated vesicles on the palmar or
plantar skin, especially along the lateral aspects of the fingers and toes (picture 27A-E). The vesicles
may coalesce to form large bullae (picture 28) and may become superinfected (picture 29). Vesicles
and bullae persist for several weeks, desiccate, and resolve with desquamation (picture 30A-B).
Erythema, scale, and fissures can occur in older lesions.
The clinical manifestations, diagnosis, differential diagnosis, and treatment of dyshidrotic eczema
are discussed in detail separately. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
NUMMULAR ECZEMA Nummular eczema, also called

nummular dermatitis or discoid eczema, is a chronic, relapsing, inflammatory skin disease
characterized by multiple pruritic, coin-shaped, eczematous lesions involving the extremities and,
less commonly, the trunk (picture 31A-E) [24]. It occurs more frequently in middle-aged individuals,
although individuals of all ages can be affected.
The clinical manifestations, diagnosis, differential diagnosis, and treatment of nummular eczema are
discussed separately. (See "Nummular eczema".)
809
●Basics topics (see "Patient education: Dermatitis (The Basics)" and "Patient education: Seborrheic
dermatitis (The Basics)")
(Beyond the Basics)" and "Patient education: Seborrheic dermatitis (including dandruff and cradle
cap) (Beyond the Basics)" and "Patient education: Eczema (atopic dermatitis) (Beyond the Basics)")
SUMMARY
●Seborrheic dermatitis is a common skin disorder characterized by erythematous, scaly patches on
the scalp, face, and upper trunk (picture 1B-J). Dandruff of the scalp is a mild form of seborrheic
dermatitis characterized by scaling with minimal inflammation (picture 3). Severe seborrheic
dermatitis is common in HIV infection. (See "Seborrheic dermatitis in adolescents and adults".)
●Atopic dermatitis (AD, eczema) is a chronic, pruritic, inflammatory skin disease that occurs most
frequently in children but also affects adults. The clinical presentation varies with age. The face,
scalp, and extensor limb surfaces are involved in infant and toddlers (picture 5A-G); the flexural
areas are involved in older children and adolescents (picture 6A-D), and the hands and face are
involved in adults (picture 9A-D). (See "Atopic dermatitis (eczema): Pathogenesis, clinical
manifestations, and diagnosis" and "Treatment of atopic dermatitis (eczema)".)
●Allergic contact dermatitis (ACD) is a delayed hypersensitivity reaction following topical exposure
to an allergen. Patients typically present with a pruritic eruption at the site of exposure (picture 16A-
B, 17A-G, 18A-B). Common allergens include the plant oleoresin urushiol found in poison ivy, metals
(eg, nickel in jewelry), preservatives, fragrances, topical antibiotics, and paraphenylenediamine
(commonly used in hair dyes). (See "Clinical features and diagnosis of allergic contact dermatitis"
and "Management of allergic contact dermatitis".)
810
●Irritant contact dermatitis (ICD) is the most common form of contact dermatitis. It results from
exposure to substances that cause physical, mechanical, or chemical irritation of the skin. The
hands are commonly affected, particularly among food handlers, health care workers, mechanical
industry workers, cleaners, and housekeepers. Patients may present with erythema, dryness, and/or
fissuring of the skin (picture 21A-C). (See "Irritant contact dermatitis in adults".)
●Juvenile plantar dermatosis (JPD) is an eczematous disorder involving the soles typically occurring
in children aged 3 to 14 years. It presents with redness and soreness of the plantar surface of the
forefoot, which assumes a shiny, glazed, and cracked appearance (picture 22A-C). (See 'Juvenile
plantar dermatosis' above.)
●Stasis dermatitis, or stasis eczema, is a common inflammatory dermatosis of the lower extremities
occurring in patients with chronic venous insufficiency. It typically presents with erythematous,
scaling, eczematous patches and hyperpigmentation on chronically edematous legs. (See "Stasis
dermatitis" and "Clinical manifestations of lower extremity chronic venous disease".)
●Asteatotic eczema, also called eczema craquelé, is a common type of pruritic dermatitis that
typically occurs on the lower extremities of older individuals with dry skin, especially during cold
winter months. It typically presents with scaling and superficial fissuring of the skin resulting in the
so-called "dried river bed" appearance, with varying degrees of inflammation (picture 26A-C). (See
'Asteatotic eczema' above.)
●Dyshidrotic eczema, also called pompholyx, is an intensely pruritic, chronic and recurrent, vesicular
dermatitis that typically involves the palms and soles and lateral aspects of the fingers. It typically
presents with multiple small, deep-seated, vesicles on the palmar or plantar skin, especially along
the lateral aspects of the fingers and toes (picture 27A-E). Large bullae may also form (picture 28).
Erythema, scale, and fissures can occur in older lesions (picture 30A-B).
●Nummular eczema, also called discoid eczema, is characterized by pruritic, round, eczematous
plaques, most frequently found on the trunk and lower extremities (picture 31A-E). (See "Nummular
eczema".)

GRAPHICS
811
Scaly, erythematous papules and plaques over the alar groove, cheek, and beard area.
812
Facial seborrheic dermatitis
Intense erythema and scaling involving the central face and nasolabial folds.
813
Faint pinkish, scaly plaques with annular configuration in this patient with seborrheic dermatitis of
the face.
814
Facial redness and scale involving the

nasolabial folds and central face.

Wilkins.
815
Thin plaque at nasolabial fold and oral commissure and fine papules over lower face.
816
This patient has involvement of the

retroauricular area.

Wilkins.
817
Scaly, pigmented plaques at nasolabial folds and perioral area.
818
Annular, hypopigmented plaques typically located at the nasolabial folds.
819
Seborrheic dermatitis of the scalp
Widespread, scaly plaques involving the scalp.
820
Seborrheic dermatitis of the chest, presenting as thin, annular plaques.
821
Intertriginous seborrheic dermatitis
Intertriginous seborrheic dermatitis of the axilla in an HIV-positive patient with secondary folliculitis.
822
Diffuse, fine scaliness of the scalp without underlying erythema.
823
Severe erythema and scaling in an HIV-positive patient with seborrheic dermatitis.
824
Severe atopic dermatitis
Widespread erythema, weeping, and crusting in an infant with severe atopic dermatitis.
825
Atopic dermatitis
Fine scaling over the face, accentuated with crusting under eyelids and nose, sparing glabella and
nose ("headlamp" sign).
826

scaling, and crusting on the face, with similar
involvement (to a lesser degree) on the trunk
and arms.

TB, Johnson RA, Wolff K, et al (Eds). Color
3rd ed, McGraw-Hill, New York, 1997. Copyright
© McGraw-Hill.
827
Hyperpigmented, lichenified patches are

present on the face of this infant with
atopic dermatitis.

rights reserved.
828

papules, crust, and scale on the face of an
infant.

TB, Johnson RA, Wolff K, et al (Eds), Color
3rd ed, McGraw-Hill, New York 1997. Copyright
© McGraw-Hill.
829
Atopic dermatitis
Acute eczema with erythema, oozing, and crusting over cheeks and chin.
830
Atopic dematitis
Widespread erythematous papules and plaques involving the face, torso, and arms.
831
Flexural atopic dermatitis
Typical appearance of atopic

dermatitis in flexural areas of
the legs.
Courtesy of James C Shaw,

MD.
Atopic dermatitis
Hyperpigmented, slightly scaly patches and lichenified plaques are present in the popliteal fossae of
this patient with atopic dermatitis.
832
Atopic dermatitis
Atopic dermatitis involving the sides of the neck. Note the scaling and characteristic reticular
pigmentation.
833
Atopic dermatitis
Severe atopic dermatitis in a 12-year-old girl showing in the typical location of the popliteal fossae.
Note the oozing of serous fluid from the most involved areas, plus the papular component and
erythema.
Courtesy of Scott Walsh, MD, FRPCP.
834
Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings) of
the knee flexures in a 22-year-old woman.
835
dermatitis.
836
Atopic dermatitis
Scaly, excoriated plaques over the forearm.
837
Atopic dermatitis
Widespread lichenification with hyper- and hypopigmentation.
838
Atopic dermatitis
A lichenified plaque on the flexor aspect of the forearm.
839
Atopic dermatitis
Papules, papulovesicles, and erosions over the antecubital fossa.
840
Nail changes in chronic hand eczema
Loss of cuticle, chronic inflammation of the nail folds, and ridging of the nail plate with transversal
lines (Beau lines) in this 35-year-old woman with chronic hand eczema.
Reproduced with permission from: Diepgen TL, Yihune G, et al. Dermatology Online Atlas. Published
online at: www.dermis.net. Copyright © 1996-2015 DermIS. All rights reserved.
841
Atopic hand eczema
Lichenified plaques with hypo- and depigmentation over bilateral hands.
842
Eyelid eczema
A finely scaled, pink plaque near the medial canthus.
843
Eyelid eczema
Scaly eyelid plaques with fine papules on the cheeks and excoriations on the nasal ala.
844
Keratosis pilaris
Multiple erythematous, keratotic, follicular papules are characteristic of keratosis pilaris.
845
Keratosis pilaris
846
Keratosis pilaris
847
Palmar hyperlinearity
Hyperlinear palms are a typical finding in atopic dermatitis.
848
Palmar hyperlinearity
Hyperlinear palms in a patient with atopic dermatitis.
849
Pityriasis alba
Hypopigmented macules are

present on the face of this young
girl with pityriasis alba.
Copyright © Nicole Sorensen, RN,

Dermatlas;
Pityriasis alba
Pityriasis alba. Hypopigmented, slightly scaly macules are present on this child's cheeks.
Williams & Wilkins.
850
Periorbital darkening in atopic dermatitis
Fine scaling and subtle hyperpigmentation sparing the glabella and nose in this child with atopic
dermatitis.
851
Dennie-Morgan fold in atopic dermatitis
An extra skin fold is present under the eyes in this patient with facial atopic dermatitis.
Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd ed, Lippincott Williams &
Wilkins, Philadelphia 2003.
852
Dennie-Morgan fold
Infraorbital folds (Dennie-Morgan lines) are present in this child with atopic dermatitis.
853
Identification of poison ivy, oak, and sumac
Characteristic features useful for identifying poison ivy, poison oak, and poison sumac. Poison ivy
and poison oak are often identified by three leaflets with flowering branches arising from axillary
positions on a single stem. Poison sumac more often forms leaflets of five, seven, or more that angle
upward toward the top of the stem.
Reproduced with permission from: Bolognia J, Jorizzo JJ, Rapini RP, et al. Dermatology. Elsevier,
Boston 2003. Copyright © 2003 Elsevier.
854
Poison oak
855
Poison ivy fruit
Cream-colored fruit of poison ivy.
856
Poison ivy leaves and flowers
Green or green-reddish leaves grow in groups of three and have smooth, fine-toothed, or lobed
margins, and small, yellow-green flowers form cream-colored fruit.
857
Eczematous eruption of the face due to contact allergy to cosmetics.
858
An intense, inflammatory eruption is present on the face.
859
Contact dermatitis due to nickel
Nickel in earrings caused this dermatitis on the

ear lobe and neck.

Disorders, 2nd ed, Lippincott Williams & Wilkins,
Philadelphia 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
Subumbilical allergic contact dermatitis from metal fasteners in pants (nickel allergy).
Courtesy of William L Weston, MD.
860
Allergic contact dermatitis due to latex allergy
An individual was visiting a family member in the hospital who was on isolation. She forgot that she
had an allergy to latex and donned latex gloves. She developed local erythema and pruritus (no
urticaria), followed by vesicles, which ruptured.
Courtesy of Vaibhav Parekh, MD, MS.
861
Contact dermatitis
This patient reacted to the rubber in the elastic waistband of her underpants. Note sparing at the
sites where the garment did not come into constant contact with the skin.
Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
862
Erythematous, scaly plaques on the dorsum of the feet of a patient with shoe allergic contact
dermatitis.
Williams & Wilkins.
863
Eczematous eruption with vesiculation and erosions on the dorsal aspect of the feet in a patient with
allergic contact dermatitis elicited by contact with shoes.
864
Acute allergic contact dermatitis
Discrete and confluent, red, scaly, weepy, crusted papules and plaques. A 25-year-old woman
consulted a dermatologist for an acute, eczematous dermatitis on her head, neck, and shoulders.
The eruption appeared five days after she had black hair dye applied to her hair at the hairdresser.
Patch tests were positive for paraphenylenediamine. Paraphenylenediamine is a dark dye used in
almost all permanent hair dyes and some semipermanent hair coloring. It is a potent allergen that
triggers severe acute contact dermatitis in sensitized individuals.
865
Contact dermatitis of the periorbital skin
Intense erythema and edema with vesiculation in this patient with allergic contact dermatitis of the
eyelids.
866
Eczematous eruption of the trunk and axillary folds from contact allergy to cloth dyes or textiles.
867
Poison ivy dermatitis
Linear, erythematous, vesicular eruption on the forearm from contact with poison ivy.
868
Poison ivy allergic contact dermatitis
Large bullae on the hand of a child with acute allergic contact dermatitis from poison ivy.
869
Poison ivy dermatitis
Erythematous, vesicular eruption on the chest from poison ivy resin.
Occupations at high risk for irritant contact dermatitis and common irritants encountered
Occupation Common irritants encountered
Agriculture Oils
Solvents
Fertilizers and pesticides
Cleansers and detergents
Plants
Animal hair, saliva, secretions
870
Wet work
Automobile industry Oils (cutting oils)
Solvents and paints
Cement and construction industry Cement
Wood preservatives
Oils
Acids and alkalis
Fiberglass
Adhesives and glues
Cleaners and housework Wet work
Abrasives
Electrical/electronics Solvents
Soldering flux
Acids and alkalis
Adhesives and glues
Food industry Wet work
Foods (especially acidic foods and food enzymes)
Hairdressing/beautician Wet work
Shampoos
Permanent wave solutions
871
Permanent wave solutions
Oxidizing agents, bleaching agents
Health care and dental Cleansers and detergents
Wet work
Alcohol and other disinfectants
Medications
Painting Solvents and paints
Acids and alkalis
Metal industry Solvents
Paints
Glues and adhesives
Oils and cutting fluids
Plastic industry Plastics
Solvents
Fiberglass
Acids
Rubber industry Solvents
Frictional/mechanical factor
Woodwork Plastics
Solvents
Wood preservatives
872
Detergents
Sawdust and other
Reproduced from: Chew AL, Maibach HI. Occupational issues of irritant contact dermatitis. Int Arch
Occup Environ Health 2003; 76:339, with kind permission from: Springer Science + Business Media
B.V. Copyright © 2003.
Chronic irritant contact dermatitis
Erythema, fissuring, and scaling on the hand resulting from repeated exposure to irritants.
873
Chronic irritant contact dermatitis
Ill-defined, dry, scaly patches with

fissuring on the finger in a patient with
chronic irritant contact dermatitis.
Courtesy of Kulthanan K. Siriraj Hospital,

Mahidol University, Bangkok, Thailand.
874
Irritant contact dermatitis
Skin dryness, desquamation, and fissuring of the fingertips in a patient with mild irritant contact
dermatitis.
875
Juvenile plantar dermatosis
Shiny-appearing plantar skin with accentuation of the skin folds and fissures in a teenager with
juvenile plantar dermatosis.
876
Juvenile plantar dermatosis 2
Shiny and cracked appearance of the plantar skin in a child with juvenile plantar dermatosis.
877
Juvenile plantar dermatosis
Forefoot and heel desquamation and mild erythema in a child.
878
Advanced stasis dermatitis
Increased scaling, peripheral edema, erosions, crusts, and secondary bacterial infection on the lower
third of the leg in a patient with subacute stasis dermatitis.
Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia, 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
879
Stasis dermatitis
Hyperpigmentation and initial sclerotic changes on the lower legs in a patient with stasis dermatitis.
880
Chronic stasis dermatitis
This patient with chronic stasis dermatitis presents with hyperpigmentation,

lipodermatosclerosis, and varicosities on the lower leg.
881
Lipodermatosclerosis
Skin induration, redness, and hyperpigmentation involving the lower third of the leg in a patient with
stasis dermatitis and lipodermatosclerosis.
882
Asteatotic eczema
Dry, scaly skin with characteristic polygonal cracks.
883
Asteatotic eczema (eczema craquelé)
Erythematous and polygonally cracked skin with fine, interconnected fissures, some of which appear
hemorrhagic.
884
Asteatotic eczema (eczema craquelé)
In this patient, the asteatotic skin of the lower leg appears dry and slightly scaly, with a characteristic
cracked appearance.
885
Dyshidrotic eczema
Pinpoint vesicles, some of which are coalescing into larger ones, are visible on the lateral and dorsal
aspects of the fingers of a patients with acute palmoplantar eczema (dyshidrotic eczema).
886
Dyshidrotic eczema
Numerous vesicles are present on the lateral and dorsal aspect of the fingers in a patient with
dyshidrotic eczema.
887
Dyshidrotic eczema of moderate severity
In palmar acute dyshidrotic eczema, the vesicles are tense, deep-seated, and multilocular, resulting
in a "tapioca pudding" appearance.
888
Dyshidrotic eczema of the hands
Deep-seated, tiny vesicles on the palm of a patient with mild dyshidrotic eczema.
889
Dyshidrotic eczema
Vesicles and bullae are present on the medial aspect of the foot in a patient with dyshidrotic
eczema.
890
eczema.
891
A severe form of dyshidrotic eczema
Large bullae and signs of bacterial superinfection on the hands of a patient with severe dyshidrotic
eczema.
892
Dyshidrotic foot eczema
Desquamation following vesicle desiccation in a patient with plantar dyshidrotic eczema.
893
Dyshidrotic eczema
Desiccated vesicles and desquamation on the palm of a patient with dyshidrotic eczema in
resolution.
894
Nummular eczema
These coin-shaped, scaly lesions on the

thigh show evidence of postinflammatory
hyperpigmentation.

Goodheart HP. Goodheart's Photoguide of
Common Skin Disorders, 2nd ed, Lippincott
Wilkins.
895
Nummular eczema
Nummular eczema on the arm, characterized by the presence of multiple coin-shaped lesions.
896
Nummular eczema
A plaque of nummular eczema with erythema, vesiculation, and crusting.
897
Nummular eczema
"Coin-shaped" patches and plaques are located

on the legs.

Disorders, 2nd ed, Lippincott Williams & Wilkins,
Philadelphia 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
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Nummular eczema
Nummular eczema of the thigh typically presenting as round, coin-shaped, erythematous, scaly
plaques.
William L Weston, MDNothing to discloseWilliam Howe, MDNothing to discloseRobert P Dellavalle,
MD, PhD, MSPHEquity Ownership/Stock Options: Altus Labs [Itch, eczema]. Grant/Research/Clinical
Trial Support: Pfizer [Patient decision aids, inflammatory and immune-mediated skin disease].
Consultant/Advisory Boards: Altus Labs [Itch, eczema]; ParaPRO [Scabies, lice]. Other Financial
Interest: Journal of Investigative Dermatology; Journal of the American Academy of Dermatology
[Stipends]; Cochrane Council meetings [Expense reimbursement].Rosamaria Corona, MD,
DScNothing to disclose
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Prurigo nodularis - UpToDate
uptodate.com/contents/prurigo-nodularis/print
INTRODUCTION Prurigo nodularis (PN) is an uncommon, chronic skin

disorder affecting primarily older adults and is characterized by symmetrically distributed, multiple,
firm, pruritic nodules (picture 1A-B). PN occurs in patients with chronic pruritus and is frequently
associated with a history of atopic dermatitis [1,2].
PN will be discussed in this topic. Other skin conditions associated with chronic pruritus, including
atopic dermatitis, scabies, lichen planus, and bullous pemphigoid, are discussed separately.
●(See "Pruritus: Etiology and patient evaluation" and "Pruritus: Overview of management".)
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●(See "Scabies: Epidemiology, clinical features, and diagnosis".)
●(See "Lichen planus".)
●(See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
EPIDEMIOLOGY The incidence and prevalence of PN are not known. PN

can occur in all age groups but primarily affects older adults. In a review of 108 cases of PN, the
median age was 62 years [3]. Both sexes are equally affected [4]. In the United States, PN seems to
be more common among African Americans than in other ethnic groups. In a single-institution study
including 909 patients with PN, African American patients were 3.4 times more likely to have PN
than white patients (odds ratio [OR] 3.4, 95% CI 2.9-3.9) [5].
PN occurs in approximately 5 percent of patients with HIV infection [6,7].
PATHOGENESIS PN is a distinctive reaction pattern occurring in a subset

of patients with chronic pruritus, as a result of continuous scratching over a prolonged period of
time. Predisposing factors include dermatologic, systemic, neurologic, and psychiatric diseases
associated with severe pruritus. However, the exact pathogenesis of PN remains unclear. Earlier
studies noted an increased number of nerve fibers in the papillary dermis, suggesting a
neurocutaneous component in the pathogenesis of PN [8]. Nerve growth factor (NGF) and its
receptor, tyrosine kinase A (TrkA), are overexpressed in PN lesions and may be associated with the
increased release and accumulation of neuropeptides, such as substance P and calcitonin gene-
related peptide [9-11]. Mast cells, which are known to release NGF, are seen in close vicinity to
nerves expressing TrkA [12,13].
Subsequent studies have noted a hypoplasia of intraepidermal nerves in PN. An

immunohistochemical study of 53 patients with PN found that intraepidermal nerve fiber density is
reduced in lesional and nonlesional skin of patients with PN. A subsequent study of 30 patients with
PN confirmed a significant reduction of intraepidermal nerve fiber density in lesional and perilesional
skin compared with normal and healed skin. These findings suggest that PN may represent a form
of subclinical, cutaneous small fiber neuropathy [14-16].
The role of T helper 1 (Th1) and T helper 2 (Th2) cytokines in the pathogenesis of PN also has been
evaluated by examining the cytokine signatures in the epidermis in 22 cases of PN, using the signal
transducers and activators of transcription (STAT) 1, 3, and 6 [17]. In 19 of 22 cases, the entire
epidermis stained with anti-pSTAT 6, a marker for the Th2 cytokines interleukin (IL) 4, IL-5, and IL-13.
Only eight cases showed scattered staining with anti-pSTAT 1, a marker for the Th1 cytokines
interferon-gamma and IL-27. These findings suggest that Th2 cytokines play a principal role in the
pathogenesis of PN.
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Aberrant expression of IL-31, a potent pruritogenic cytokine preferentially expressed by CD4+ Th2
cells, and other nonhistamine pruritogenic mediators, including NGF, thymic stromal lymphopoietin,
and endothelin, has been described in PN lesions [18,19].
HISTOPATHOLOGY The histopathology of PN shows thick, compact

orthohyperkeratosis; irregular epidermal hyperplasia or pseudoepitheliomatous hyperplasia; focal
parakeratosis with irregular acanthosis; diminished nerve fiber density; and a nonspecific dermal
infiltrate containing lymphocytes, macrophages, eosinophils, and neutrophils (picture 2) [20-23]. A
hair follicle may be seen in the center of the lesion [24].
CLINICAL MANIFESTATIONS PN typically presents

with firm, dome-shaped, itchy nodules ranging in size from a few millimeters to several centimeters
and often symmetrically distributed on the extensor surfaces of the arms and legs and on the trunk
(picture 1A-F). Nodules can be flesh-colored, erythematous, or brown/black and range in number
from few to hundreds (picture 1B, 1G).
The extensor surfaces of the extremities are characteristically involved, but the upper back,
abdomen, and sacrum also can be involved; the difficult-to-reach upper midback area is usually
spared ("butterfly" sign) [23]. The palms, soles, face, and flexural areas are rarely involved.
Pruritus is always severe and distressing; it can be paroxysmal, sporadic, or continuous and is
worsened by heat, sweating, or irritation from clothing. In many cases, the cause of pruritus is
unknown. In a multicenter, cross-sectional, European study of 509 patients with PN, 71 percent of
patients experience itch often or always and 53 percent reported that their daily life was negatively
affected [25].
In some patients, a coexistent pruritic skin condition (eg, atopic dermatitis, xerosis) may be the initial
cause of pruritus. Rarely, PN may be the presenting symptom of a systemic disease, such as
infection with HIV or mycobacteria, parasitic infestation, or lymphoma [7,26-29].
A clinical presentation characterized by the coexistence of prurigo nodules and multiple

keratoacanthomas on pruritic, actinically damaged skin has been described in several patients [30].
(See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)
ASSOCIATED CONDITIONS Approximately half of all

cases of PN have a history of atopic dermatitis [3]. These patients may have PN at an earlier age
than nonatopic patients [31].
Systemic diseases (eg, diabetes, chronic renal failure, cardiovascular disease, hepatitis C, gluten
enteropathy, HIV infection), psychiatric disorders (eg, anxiety, depression), and emotional stress
have also been reported with high frequency in patients with PN [3,5,32-35]. PN occurs in
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approximately 5 percent of patients with HIV infection, particularly among individuals with a CD4+
count <200 cells/mm3 [6,7]. However, the exact role of these underlying conditions in the
development of PN is unclear.
DIAGNOSIS The diagnosis of PN is clinical, based upon a history of chronic,

severe pruritus and the clinical finding of characteristic excoriated, nodular lesions often
symmetrically distributed (picture 1C-E, 1G) [25]. A skin biopsy is not routinely performed to confirm
the diagnosis.
However, a skin biopsy may be indicated in cases where the clinical diagnosis is in question or there
is a poor response to first-line therapies. Immunofluorescence studies and enzyme-linked
immunosorbent assay to detect the presence of circulating autoantibodies against bullous
pemphigoid may be performed if suggested by history and clinical examination. (See 'Differential
diagnosis' below.)
In patients with PN who do not have a history of atopic dermatitis or other pruritic skin conditions,
systemic causes of chronic pruritus (eg, chronic kidney disease, liver disease, thyroid disease, HIV
infection, parasitic infestation, malignancy) should be investigated. The initial laboratory and
imaging evaluation may include (see "Pruritus: Etiology and patient evaluation"):
●Complete blood cell count
●Liver function tests
●Blood urea nitrogen and creatinine
●Thyroid-stimulating hormone
●HIV test
●Urinalysis
●Stool examination for ova and parasites
●Chest radiograph
DIFFERENTIAL DIAGNOSIS Skin diseases that may

mimic PN include:
●Acquired reactive perforating dermatoses – Acquired reactive perforating dermatoses are a group
of rare skin disorders most commonly associated with chronic renal failure and diabetes mellitus,
characterized by transepithelial elimination of dermal material. They present with pruritic, dome-
shaped, umbilicated papules with a central keratinous plug located on the trunk and limbs (picture
3A-D) [36]. Histology reveals a cup-shaped depression of the epidermis filled with a plug consisting
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of keratin, collagen, and inflammatory debris. The underlying epidermis shows fine slits through
which basophilic collagen fibers in vertical orientation are extruded. (See "Perforating dermatoses",
section on 'Acquired perforating dermatosis'.)
●Pemphigoid nodularis – Pemphigoid nodularis is a rare variant of bullous pemphigoid (BP)

characterized by pruritic nodules, papules, or plaques that mimic PN clinically and histologically
[21,37]. The diagnosis is confirmed by direct immunofluorescence, showing linear immunoglobulin G
(IgG) and/or complement component 3 (C3) staining along the basement membrane zone, and
presence of circulating autoantibodies against BP antigens [37,38]. (See "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Nodular scabies – A history of exposure and histologic examination can usually differentiate PN
from nodular scabies (picture 4A-C). Usually, other typical signs of scabies, such as burrows and
excoriations, are present. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on
'Diagnosis'.)
●Hypertrophic lichen planus – Hypertrophic lichen planus is a variant of lichen planus characterized
by the presence of thick, hyperkeratotic plaques, often on the anterior aspect of the legs (picture 5).
Histology can clarify the diagnosis. (See "Lichen planus".)
●Multiple keratoacanthomas – Multiple keratoacanthomas are a feature of several rare familial or

sporadic disorders (table 1), including Ferguson-Smith syndrome and Grzybowski syndrome (picture
6) [39]. The absence of pruritus, histologic features, and clinical course differentiate multiple
keratoacanthomas from PN. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis",
section on 'Multiple keratoacanthomas'.)
●Epidermolysis bullosa pruriginosa – Epidermolysis bullosa (EB) pruriginosa is a rare, localized

variant of dystrophic EB characterized by skin fragility, intense pruritus, and skin lesions resembling
hypertrophic lichen planus or PN [40,41]. The clinical suspicion of inherited EB needs to be
confirmed by appropriate immunofluorescence studies. (See "Epidemiology, pathogenesis,
classification, and clinical features of epidermolysis bullosa", section on 'Rare subtypes'.)
MANAGEMENT Treatment of PN is difficult and requires a multifaceted

approach, involving patient education to adopt general measures to reduce skin irritation and
scratching, symptomatic treatment of pruritus, and topical or systemic therapies aimed at
interrupting the itch-scratch cycle and flattening the skin lesions. Topical and systemic therapies for
PN have not been adequately evaluated in randomized trials. Evidence for their use is based upon a
few small, randomized trials; small case series; and clinical experience [42].
Symptomatic control of pruritus — In patients with PN, gentle

skin care using mild cleansers for bathing or showering and applying emollients multiple times per
day to soothe the skin and reduce dryness should be encouraged. Additional relief can be provided
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by lotions that provide a cooling sensation on the skin, such as calamine lotion or lotions containing
menthol and camphor, and those containing pramoxine hydrochloride, a local anesthetic.
To minimize the consequences of scratching and avoid excoriations, patients should keep their nails
short and may wear gloves at night. Occluding the involved areas with bandages (eg, Unna boots) or
dressings may provide further relief. Any underlying compulsive behavior (eg, skin picking) should
be treated. (See "Skin picking (excoriation) disorder and related disorders", section on 'General
considerations'.)
Pharmacologic therapy with first-generation sedating antihistamines (eg, hydroxyzine,

diphenhydramine) administered at bedtime may be useful in controlling nocturnal pruritus. Both
selective serotonin reuptake inhibitors and tricyclic antidepressants are also employed for chronic
pruritus, especially when a component of depression is present. (See "Pruritus: Overview of
management".)
Patients with limited disease

Topical and intralesional corticosteroids — For patients with a
limited number of nodular lesions, we suggest superpotent topical corticosteroids (group 1 (table 2))
as first-line therapy. Topical corticosteroids, such as clobetasol dipropionate 0.05% ointment, are
applied under occlusion with plastic wrap once at nighttime for at least two to four weeks, though a
longer course of treatment may be needed. Twice-daily application is recommended if occlusion is
not used. Once control is achieved, topical corticosteroids can be tapered to once or twice weekly
and continued as a long-term maintenance regimen.
The efficacy of topical corticosteroids for the treatment of PN has not been adequately evaluated in
randomized trials. In a single small study including 12 patients with PN, a betamethasone valerate
0.1% medicated tape was more effective than an anti-itch moisturizer in reducing the intensity of
pruritus and provided the additional benefit of preventing scratching [43].
Based upon clinical experience, intralesional injection of corticosteroids is effective in reducing

pruritus and flattening the nodules. It may be a treatment option in patients who have only a few
large PN lesions. Triamcinolone acetonide in concentrations of 5 to 20 mg/mL (based upon the size
of the lesion and response to therapy) is injected in the lesions every four weeks until pruritus
subsides and the nodules are flattened. Once significant improvement is noted, intralesional
corticosteroids can be discontinued. Early recurrences can be treated with superpotent topical
corticosteroids.
Other topical therapies — Other topical treatments that have been used with
some success in patients with limited PN include topical capsaicin, topical calcineurin inhibitors,
and topical vitamin D analogues. None of these treatments has been adequately evaluated in
randomized trials, and their use is based upon clinical experience and limited evidence from small
observational studies.
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Topical capsaicin may be a treatment option for motivated patients willing to adhere to a time-
consuming schedule. Topical capsaicin 0.025% cream is applied four to six times per day for two
weeks to up to several months, as tolerated.
Topical capsaicin exerts an analgesic and antipruritic effect by inducing the depletion of the
neuropeptide substance P from local sensory nerve terminals in the skin, degeneration of epidermal
nerve fibers, and desensitization of nociceptive nerve endings [44,45]. In one study, 33 patients with
PN were treated with topical capsaicin 0.025 to 0.3% four to six times per day for 2 weeks up to 10
months [46]. Complete remission of pruritus was reported by all patients within 12 days of
treatment. The nodules flattened and softened within two months in 24 patients. However, pruritus
and skin nodules recurred in 16 patients upon discontinuation of treatment.
Other topical treatments reported as beneficial in small case series include topical tacrolimus,
topical pimecrolimus, topical vitamin D analogues (eg, calcipotriol, tacalcitol), and a compounded
mixture of topical ketamine, amitriptyline, and lidocaine [47-51].
Patients with widespread or recalcitrant

disease
Phototherapy — For patients with widespread disease and for those with recalcitrant
disease that does not respond to topical or intralesional corticosteroids, we suggest narrowband
ultraviolet B (NBUVB) phototherapy as first-line therapy. NBUVB is administered two to three times
weekly for up to 10 weeks in combination with topical corticosteroids. Oral antihistamines, the
tricyclic antidepressants doxepin or amitriptyline, or gabapentin/pregabalin may be given as
adjunctive treatment to control pruritus. Emollients and topical corticosteroids may also be used as
needed.
Psoralen plus ultraviolet A (PUVA) can be an alternative form of phototherapy if NBUVB is not
available. (See "UVB therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA)
Limited evidence for efficacy of phototherapy, including NBUVB, systemic and bath/topical PUVA,
ultraviolet A1 (UVA1), and monochromatic 308 nm excimer light, for the treatment of PN is derived
from small observational studies and a single randomized trial [52-57]:
●In one study, 63 patients with PN were treated with topical PUVA [56]. Approximately 80 percent of
patients improved after the first treatment cycle of two to four weeks.
●In another study, 22 patients with PN were randomized to use bath PUVA or bath PUVA plus
targeted 308 nm excimer laser therapy. Six of 11 patients receiving bath PUVA alone and 7 of 10
receiving combined therapy had complete clearance [54]. Patients assigned to bath PUVA alone
received an average of 20 treatment sessions, whereas patients assigned to combination therapy
received an average of 10 bath PUVA sessions.
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●NBUVB therapy was used to treat 10 patients with recalcitrant PN [57]. Improvement of skin lesions
was reported in all patients after a median number of 16 weekly treatments.
●Monochromatic excimer light (308 nm) laser therapy induced partial or complete remission in 11
patients with PN after an average of 7.5 treatments [52].
●A modified Goeckerman regimen was successfully used in a small study of four patients with
recalcitrant PN who had failed previous treatment with standard NBUVB and broadband UVB
therapy [58]. The regimen consisted of daily broadband UVB therapy followed by application of
crude coal tar and topical corticosteroids under occlusion for four hours.
Systemic therapies — Patients with widespread or recalcitrant PN who fail to

respond to phototherapy and those for whom phototherapy is not feasible may benefit from
systemic treatments. These include systemic immunosuppressants, thalidomide, lenalidomide, and
anticonvulsants [59]. These treatments are associated with potential significant toxicity, and their
efficacy in patients with recalcitrant PN has not been established.
In multiple reports, dupilumab, an interleukin (IL) 4 receptor inhibitor approved for the treatment of
atopic dermatitis in adults and adolescents, was effective in reducing pruritus and resolving the skin
lesions in patients with recalcitrant PN. Dupilumab may be an additional therapeutic option for
recalcitrant PN, especially in patients with underlying atopic dermatitis. (See 'Dupilumab' below.)
Systemic immunosuppressants — Low-dose methotrexate (7.5 to 20 mg per

week) or oral cyclosporine (3 to 5 mg/kg per day) may be beneficial in patients with recalcitrant PN,
based upon clinical experience and a few small observational studies.
In a series of 13 patients with PN resistant to conventional therapies, low-dose methotrexate (7.5 to

20 mg per week) was used for a minimum of six months. Ten patients achieved remission or marked
improvement, measured as a reduction of the number and severity of skin lesions and pruritus [60].
Oral cyclosporine has been shown to induce rapid control of pruritus in patients with recalcitrant PN
[61-63]. In one study including 14 patients treated with cyclosporine 3 to 5 mg/kg per day, 10
patients reported a "very good response" after an average treatment time of 2.7 months [62]. In
another report, eight patients with PN refractory to multiple topical and systemic therapies were
treated with cyclosporine 2 to 4 mg/kg per day for 2 to 48 months; six achieved remission (absence
of active or new lesions) after the first two to four weeks of treatment [63]. However, long-term
treatment with cyclosporine is limited by adverse effects, such as elevation of blood pressure and
serum creatinine.
Thalidomide — In selected patients with refractory disease, a trial of thalidomide may be

considered. However, thalidomide is teratogenic, and its use is associated with a dose-dependent
risk of peripheral neuropathy that may be nonreversible, thromboembolism, and neutropenia. In the
United States, patient and provider participation in the THALOMID Risk Evaluation and Mitigation
Strategy (REMS) program is mandatory to obtain and dispense thalidomide.
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Thalidomide is thought to have sedative, immunomodulatory, anti-inflammatory, and antiangiogenic
properties [64]. Thalidomide has been used for the treatment of PN in both immunocompetent
patients and in patients with HIV infection [65-70]. In a retrospective study, 42 patients with PN were
treated with thalidomide at an average dose of 100 mg/day for an average of two years [66]. The
average duration of thalidomide treatment before discontinuation due to neuropathy was 89 weeks
(range: 1 week to 7.5 years). There was moderate to marked improvement in 50 percent of the
patients; 12 patients showed only slight improvement or no effect.
Lenalidomide is a thalidomide analogue with more potent anti-inflammatory and antiangiogenic

properties but with a reduced risk of peripheral neuropathy. Lenalidomide has been successfully
used in a few patients with refractory PN [71-73].
Dupilumab — Multiple reports have documented the efficacy of dupilumab, an IL-4 receptor
inhibitor approved for the treatment of atopic dermatitis in adults and adolescents, in reducing
pruritus and resolving the skin lesions in patients with recalcitrant PN [74-80]:
●In a series of four patients with chronic, treatment-resistant PN, all four were treated with
subcutaneous dupilumab 600 mg followed by 300 mg every other week [74]. At 12 weeks, all four
patients reported a numeric rating scale of itch intensity (ranging from 0 to 10, with higher numbers
indicating worse itch) of 0.
●In a series of nine adult patients with atopic dermatitis manifesting as generalized PN, dupilumab
at the standard dosing regimen (600 mg induction dose followed by 300 mg every two weeks)
induced a marked clinical improvement in skin lesions, pruritus, and life quality in all patients [81].
●In a French, multicentric cohort of 16 adult patients with chronic PN refractory to multimodal
treatment regimens, dupilumab induced a complete or partial response of skin lesions and pruritus
in 15 patients and no response in 1 patient at three months [80].
Other — There are a few reports of successful treatment of recalcitrant PN with neuromodulators,
such as gabapentin [82,83] and pregabalin [84-86], the mu-opioid receptor antagonist naltrexone [87],
and a combination of montelukast and fexofenadine [88].
In an uncontrolled study including 20 patients (13 with PN) with intractable chronic pruritus, short-
term treatment (<2 weeks) with aprepitant, a neurokinin receptor 1 antagonist, induced complete or
partial resolution of pruritus in 12 patients [89]. However, in a subsequent randomized, cross-over
trial including 58 patients with chronic PN, four-week treatment with aprepitant 80 mg per day was
no more effective than placebo in reducing pruritus intensity in both intention-to-treat and per
protocol analysis [90]. Nonsevere adverse events occurred with equal frequency in the aprepitant
and placebo groups.
EXPERIMENTAL THERAPIES Nemolizumab is a

humanized antihuman interleukin (IL) 31 receptor monoclonal antibody that inhibits the binding of
IL-31 to its receptor and subsequent signal transduction. In phase II clinical trials, nemolizumab
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showed efficacy in reducing pruritus associated with atopic dermatitis [91-93].
The efficacy of nemolizumab for the treatment of PN was evaluated in a randomized, phase II trial
including 70 patients with moderate to severe PN (defined as presence of 20 or more nodules) and
severe pruritus (defined as a mean score of at least 7 for the worst daily intensity of pruritus on a
numerical rating scale of 0 to 10) for at least six months [94]. Patients received subcutaneous
nemolizumab 0.5 mg/kg or placebo at baseline, week 4, and week 8. The primary outcome was the
percent change from baseline in the peak pruritus score at week 4. Secondary outcomes included
the reduction in the number of skin nodules at week 12. At week 4, the average peak pruritus score
was reduced by 4.5 points (-53 percent) from baseline compared with a reduction by 1.7 points (-20
percent) in the placebo group (percentage difference 32.8, 95% CI -46.8 to -18.8). At week 12, the
reduction in the mean lesion count was greater in the nemolizumab group than in the placebo group
(least squares mean -12.6 versus -6.1 lesions, 95% CI -12.5 to -0.6). Adverse events associated with
nemolizumab included abdominal pain, diarrhea, and musculoskeletal pain.
In a randomized trial including 128 patients with chronic, treatment-refractory PN, serlopitant, a
novel oral neurokinin 1 (NK1) antagonist, given at the dose of 5 mg orally once daily for eight weeks
was more effective than placebo in reducing the average itch visual analog scale scores (least
squares mean difference [serlopitant minus placebo] was -1 at week 4 and -1.7 at week 8) [95].
Adverse events in the serlopitant group included nasopharyngitis, diarrhea, and fatigue.
PROGNOSIS PN is a chronic and often intractable disease that may last for
years, with a profound impact on the patient's quality of life. Complete resolution of lesions is rare,
even after the itch-scratch cycle has been successfully interrupted. Recurrence is common.
SUMMARY AND
RECOMMENDATIONS
●Prurigo nodularis (PN) is a chronic skin disorder characterized by multiple firm, itchy nodules
typically localized to the extensor surface of the extremities (picture 1C-E, 1G). Pruritus is always
severe and distressing; it can be paroxysmal, sporadic, or continuous and is worsened by heat,
sweating, or irritation from clothing. (See 'Introduction' above and 'Clinical manifestations' above.)
●The diagnosis of PN is clinical, based upon a history of chronic, severe pruritus and the clinical
finding of characteristic excoriated, nodular lesions symmetrically distributed. Cutaneous and
systemic causes of chronic pruritus should be investigated. (See 'Diagnosis' above and "Pruritus:
Etiology and patient evaluation", section on 'Potential causes'.)
●Treatment of PN is difficult and requires a multifaceted approach, involving patient education to

adopt skin care measures to reduce skin irritation and scratching, symptomatic treatment of
pruritus, and topical or systemic therapies aimed at interrupting the itch-scratch cycle and flattening
910
the skin lesions. (See 'Management' above and 'Symptomatic control of pruritus' above.)
●For patients with a limited number of nodular lesions, we suggest superpotent topical
corticosteroids (group 1 (table 2)) as first-line therapy (Grade 2C). Intralesional injection of
corticosteroids may be an additional or alternative treatment modality for patients with very few
lesions. Sedating antihistamines, such diphenhydramine, hydroxyzine, or others, are routinely used.
(See 'Patients with limited disease' above.)
●For patients with widespread or recalcitrant disease, we suggest phototherapy with narrowband
UVB (NBUVB) in combination with topical corticosteroids and oral antihistamines rather than
systemic agents (Grade 2C). Topical or oral psoralen plus ultraviolet A (PUVA) can be alternative
forms of phototherapy if NBUVB is not available. (See 'Patients with widespread or recalcitrant
disease' above.)
●For patients with widespread or recalcitrant disease who fail to respond to phototherapy and for
those for whom phototherapy is not feasible, we suggest dupilumab (Grade 2C). Other therapeutic
options include methotrexate, oral cyclosporine, or thalidomide. Neuromodulators, such as
gabapentin and pregabalin, may be beneficial in some patients. (See 'Dupilumab' above and
'Systemic therapies' above.)
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Seborrheic dermatitis in adolescents and adults
uptodate.com/contents/seborrheic-dermatitis-in-adolescents-and-adults/print
INTRODUCTION Seborrheic dermatitis is a chronic, relapsing, and usually

mild form of dermatitis that occurs in infants and in adults. The severity may vary from minimal,
asymptomatic scaliness of the scalp (dandruff) to more widespread involvement. Affected
individuals are usually healthy, although seborrheic dermatitis has been associated with HIV
infection, Parkinson disease, a number of other neurologic disorders, and use of neuroleptic
medications.
This topic will discuss the pathogenesis, clinical manifestations, and management of seborrheic
dermatitis in adolescents and adults. The infantile form of seborrheic dermatitis is discussed
separately. (See "Cradle cap and seborrheic dermatitis in infants".)
EPIDEMIOLOGY Seborrheic dermatitis has a biphasic incidence,

occurring in infants between the ages of 2 weeks and 12 months and, later, during adolescence and
adulthood. The prevalence of clinically significant seborrheic dermatitis is approximately 3 percent,
with peak prevalence in the third and fourth decades [1]. The actual prevalence is probably much
higher when mild cases are included. Men are affected more frequently than women.
The prevalence of seborrheic dermatitis is increased among individuals with HIV infection, in whom
it may be a presenting sign. The prevalence has been estimated to be around 35 percent among
patients with early HIV infection and up to 85 percent among patients with AIDS [2,3].
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Patients with parkinsonism frequently present with seborrhea (oily skin) and seborrheic dermatitis,
both of which may improve with L-dopa therapy [4,5]. (See "Clinical manifestations of Parkinson
disease", section on 'Nonmotor symptoms'.)
PATHOGENESIS The cause of seborrheic dermatitis is not known.

Seborrheic dermatitis is not a disease of the sebaceous glands nor is the rate of sebum excretion
increased in patients with seborrheic dermatitis [6]. Nonetheless, sebaceous glands appear to be
necessary for the development of seborrheic dermatitis as indicated by the predilection for body
sites with increased numbers of sebaceous glands and larger sebaceous glands (face, scalp, upper
trunk, external auditory meatus, and anogenital area). In addition, the infantile form is common early
in the first year of life, when androgen-producing, enlarged, neonatal adrenal glands and
transplacental transfer of maternal androgens stimulate the growth of the infant's sebaceous
glands.
Sebaceous glands may play a permissive role in the pathogenesis of seborrheic dermatitis, possibly
by creating a favorable milieu for the growth of fungi of the genus Malassezia. The lipid-dependent
Malassezia (formerly known as Pityrosporum ovale) is a saprophyte of normal skin that thrives at the
sites of predilection for seborrheic dermatitis [7,8]. The use of molecular markers, such as 26S rDNA,
ITS, and 5.8S, has allowed better species identification and revealed intraspecies differences that
could be related to pathogenicity [9,10]. However, there is limited direct evidence that Malassezia is
implicated in the etiology of seborrheic dermatitis. Studies have failed to demonstrate a higher
density of Malassezia on the skin of affected individuals or a relationship between the intensity of
skin colonization and severity of seborrheic dermatitis, although some specific Malassezia species
have been detected more frequently on affected skin than on normal skin [11-13]. A higher density of
Malassezia has been demonstrated in patients with Parkinson disease and seborrheic dermatitis
compared with controls, with a predominance of Malassezia globosa displaying high production of
lipases and phosphatases [14].
Indirect evidence for a role of Malassezia in seborrheic dermatitis derives from the observation that
most of the effective therapeutic agents have antifungal activity. However, the nonspecific anti-
inflammatory effect of the azole antifungal agents commonly used for seborrheic dermatitis may
also explain their efficacy, given that some studies have been unable to demonstrate in vivo a
decrease in Malassezia colonization after treatment with topical ketoconazole [15].
Observational studies suggest that in some patients seborrheic dermatitis may result from the host's
immune response to Malassezia or to its byproducts (eg, lipases or free fatty acids) [16,17]. Other
studies, however, were unable to find humoral or cellular immunologic abnormalities in patients with
seborrheic dermatitis [18]. The inflammation of seborrheic dermatitis may be irritant-mediated rather
than immune-mediated, due to Malassezia production of free fatty acids, lipase, and reactive oxygen
species [16]. The lipases and phospholipases produced by Malassezia cleave free fatty acids from
triglycerides present in sebum, which are known irritants and can induce inflammation. In addition,
lipases and phosphatases damage surrounding cells with release of oleic and arachidonic acid from
913
their walls. Arachidonic acid is further metabolized by cyclooxygenase in proinflammatory
eicosanoids [14]. Additional factors that may be playing a role in the inflammation of seborrheic
dermatitis include oxidative stress and the overproduction of cell-damaging oxygen radicals [19].
The reason for the increased susceptibility of patients with HIV infection to seborrheic dermatitis is
not known. A transgenic mouse deficient in CD4+ and CD8+ cells has been shown to develop a
seborrheic dermatitis-like skin disease, an overgrowth of yeast cells in hair follicles, and an
improvement with fluconazole [19]. This suggests that dysregulation of the immune system may
play a role in the increased prevalence of seborrheic dermatitis in the immunocompromised host.
The relationship between seborrheic dermatitis and neurologic disorders is also poorly understood.
Patients with Parkinson disease often have increased sebum production; in these patients,
seborrhea and seborrheic dermatitis improve with L-dopa therapy [4,5].
CLINICAL MANIFESTATIONS Seborrheic

dermatitis may first appear soon after puberty or later in life. It is usually characterized by well-
demarcated, erythematous plaques with greasy-looking, yellowish scales distributed on areas rich in
sebaceous glands, such as the scalp, the external ear, the center of the face, the upper part of the
trunk, and the intertriginous areas (picture 1A-C).
Scalp — The mildest and most common form of scalp seborrheic dermatitis is dandruff, also
known as pityriasis sicca, in which the scalp shows fine, white, diffuse scaliness without underlying
erythema (picture 2). Dandruff may be asymptomatic or accompanied by mild pruritus. More severe
forms of scalp seborrheic dermatitis present with visible inflammation, consisting of patchy, orange
to salmon-colored or grayish plaques covered with yellowish, greasy scales (pityriasis steatoides),
mostly over the temporoparietal areas (picture 3A-B) or with concretions of scale around hair shafts
(pityriasis amiantacea) (picture 3C). Lesions may extend to the postauricular areas (picture 1B),
where they often develop fissures, oozing, and crusting, and to the outer canal and concha of the ear,
sometimes with marked pruritus and superinfection (otitis externa). (See "External otitis:
Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis and risk factors'.)
Face — Facial lesions favor the forehead below the hairline, the eyebrows and glabella (picture
3B), and the nasolabial folds. They may extend to the cheeks and malar areas in a butterfly
distribution (picture 1C-E). The mustache and beard area are frequently involved in men with facial
hair. Shaving helps with treatment and control of the disease.
Periocular — Blepharitis with redness of the free margin of the eyelids and yellow
crusting between the eyelashes may be the sole manifestation of seborrheic dermatitis or may
accompany its more classic distribution. (See "Blepharitis", section on 'Clinical findings'.)
Trunk — Five patterns of truncal involvement have been described:
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●Moist, erythematous intertrigo of the axillae, inframammary folds, umbilicus, and genitocrural area
(picture 1F)
●The "petaloid pattern," consisting of polycyclic, finely scaly, thin plaques over the sternum or
interscapular area
●Annular or arcuate, round to oval, slightly scaly plaques on the trunk, sometimes with
hypopigmented central clearing, known as "seborrheic eczematids"
●The pityriasiform pattern mimicking pityriasis rosea, comprised of 5 to 15 mm, oval-shaped, scaly
lesions distributed along the skin tension lines
●The psoriasiform pattern with larger red, rounded plaques, covered with thicker scales
In patients with HIV — Seborrheic dermatitis tends to be more extensive and

severe in HIV/AIDS patients. It sometimes involves unusual sites, such as the extremities, and may
be difficult to control [3,20]. Seborrheic dermatitis is frequently observed in patients with CD4 counts
<400 cells/microL and is more diffuse and severe in patients with CD4 counts <200 cells/microL
[21,22]. It may regress with antiretroviral therapy (ART). However, seborrheic dermatitis also may be
a cutaneous manifestation of the immune reconstitution inflammatory syndrome in patients on ART
[23]. (See "Immune reconstitution inflammatory syndrome", section on 'Miscellaneous syndromes
possibly associated with IRIS'.)
CLINICAL COURSE Seborrheic dermatitis is a chronic, relapsing

condition that may go on for decades. It tends to worsen with stress and during the cold and dry
winter months. It tends to improve during the summer months, probably from sun exposure,
although it may be precipitated by psoralen plus ultraviolet A (PUVA) therapy [24]. The available
treatments do not cure seborrheic dermatitis and must be repeated or continued intermittently to
prevent recurrence. (See 'Management' below.)
DIAGNOSIS The diagnosis of seborrheic dermatitis is usually made clinically

based on the appearance and location of the lesions. (See 'Clinical manifestations' above.)
Biopsy is not routinely necessary but may be indicated when the diagnosis is uncertain. (See
'Differential diagnosis' below.)
Histopathology — There are no uniquely characteristic or pathognomonic

histologic features in seborrheic dermatitis. In HIV-negative patients, histology shows focal
parakeratosis in the horny layer of the epidermis; mounds of scale-crusts with pyknotic neutrophils
on the lips of dilated, sometimes plugged, follicular ostia; psoriasiform acanthosis; and mild to
moderate spongiosis. The dermis harbors a sparse, perivascular, lymphohistiocytic inflammatory
915
infiltrate. In chronic cases, the histologic picture may be difficult to distinguish from psoriasis, but
the presence of even a minimal degree of spongiosis should favor a diagnosis of seborrheic
dermatitis.
In HIV/AIDS patients, the histopathologic changes parallel the severity of the disease. Parakeratosis
is more widespread, and the epidermis shows necrotic keratinocytes. Spongiosis is less prominent;
the inflammatory infiltrate is denser and in some areas obliterates the dermoepidermal junction. It
contains numerous plasma cells and foci of leukocytoclasis [3].

of seborrheic dermatitis includes psoriasis, rosacea, tinea versicolor, pityriasis rosea, tinea corporis,
secondary syphilis, systemic lupus erythematosus (SLE), and pemphigus foliaceous. Most of these
conditions can be distinguished clinically; syphilis, SLE, and pemphigus foliaceous require
laboratory confirmation. Allergic contact dermatitis may also be considered, particularly when the
presentation is atypical or pruritus is significant.
●Psoriasis – Psoriasis is the main condition in the differential diagnosis of seborrheic dermatitis in
adolescents and adults. Sometimes the two diseases may coexist, and the term "sebopsoriasis" has
been given to those cases where the distinction cannot be made. Usually, however, psoriatic lesions
are sharply demarcated and erythematous, and the scales are more abundant and silvery white
(picture 4). In most cases the extensor areas such as the elbows and knees are involved, although
the lesions can occur in the body folds (inverse psoriasis) (picture 5). Characteristic nail changes
(picture 6A-B), as well as the presence of arthritis or a positive family history may help establish the
diagnosis of psoriasis. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis",
●Rosacea – Rosacea is another condition that commonly targets the face and sometimes coexists
with seborrheic dermatitis. In contrast with seborrheic dermatitis, rosacea shows a predominance of
telangiectasias and papulopustules, with frequent involvement of the nose, malar, and perioral areas
and minimal or no scaliness (picture 7A-E). (See "Rosacea: Pathogenesis, clinical features, and
diagnosis", section on 'Clinical features'.)
●Allergic contact dermatitis – Allergic contact dermatitis may be suspected in patients with
seborrheic dermatitis that does not respond to standard therapy, especially if pruritus is the
predominant symptom. Allergic contact dermatitis may occur concurrently or be a complication of
seborrheic dermatitis in patients allergic to components of topical medications for seborrheic
dermatitis or regular skin and hair care products. Patch testing may be necessary to confirm the
diagnosis [25]. (See "Clinical features and diagnosis of allergic contact dermatitis".)
●Tinea versicolor – On the trunk, petaloid lesions of seborrheic dermatitis may be mistaken for tinea
versicolor, which usually lacks erythema (picture 8). (See "Tinea versicolor (pityriasis versicolor)",
section on 'Clinical features'.)
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●Pityriasis rosea – Pityriasis rosea is distinguished from seborrheic dermatitis by its abrupt onset,
presence of a herald patch, and resolution within a few weeks (picture 9A-B). The pityriasiform
variant of seborrheic dermatitis should be suspected when lesions appear more progressively,
persist for more than three months, and are accompanied by lesions on areas usually spared by
pityriasis rosea (the face and intertriginous areas). (See "Pityriasis rosea", section on 'Clinical
features'.)
●Tinea corporis – Annular or arciform seborrheic dermatitis lesions on the trunk can be confused
with tinea corporis (picture 10); tinea corporis can be ruled out by negative potassium hydroxide
(KOH) microscopic examination and negative fungal culture. (See "Dermatophyte (tinea) infections",
section on 'Tinea corporis'.)
●Secondary syphilis – Secondary syphilis, the great imitator, can trigger widespread pityriasiform or
psoriasiform eruptions that can be mistaken for seborrheic dermatitis. Additional signs such as
palmoplantar and mucosal lesions or peripheral adenopathy should be looked for, and appropriate
serologic testing ordered when indicated.
●Lupus erythematosus – Seborrheic dermatitis of the face may be mistaken for the butterfly
eruption of acute systemic lupus erythematosus (SLE) or the discoid plaques of cutaneous LE
(picture 11A-B). The acute eruption of SLE rarely involves the nasolabial sulcus or crosses the bridge
of the nose. Discoid lesions exhibit atrophy and sometimes scarring, along with adherent scales that
may have "carpet tacking" on their undersurface (spiny projections that plug dilated follicular
openings). Histologic examination and serologic testing for antinuclear autoantibodies should be
performed to confirm the diagnosis. (See "Overview of cutaneous lupus erythematosus".)
●Pemphigus foliaceous – Pemphigus foliaceous is characterized by erythema, scaling, painful

erosions, and crusting that first appear on the face and scalp (picture 12A-B) and later involves the
chest and back. Histology, direct immunofluorescence, and the measurement of circulating
autoantibodies against desmoglein establish the diagnosis. Pemphigus erythematosus of Senear
and Usher is a superficial variant of pemphigus foliaceous that is most likely to mimic seborrheic
dermatitis. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on
'Pemphigus foliaceus'.)
MANAGEMENT
Overview — Seborrheic dermatitis is a chronic condition. The main goal of therapy is to
clear the visible signs of the disease and reduce associated symptoms, such as erythema and
pruritus. Repeated or long-term maintenance treatment is often necessary. The available treatments
include topical antifungal agents, topical anti-inflammatory agents, and several topical agents with
nonspecific antimicrobial, anti-inflammatory, or keratolytic properties. Oral antifungal agents may be
a therapeutic option in patients with moderate to severe seborrheic dermatitis that is not adequately
controlled with topical therapies. (See 'Severe or refractory seborrheic dermatitis' below.)
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●Topical antifungals – Topical antifungal agents (eg, ketoconazole, other azoles, ciclopirox olamine)
are well established in the treatment of seborrheic dermatitis of the scalp and face because of their
ability to decrease the population of Malassezia furfur on the affected skin and their anti-
inflammatory property [26,27]. A 2015 systematic review and meta-analysis including 51
randomized trials with over 9000 participants found that in patients with seborrheic dermatitis of the
face and scalp, topical ketoconazole 2% applied once or twice daily was more effective than placebo
in improving erythema, pruritus, and scaling at four weeks [26]. In studies comparing topical
ketoconazole with topical corticosteroids, both agents had similar efficacy, although topical
corticosteroids showed a two-fold greater risk of side effects compared with ketoconazole [26]. In a
small randomized study, the efficacy of a noncorticosteroid combination shampoo containing the
antifungal agent piroctone olamine, lactic acid as a keratolytic, and dipotassium glycyrrhizate, a
licorice extract with mild anti-inflammatory properties, was compared with that of ketoconazole 1%
shampoo in 20 patients with mild to moderate seborrheic dermatitis of the scalp [28]. Both
treatments were found to be equally effective, although the noncorticosteroid product showed better
relief of pruritus.
●Topical anti-inflammatory agents – Topical corticosteroids are widely used for the treatment of
seborrheic dermatitis because they reduce inflammation, erythema, and pruritus. Topical calcineurin
inhibitors (tacrolimus and pimecrolimus) may be used as an alternative to topical corticosteroids
because of their anti-inflammatory properties and lack of adverse effects associated with prolonged
use of topical corticosteroids (eg, skin atrophy, telangiectasia) [29-33].
A 2014 systematic review including 36 randomized trials (2706 participants) found that short-term
(≤4 weeks) treatment with topical corticosteroids (eg hydrocortisone, betamethasone), topical
calcineurin inhibitors (ie, tacrolimus, pimecrolimus), and topical preparations of lithium salts all
reduced the symptoms of seborrheic dermatitis when compared with placebo [34]. The median rate
of total clearance with anti-inflammatory treatments was 53 percent across studies. The frequency
of adverse effects, including erythema, burning, dryness, and itching, was similar across all
treatment groups. The quality of the included studies was generally low.
In a single case report, crisaborole 2% cream, a topical anti-inflammatory agent approved for the
treatment of mild to moderate atopic dermatitis, may be an option for the treatment of chronic facial
seborrheic dermatitis [35]. Crisaborole is an inhibitor of phosphodiesterase 4 (PDE4) that raises
intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in decreased levels of the
proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 17a. (See
"Treatment of atopic dermatitis (eczema)", section on 'Crisaborole'.)
●Other topical agents – Topical agents available over the counter in various vehicles for the
treatment of seborrheic dermatitis include selenium sulfide, lithium succinate and gluconate, zinc
pyrithione, salicylic acid, and coal tar.
•Selenium sulfide is a heavy metal salt with antifungal properties. The efficacy of selenium sulfide
shampoo for the treatment of seborrheic dermatitis of the scalp has been evaluated in one
randomized trial including 149 participants [36]. In this study, more patients treated with selenium
sulfide 2.5% shampoo for four weeks were cleared or had an excellent or good response than those
918
treated with placebo (55 versus 29 percent). Adverse effects of selenium sulfide shampoo include
pruritus, burning sensation, and hair/scalp discoloration. Sulfur itself, in the form of precipitated
sulfur 3%, colloidal sulfur 5%, or sodium sulfacetamide 10%, in cream or lotion base, remains an old
but effective remedy, although patients may object to its odor [37,38].
•Topical lithium sulfate or gluconate (available in Europe but not in the United States) have been
shown to be effective in treating seborrheic dermatitis in areas other than the scalp, probably
because of their anti-inflammatory properties [39-41]. In a randomized trial, more patients treated
with eight weeks of lithium gluconate 8% cream than those treated with ketoconazole 2% cream had
improvement in erythema and desquamation (52 versus 30 percent) [42]. Local irritant reactions
have been reported in approximately 10 percent of patients using topical lithium salts.
•Zinc pyrithione has antibacterial and antifungal properties [43]. Shampoos containing zinc
pyrithione 1% are commonly used to treat dandruff and mild seborrheic dermatitis of the scalp. In
one randomized trial including 343 subjects with severe dandruff and seborrheic dermatitis,
treatment with ketoconazole 2% shampoo or zinc pyrithione 1% shampoo for four weeks induced
improvement in a similar proportion of participants (73 and 67 percent, respectively) [44].
•Shampoos containing salicylic acid and coal tar have keratolytic properties and may be helpful in
softening thick scales [45,46]. Tar may be combined with zinc pyrithione [47] or even used under
occlusion for refractory seborrheic dermatitis or psoriasis [48]. As with sulfur, patients may find the
odor of tar objectionable or be concerned about its potential carcinogenicity [49].
●Experimental topical agents – In a pilot study of 20 patients with seborrheic dermatitis, a topical
formulation containing N-butanoyl glutathione (GSH-C4) 0.4% in hyaluronic acid 0.25% induced
marked improvement at four weeks, as assessed by the Investigator Global Assessment, Patient
Global Assessment, and Pruritus Visual Analogue Scale [50]. Glutathione, a scavenger of free
radicals, reduces oxidative stress, which plays a role in the induction of inflammation. In addition,
glutathione may also have a direct anti-inflammatory activity by reducing the expression of
proinflammatory cytokines through the nuclear factor-kappa B pathway.
●Oral antifungal agents – Oral antifungal agents, including itraconazole, ketoconazole, fluconazole,
and terbinafine, may be a treatment option for seborrheic dermatitis involving multiple body areas
and for recalcitrant dermatitis that is not adequately controlled with topical therapies. However,
evidence supporting their use is limited.
•A 2014 systematic review including nine uncontrolled, poor-quality studies evaluating oral
itraconazole for seborrheic dermatitis found that itraconazole was effective in inducing clinical
improvement and mycologic cure in 59 to 93 percent and 40 to 86 percent of patients, respectively
[51]. The regimen most frequently used involved the oral administration of itraconazole 200 mg per
day for seven days followed by varying intermittent therapy for 2 to 11 months.
•In a randomized trial, 68 patients with moderate to severe seborrheic dermatitis received topical 1%
hydrocortisone ointment once daily and 2% ketoconazole cream twice daily plus either oral
itraconazole 200 mg/day or placebo for one week, followed by a maintenance treatment with oral
919
itraconazole 200 mg/day or placebo given on the first two days of the following three months [52]. At
four months, 10 patients in the itraconazole group, but none in the placebo group, achieved complete
clearing; moderate to marked improvement was reported in 65 and 79 percent of patients in the
itraconazole and placebo groups, respectively.
●Other systemic agents – A case report describes the successful use of the oral PDE4 inhibitor
apremilast in three patients with recalcitrant seborrheic dermatitis who had failed all topical
therapies [53]. Apremilast is approved for the treatment of psoriasis, and its mechanism of action is
the same as for topical crisaborole described above. (See "Treatment of psoriasis in adults", section
on 'Apremilast'.)
Seborrheic dermatitis of the scalp — For patients with mild

seborrheic dermatitis of the scalp who have diffuse, fine desquamation without inflammation
(dandruff), we suggest treatment with an antifungal shampoo. Antifungal shampoos include
ketoconazole 2% and ciclopirox 1%, available by prescription, and zinc pyrithione 1% and selenium
sulfide 2.5% shampoo, available over the counter.
Five to 10 mL of shampoo should be left on for three to five minutes before rinsing off. Ketoconazole
shampoo should be used twice a week for two to four weeks in the treatment phase.
The recommendations for ciclopirox shampoo call for twice-weekly use for four weeks, with a
suggestion from the manufacturer not to use it more often than every three days. The Canadian
monograph for ciclopirox shampoo recommends usage two to three times per week or as often as
necessary.
Subsequently, the use of the medicated shampoo once a week may be helpful to prevent relapse
[54]. Minor adverse effects, such as irritation and/or burning sensation, are common with antifungal
shampoo [36,55].
Patients sometimes complain that their shampoo is no longer effective. Given that some strains of
Malassezia eventually become resistant to azole antifungals [19], it may be wise to effectuate, every
few weeks to months, a rotation among shampoos based on different molecules.
For patients with moderate to severe seborrheic dermatitis of the scalp who have scale,
inflammation, and pruritus, we suggest treatment with an antifungal shampoo (eg, ketoconazole 2%
shampoo) in combination with a high-potency topical corticosteroid (table 1) in a formulation (lotion,
spray aerosol, or foam) of patient choice. Topical corticosteroids can be used daily for two to four
weeks.
The addition of a salicylic acid shampoo to the above regimen may be helpful for patients with thick
scale.
Seborrheic dermatitis of the face — For patients with

seborrheic dermatitis of the face, we suggest treatment with a low-potency topical corticosteroid
cream (group 7 or 6 (table 1)), a topical antifungal agent (ketoconazole 2% cream, other azole
920
creams, or ciclopirox 1% cream, (table 2)), or a combination of the two. The topical corticosteroid
cream is applied to the affected areas once or twice daily only until symptoms subside to avoid
potential adverse effects associated with prolonged use of topical corticosteroids on the face. (See
"Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Topical calcineurin inhibitors (tacrolimus 0.1% ointment and pimecrolimus 1% cream) may be used
as an alternative to topical corticosteroids for the treatment of facial seborrheic dermatitis
[32,56,57]. Lithium succinate and lithium gluconate cream or gel are available in Europe and have
been shown to be effective in treating seborrheic dermatitis in areas other than the scalp [39-41].
For men with seborrheic dermatitis of the face who have mustaches and beards, we suggest
ketoconazole 2% shampooing of the facial hair daily until remission and then once per week. A low-
potency corticosteroid (group 7 (table 1)) can be added to the initial treatment to control
inflammation and itching.
Seborrheic blepharitis — The management of blepharitis, including

seborrheic blepharitis, is discussed separately. (See "Blepharitis", section on 'Management'.)
Seborrheic dermatitis of the trunk and

intertriginous areas — For patients with seborrheic dermatitis of the trunk
and intertriginous areas, we suggest treatment with topical antifungal agents, topical corticosteroid
creams, or a combination of the two. A low-potency topical corticosteroid cream should be used in
the intertriginous areas; medium-potency topical corticosteroids (table 1) can be used for seborrheic
dermatitis involving the chest or the upper back. The topical corticosteroid cream is applied to the
affected areas once or twice daily only until symptoms subside to avoid potential adverse effects.
Alternative topical antifungal agents include ketoconazole 2% cream, other azole creams, and
ciclopirox cream. Topical antifungal agents are applied to affected areas once or twice daily until
symptoms subside. Adverse effects are uncommon with topical antifungal agents.
Seborrheic dermatitis in patients with HIV

infection — Seborrheic dermatitis is more diffuse and severe in HIV-positive patients and
may require a prolonged course of treatment. There are no studies evaluating the treatment of
seborrheic dermatitis in HIV-positive patients. Initial management is the same as for patients who
are not HIV-positive [58,59]. In severe cases or in cases that are refractory to topical treatment, a
course of oral itraconazole (200 mg/day orally for one week) may be warranted.
Severe or refractory seborrheic dermatitis — There

is little evidence to guide treatment of severe or refractory seborrheic dermatitis in non-HIV-positive
patients. Agents that have been used in observational studies or small randomized trials include oral
921
ketoconazole, itraconazole, fluconazole, and terbinafine [51,52]. Among these, we suggest oral
itraconazole. Oral itraconazole is given at the dose of 200 mg per day for seven days.
Whenever apparent seborrheic dermatitis does not respond to appropriate therapy, the diagnosis
should be reconsidered. (See 'Differential diagnosis' above.)
Coexistent seborrheic dermatitis and

rosacea — In patients with coexistent facial seborrheic dermatitis and rosacea, adequate
treatment of both conditions may be difficult. Prolonged use of even mild topical corticosteroids
prescribed for seborrheic dermatitis may exacerbate rosacea and should ideally be avoided or used
very sparingly and intermittently. By contrast, topical metronidazole 1% gel or cream, used for
rosacea, may also help mild seborrheic dermatitis. In patients who have papulopustular rosacea and
facial seborrheic dermatitis, topical azelaic acid, which has antibacterial and antifungal properties,
has been suggested as a treatment option for both conditions [60]. (See "Management of rosacea",
section on 'Topical azelaic acid'.)
PREVENTION OF RELAPSE For most patients with

seborrheic dermatitis, we suggest intermittent use of topical therapies to prevent relapse.
Ketoconazole 2% shampoo and ciclopirox 1% shampoo, used intermittently, have been shown to be
effective in preventing relapses of scalp seborrheic dermatitis [54,61].
●In a six-month trial in which 312 patients who responded to initial treatment of scalp seborrheic
dermatitis were randomly assigned to ketoconazole 2% shampoo once weekly, every two weeks, or
placebo, relapses were observed in 19, 31, and 47 percent of the patients, respectively [61].
●In a similar study in which 428 patients were randomly assigned to four months of treatment with
ciclopirox shampoo once weekly, every two weeks, or placebo, the relapse rates were 15, 22, and 35
percent, respectively [54].
The prevention of relapse of seborrheic dermatitis of the face, trunk, and intertriginous areas has not
been well studied. However, it is common practice to use antifungal cream or ketoconazole 2%
shampoo (as facial or body wash) intermittently to prevent relapse. The risk of side effects with this
approach is minimal.

provided separately. (See "Society guideline links: Seborrheic dermatitis".)
922
●Basics topic (see "Patient education: Seborrheic dermatitis (The Basics)")
●Beyond the Basics topics (see "Patient education: Seborrheic dermatitis (including dandruff and
cradle cap) (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Seborrheic dermatitis is a chronic, relapsing, and usually mild form of dermatitis of unknown origin
occurring in areas rich in sebaceous glands (scalp, face, upper trunk, intertriginous areas); indirect
evidence supports a pathogenetic role for the Malassezia yeast. (See 'Pathogenesis' above.)
●The mildest and most common form of scalp seborrheic dermatitis is dandruff, a fine, white,
diffuse scaliness of the scalp without underlying erythema (picture 2). Manifestations of severe
seborrheic dermatitis of the scalp (picture 3A-C) or other body sites include inflamed, erythematous
plaques covered with yellowish, greasy scales (picture 1C, 1E-F). (See 'Clinical manifestations'
above.)
●The diagnosis of seborrheic dermatitis is usually made clinically based on the appearance and
location of the lesions. The differential diagnosis includes psoriasis (picture 4), rosacea (picture 7A-
E), tinea versicolor (picture 8), pityriasis rosea (picture 9A-B), tinea corporis (picture 10), secondary
syphilis, lupus erythematosus (picture 11A-B), and pemphigus foliaceous (picture 12A-B). These
conditions can be differentiated clinically and/or through laboratory tests and histology. (See
'Diagnosis' above and 'Differential diagnosis' above.)
●For patients with mild seborrheic dermatitis of the scalp without inflammation (dandruff), we
suggest treatment with antifungal shampoos (ketoconazole 2%, ciclopirox 1%) (Grade 2B).
Alternative medicated fungal shampoos available over the counter include zinc pyrithione 1% and
923
selenium sulfide 2.5%. The medicated shampoo should be used frequently (daily or at least two or
three times per week) for several weeks, until remission is achieved. (See 'Seborrheic dermatitis of
the scalp' above.)
For patients with moderate to severe seborrheic dermatitis of the scalp who have scale,
inflammation, and pruritus, we suggest treatment with an antifungal shampoo (eg, ketoconazole 2%
shampoo) in combination with a high-potency topical corticosteroid (table 1) in a formulation (lotion,
spray, foam) of patient choice (Grade 2B). The topical corticosteroid can be used once daily for two
to four weeks. (See 'Seborrheic dermatitis of the scalp' above.)
●For patients with seborrheic dermatitis of the face, we suggest treatment with low-potency topical
corticosteroid cream (groups 6 or 7 (table 1)), topical antifungal agent (ketoconazole 2% cream,
other azole creams, or ciclopirox 1% cream (table 2)), or a combination of the two (Grade 2B). The
topical therapy is applied to the affected areas once or twice daily only until symptoms subside. (See
'Seborrheic dermatitis of the face' above.)
For men with seborrheic dermatitis of the face who have mustaches and beards, we suggest
ketoconazole 2% shampooing of the facial hair (Grade 2C). The shampoo is used daily until
remission and then once per week. A low-potency corticosteroid (group 7 (table 1)) can be added to
the initial treatment to control inflammation and itching.
●For patients with seborrheic dermatitis of the trunk and intertriginous areas, we suggest treatment
with low-potency (groups 6 or 7) topical corticosteroid cream (table 1), topical antifungal agents, or a
combination of the two (Grade 2C). Medium-potency topical corticosteroids (groups 4 or 5) can be
used for seborrheic dermatitis involving the chest or the upper back. The topical therapy is applied to
the affected areas once or twice daily only until symptoms subside. (See 'Seborrheic dermatitis of
the trunk and intertriginous areas' above.)
●For most patients with seborrheic dermatitis, intermittent use of topical therapies may be helpful to
prevent relapse (see 'Prevention of relapse' above):
•Ketoconazole 2% shampoo or ciclopirox 1% shampoo once per week for seborrheic dermatitis of
the scalp.
•Ketoconazole 2% shampoo (as facial or body wash) or ketoconazole 2% cream, other azole cream,
or ciclopirox 1% cream once per week for seborrheic dermatitis of the face, trunk, and intertriginous
areas.
924
Stasis dermatitis - UpToDate
uptodate.com/contents/stasis-dermatitis/print
INTRODUCTION Stasis dermatitis, or stasis eczema, is a common

inflammatory dermatosis of the lower extremities occurring in patients with chronic venous
insufficiency, often in association with varicose veins, dependent chronic edema, hyperpigmentation,
lipodermatosclerosis, and ulcerations. Stasis dermatitis may rarely involve the upper limbs in
patients with artificial arteriovenous (AV) fistulas for hemodialysis, or congenital AV malformations
[1,2].
This topic will discuss the pathogenesis, clinical presentation, complications, and treatment of stasis
dermatitis. The pathophysiology, clinical and diagnostic evaluation, and treatment of lower extremity
chronic venous disease are discussed separately.
●(See "Pathophysiology of chronic venous disease".)
●(See "Diagnostic evaluation of lower extremity chronic venous insufficiency".)
●(See "Post-thrombotic (postphlebitic) syndrome".)
●(See "Medical management of lower extremity chronic venous disease".)
925
EPIDEMIOLOGY Skin changes related to chronic venous insufficiency,
including edema, hyperpigmentation, eczema, fibrosis, atrophy, and ulceration, are reported in 1 to 20
percent of women and in 1 to 17 percent of men [3]. In one study, stasis dermatitis was reported in
6.2 percent of patients over the age of 65 [4]. Established risk factors for varicose veins and chronic
venous insufficiency include age, family history of venous disease, female sex, standing occupation,
obesity, and history of deep vein thrombosis [3,5]. Heart failure and hypertension are aggravating
factors.
The epidemiology of chronic venous insufficiency is discussed separately. (See "Overview of lower
extremity chronic venous disease", section on 'Epidemiology and risk factors'.)
PATHOPHYSIOLOGY The final common pathway that leads to

chronic venous insufficiency is the development of venous hypertension [6]. In most cases, venous
hypertension results from dysfunction of the venous valves, obstruction to the venous flow, or failure
of the "venous pump" [7]. If the valves of deep or perforator veins are incompetent, the increased
pressure generated during standing or calf muscle contraction causes blood to reflux into the
superficial venous system, converting it into a high-pressure system. (See "Pathophysiology of
chronic venous disease", section on 'Genesis and consequences of chronic venous hypertension'.)
In some patients, chronic edema of the lower extremities induced by drugs (table 1) may be a
contributor factor in the pathogenesis of stasis dermatitis [8].
PATHOLOGY Hyperkeratosis, parakeratosis, acanthosis, and mild spongiosis

are the epidermal changes usually seen in uncomplicated stasis dermatitis. Spongiosis may be
prominent in cases with a superimposed contact dermatitis. Dermal changes include proliferation of
small blood vessels in the papillary dermis, variable dermal fibrosis, perivascular lymphocytic
infiltration, extravasated erythrocytes, and hemosiderin-laden macrophages [9]. A positive iron stain
and the evaluation of the iron deposition pattern may be helpful to confirm the diagnosis [10].
Signs of venous hypertension also may be seen in the dermis, including dilated capillaries with fibrin
cuffs, hemosiderin deposits, and hyperplastic venules. Morphometric and ultrastructural findings
include increased mast cell number, thickening of basal lamina of capillaries, and presence of
transforming growth factor-beta 1 (TGF-beta 1) [11]. Septal involvement of the subcutaneous fat, fat
necrosis, microcyst formation, lipomembranous changes, elastosis, and calcification of adipocytes
are typical features of lipodermatosclerosis [12,13].
CLINICAL PRESENTATION Stasis dermatitis is a late

manifestation of chronic venous disease (stage C4 of the Clinical Etiological Anatomical
Pathological [CEAP] classification (table 2)) [14]. (See "Classification of lower extremity chronic
venous disorders", section on 'CEAP classification'.)
926
Stasis dermatitis typically presents with erythematous, scaling, and eczematous patches or plaques
on chronically edematous legs [2]. The medial ankle is most frequently and severely involved,
although the skin changes may extend up to the knee and down to the foot (picture 1A-D). Pruritus is
variable but, when present, results in lichenification from chronic scratching or rubbing. Acute forms
may present with severely inflamed, weeping plaques, vesiculation, and crusting. Impetiginized
crusts and/or pustules due to bacterial or candidal superinfection may also be seen. Chronic forms
are characterized by hyperpigmentation, due to dermal hemosiderin deposition, scaling, and
potential development of lipodermatosclerosis.
Lipodermatosclerosis is a chronic form of panniculitis resulting from chronic inflammation, fat

degeneration, and fibrosis. In the acute phase, lipodermatosclerosis presents with a painful
erythema of the medial perimalleolar region that mimics cellulitis [15]. However, in contrast with
cellulitis, lipodermatosclerosis develops slowly, over weeks to months, and usually involves both
legs. The chronic phase is characterized by hyperpigmented and indurated skin that constricts the
ankle region, giving the legs an appearance of an inverted champagne bottle (picture 2).
Patients with stasis dermatitis may present with other signs of chronic venous insufficiency and
related comorbidities, including (see "Clinical manifestations of lower extremity chronic venous
disease"):
●Varicosities
●Secondary lymphedema
●Atrophie blanche (stellate, porcelain-white scarring areas resulting from microthromboses) (picture
3)
●Secondary cellulitis
●Ulceration
CUTANEOUS COMPLICATIONS
Contact sensitization — Patients with stasis dermatitis and venous leg
ulcers have a higher frequency of contact allergy than the general population. (See "Basic
mechanisms and pathophysiology of allergic contact dermatitis".)
The prevalence of contact sensitization to at least one substance among patch-tested patients with
stasis dermatitis or leg ulcers ranged from 46 to 82 percent in several case series [16-23]. However,
a German retrospective study including over 5264 patients with stasis dermatitis, venous
insufficiency, or leg ulcers observed between 2003 to 2014 found a sensitization rate of
approximately 17 percent; interestingly, this rate was lower than the 27 percent rate found in a
historical control group of 4881 patients with similar diagnoses seen between 1994 to 2003 [24].
927
Polysensitization is common; a multicenter study of 423 patients found an average of four positive
patch tests per patient [16]. The number of sensitivities increased with the disease duration [16].
The increased susceptibility to contact dermatitis in patients with stasis dermatitis and leg ulcers
may be due to several factors, including [25-27]:
●Prolonged and repeated contact with topical preparations containing strong sensitizers
●Local hypervascularization
●Increased number of lymphocytes and Langerhans cells in the affected skin
●Impairment of the skin barrier function
The substances most frequently responsible for contact sensitization among patients with stasis
dermatitis and/or leg ulcers are ingredients of many emollients and topical prescriptions or over-the-
counter preparations, including [16-18,24,28-31] (see "Common allergens in allergic contact
dermatitis"):
●Myroxylon pereirae (formerly called balsam of Peru) and fragrances.
●Lanolin (wool alcohol).
●Rubber and constituents of rubber, rubber accelerators, and latex products.
●Bandages, dressings, or adhesives (eg, colophony, epoxy resin, and formaldehyde resin). Modern
hydrocolloid dressings are generally well tolerated. However, reactions to hydrocolloid gels have
been reported and may be due to pentaerythritol ester of hydrogenated rosin, a tackifying agent that
commonly cross-reacts with colophony [29,32].
●Topical antibiotics (eg, neomycin, bacitracin, and aminoglycosides) and antiseptics (eg, povidone-
iodine, benzalkonium chloride, chlorhexidine, and clioquinol).
●Topical corticosteroids. A list of cross-reacting topical corticosteroids is provided in a figure (figure

1).
●Paraben preservatives.
Autosensitization — Autosensitization (autoeczematization or "id" reaction)

refers to an acute, pruritic papulovesicular eruption that develops at cutaneous sites distant from a
primary focus and is unrelated to the inciting cause of the primary inflammation [33].
Autosensitization has been reported in association with stasis dermatitis, contact dermatitis, and
bacterial or fungal infections [34,35]. Typically, the autoeczematization develops one to two weeks
after the primary inflammation and most frequently involves the forearms, thighs, trunk, and face
[33].
928
The pathogenesis is not fully understood. One hypothesis is that autoeczematization is due to
hyperirritability of the skin induced by immunologic or nonimmunologic stimuli and mediated by
epidermal cytokines. Histologic findings are nonspecific and include spongiosis and a dermal
lymphohistiocytic infiltrate with eosinophils.
Superinfection — In patients with acute stasis dermatitis, moist, exudative lesions

are often extensively colonized by bacteria and fungi. The disruption of the epidermal barrier
integrity by inflammation or scratching favors the secondary infection of eczematous lesions.
Staphylococcus aureus and Streptococcus pyogenes are the most frequent cause of superficial
(impetiginization) or deep (cellulitis and erysipelas) superinfection of stasis dermatitis [15]. (See
"Impetigo" and "Cellulitis and skin abscess: Clinical manifestations and diagnosis".)
Acroangiodermatitis — Acroangiodermatitis, also called "pseudo-Kaposi

sarcoma," is a rare reactive vasoproliferative disorder resembling Kaposi sarcoma occurring on the
lower limbs as a result of vascular hyperplasia secondary to hypostasis and elevated venous
pressure [36,37]. It presents with purpuric macules and papules that may coalesce and form large,
purple-brown plaques on the extensor surfaces of the legs and dorsa of the feet (picture 4A-B).
Acroangiodermatitis can mimic and complicate stasis dermatitis. Histologically, the lesions consist
of a proliferation of small, dilated dermal capillaries lined by plump endothelial cells with minimal or
no atypia that are positive for CD31 and CD34 but, in contrast with true Kaposi sarcoma, negative for
human herpesvirus (HHV)-8 [36]. (See "Classic Kaposi sarcoma: Epidemiology, risk factors,
pathology, and molecular pathogenesis".)
DIAGNOSIS The diagnosis of stasis dermatitis is usually clinical, based upon the
clinical appearance of the skin lesions, ranging from erythema, scaling, and hyperpigmentation to
edema, erosions, and crusts (picture 1A-B, 1E); history of venous insufficiency; and other clinical
signs of chronic venous insufficiency, including varicosities, pitting edema, and hyperpigmentation.
In patients in whom the diagnosis of stasis dermatitis is uncertain or who have atypical features (eg,
solitary lesion or lack of ankle involvement), biopsy and histopathologic examination may confirm
the diagnosis and/or exclude other skin diseases, such as allergic contact dermatitis, asteatotic
eczema, or cutaneous malignancies (particularly in patients with a solitary lesion) [38] (see
'Pathology' above). However, a skin biopsy should be made with caution or avoided in patients with
concomitant peripheral arterial insufficiency, which is not uncommon. These patients have an
increased the risk of developing a nonhealing wound at the biopsy site, due to insufficient blood
supply. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
Patch testing is often necessary to determine if a secondary allergic contact dermatitis is present.
(See 'Differential diagnosis' below and 'Patch testing' below.)
929
Color Doppler assessment of the blood flow in the lower limbs is helpful in evaluating venous
incompetence and/or diagnosing deep venous thrombosis in patients with skin findings but without
obvious manifestations of venous insufficiency. Arterial study may be necessary to evaluate arterial
disease in patients with trophic changes (eg, atrophie blanche or ulcerations). (See "Diagnostic
evaluation of lower extremity chronic venous insufficiency", section on 'Duplex ultrasonography'.)
ADDITIONAL EVALUATION Laboratory tests are not

usually necessary for the diagnosis of stasis dermatitis. However, laboratory evaluation may be
indicated in the assessment of chronic venous insufficiency, particularly prior to intervention (eg,
vein ablation procedure) [39].
Bacterial cultures and/or mycologic studies (eg, potassium hydroxide [KOH] preparation) are useful
when bacterial or fungal superinfection or primary tinea corporis are suspected.
Patch testing — Patch testing for contact sensitization may be warranted for patients
who experience a worsening of symptoms despite appropriate skin care and topical therapy.
Standard series of allergens should be used, in addition to other series selected on the basis of
exposure history and clinical suspicion (eg, corticosteroids, rubber, preservative, excipients,
antioxidants, fragrance, textiles, and topical medicines or products used by the patient). (See "Patch
testing" and "Common allergens in allergic contact dermatitis".)
The specific standard series may vary depending upon the location of the patch testing center [40].
Descriptions of the test substances included in the most common standard series are available
through DermNet NZ.
DIFFERENTIAL DIAGNOSIS Skin disorders that may

mimic stasis dermatitis include:
●Irritant or allergic contact dermatitis (picture 5)
●Asteatotic eczema (eczema craquelé) (picture 6)
●Lichen simplex chronicus (picture 7)
●Psoriasis (picture 8) (see "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section
on 'Chronic plaque psoriasis')
●Dermatophyte infection (tinea corporis) (picture 9), which may also be a complication of stasis
dermatitis (see 'Superinfection' above and "Dermatophyte (tinea) infections", section on 'Tinea
corporis')
●Lower limb cellulitis, which may also be a complication of stasis dermatitis (see "Cellulitis and skin
abscess: Clinical manifestations and diagnosis")
930
●Actinically damaged skin (multiple actinic keratoses) (see "Epidemiology, natural history, and
diagnosis of actinic keratosis")
●Hypertrophic lichen planus (picture 10A-B) (see "Lichen planus", section on 'Clinical features')
●Necrobiosis lipoidica (picture 11A-B) (see "Necrobiosis lipoidica")
●Pretibial myxedema (picture 12) (see "Pretibial myxedema (thyroid dermopathy) in autoimmune
thyroid disease", section on 'Clinical features')
●Skin cancer (squamous cell carcinoma, basal cell carcinoma) (see "Cutaneous squamous cell
carcinoma (cSCC): Clinical features and diagnosis" and "Epidemiology, pathogenesis, and clinical
features of basal cell carcinoma", section on 'Clinical presentation')
MANAGEMENT The management of the patient with stasis eczema

involves the treatment of the underlying chronic venous insufficiency; symptomatic treatment of
skin dryness, pruritus, and inflammation; prevention of ulceration; and patient education.
Patient education — Patient education on a standardized basis at a level

comprehensible to them is critical for the success of implemented treatment and prevention
measures, improved outcomes, and decreased need for repeat clinician visits or recurrent
hospitalization. One study demonstrated that the use of a standardized approach to hospitalized
patients and regular application of expectation management and medical information modules
resulted in fewer clinician referrals, a decrease in readmission to hospital rates, and improved
outcomes [41].
Treatment of underlying chronic venous

insufficiency — Treatment of the underlying venous hypertension is the mainstay of
treatment of stasis dermatitis. It may involve:
●General measures to reduce edema and venous hypertension (eg, leg elevation, daily walking,
exercise, weight reduction) (see "Medical management of lower extremity chronic venous disease",
section on 'General measures')
●Continuous compression therapy (see "Medical management of lower extremity chronic venous
disease", section on 'Compression therapy' and "Compression therapy for the treatment of chronic
venous insufficiency" and "Compression therapy for the treatment of chronic venous insufficiency",
section on 'Static compression therapy')
●Systemic therapy, including venoactive or phlebotonic drugs (eg, hydroxyethylrutoside, escin [horse
chestnut extract], calcium dobesilate), flavonoids (eg, diosmin and hesperidin, diosmiplex), or
pentoxifylline [42-44] (see "Medical management of lower extremity chronic venous disease", section
931
on 'Pharmacologic therapy')
●Ablation therapy (see "Endovenous laser ablation for the treatment of lower extremity chronic
venous disease" and "Radiofrequency ablation for the treatment of lower extremity chronic venous
disease" and "Open surgical techniques for lower extremity vein ablation")
Skin care — Gentle skin cleansing and frequent use of bland emollients are indicated for
the symptomatic treatment of skin dryness and pruritus associated with stasis dermatitis. Patients
should gently wash their legs daily using mild nonsoap (synthetic) liquid cleansers to remove scale,
bacteria, and crusts. Products without common preservative allergens or fragrance are less irritating
and less likely to induce contact sensitization.
Emollients provide a film of oil to lubricate the skin, which limits dryness and itching. Petrolatum-
based products are preferred to emollients containing lanolin or fragrances to reduce the risk of
contact sensitization. White petroleum jelly is effective, inexpensive, and nonsensitizing. Emollients
can be applied multiple times per day. Emollients are best applied when the skin is damp (ie,
immediately after showering or bathing) and may be applied after wet dressings to seal in hydration.
Patients with acute stasis dermatitis

Topical corticosteroids — We suggest topical corticosteroids for patients with
stasis dermatitis who have erythema, pruritus, vesiculation, and oozing. High- or mid-potency
corticosteroids (groups III and IV (table 3)) in an ointment formulation can be applied to the affected
skin once or twice daily for one to two weeks. A prolonged use of high-potency corticosteroids
should be avoided, since they may induce skin atrophy and increase the risk of ulceration.
Corticosteroid preparations containing emulsifiers and additives should be avoided to minimize the
risk of sensitization; petrolatum-based topical corticosteroids (eg, triamcinolone ointment,
fluocinolone ointment) are preferred because they do not contain any additives. Nonetheless,
contact sensitization to topical corticosteroids may occur; a list of cross-reacting topical
corticosteroids is provided in a figure (figure 1).
There are few low-quality studies evaluating topical corticosteroids for the treatment of stasis
dermatitis [31,45]. In a small trial, patients treated with betamethasone valerate foam 0.12% or
placebo twice daily for 28 days had similar improvement of edema, postinflammatory
hyperpigmentation, or pruritus [31]. However, patients in the betamethasone group had greater
improvement compared with baseline than those in the placebo group. Whether stronger potency
corticosteroids or an ointment preparation rather than foam would be more beneficial is not known.
Wet dressings — For patients with exudative eczema, wet dressings may facilitate the
removal of crusts and exudate and reduce pruritus. Wet dressings are applied using tap water,
saline, or an appropriate anti-infective solution diluted from stock (eg, zinc and copper sulfate
932
solution; acetic acid; potassium permanganate; or aluminum acetate [Burow's solution] or
subacetate).
Saturated, but not dripping, soft cotton dermatologic roll gauze or cloths are applied directly to
affected areas and covered with dry cotton that is light and air permeable. The wet dressing is left in
place for two to three hours and may be applied two to three times daily or continuously in more
severe cases and motivated patients. Emollients may be applied after removal to moisturize and seal
in attained hydration.
Wet dressings may be used in conjunction with topical corticosteroids. The addition of dermatologic
wet dressings to topical corticosteroids may increase the penetration and absorption of the
corticosteroids.
In patients with bacterial superinfection, antibacterial wet dressings may help clear secondary
impetiginization and obviate the need for topical or oral antibiotic therapy.
Compression bandages — Compression bandages, such as multilayer

compression bandages and Unna boots, are beneficial for patients with acute stasis dermatitis. The
Unna boot is a closed topical dressing consisting of a moist, zinc oxide-impregnated bandage that
provides nonelastic compression and topical treatment that has drying and anti-inflammatory
properties. Both types of compression bandages should be applied by trained personnel and
changed by them once or twice a week. (See "Compression therapy for the treatment of chronic
venous insufficiency", section on 'Compression bandages'.)
Patients with recalcitrant stasis

dermatitis — Patients in whom topical corticosteroids do not adequately relieve
symptoms of inflammation or who experience a worsening of symptoms despite appropriate skin
care and topical therapy may have a secondary allergic contact dermatitis and/or autosensitization
(see 'Cutaneous complications' above). For these patients, a short course of systemic
corticosteroids (eg, prednisone 20 to 30 mg daily for five to seven days) may be indicated. An
alternative is a single dose of intramuscular triamcinolone (40 mg).
Data on the efficacy of systemic corticosteroids for the treatment of recalcitrant stasis dermatitis
are lacking. Their use is based upon indirect evidence of efficacy in severe allergic contact
dermatitis and clinical experience. (See "Management of allergic contact dermatitis".)
Treatment of superinfection
Impetiginized lesions — We suggest topical antibiotic therapy for patients with
stasis dermatitis and impetiginized lesions. Topical antibacterial ointments should be selected
based upon the results of bacterial culture, if available, and risk of contact sensitization. Mupirocin is
933
the topical antibiotic of choice because it is unlikely to cause cutaneous sensitization [46,47].
Topical erythromycin ointment is an alternative treatment when mupirocin is not tolerated [48]. (See
"Impetigo", section on 'Topical therapy'.)
Contact sensitivity to bacitracin, neomycin, and aminoglycosides is frequently seen in patch-tested

patients with stasis dermatitis or contact dermatitis, and these agents should be avoided. Triclosan-
based topical antimicrobial preparations are an infrequent cause of contact sensitization and may
be used as an alternative to topical antibiotics [49]. Direct chlorhexidine scrubs in the shower or
dilute bleach baths (one-half cup in a bathtub half full of tepid water) are also useful to decrease the
cutaneous bacterial load.
Secondary cellulitis — For patients with more extensive infection and signs of
cellulitis or other soft tissue infection, we suggest systemic antibiotics. Pending culture results,
empiric therapy options for group B Streptococcus, methicillin-resistant S. aureus, and other beta-
hemolytic streptococci include oral clindamycin, trimethoprim-sulfamethoxazole, tetracyclines, and
linezolid. (See "Cellulitis and skin abscess in adults: Treatment".)
Treatment of lipodermatosclerosis — Compression therapy

is widely accepted as first-line treatment for patients with chronic dermatosclerosis [50].
Compression therapy and pharmacologic therapy for patients with lipodermatosclerosis are
discussed in detail separately. (See "Medical management of lower extremity chronic venous
disease".)
Prevention of venous ulcers — Patients with stasis dermatitis

should be educated about the importance of lifestyle changes and specific interventions to prevent
venous ulcers, including [51]:
●Minimize prolonged standing; elevating legs
●Using compression hosiery
●Undertaking a program of regular physical activity
●Losing weight
●Avoiding local trauma
●Seeking early medical intervention if skin damage is noticed
TREATMENT OF ULCERS The management of ulcers in

patients with stasis dermatitis is discussed separately. (See "Medical management of lower
extremity chronic venous disease", section on 'Ulcer care'.)
934
●Basics topics (see "Patient education: Varicose veins and other vein disease in the legs (The
Basics)")
SUMMARY AND
RECOMMENDATIONS
●Stasis dermatitis, or stasis eczema, is a common inflammatory dermatosis of the lower extremities
that occurs in patients with chronic venous insufficiency, often in association with other signs of
chronic venous disease, such as varicose veins, dependent chronic edema, lipodermatosclerosis,
and ulcerations. (See 'Introduction' above.)
●Signs and symptoms of stasis dermatitis include edema, inflammatory and trophic skin changes,
pruritus, and hyperpigmentation. Manifestations of more advanced venous disease include
lipodermatosclerosis (picture 2), lymphedema, and ulceration. (See 'Clinical presentation' above.)
●Contact sensitization is a common complication of stasis dermatitis. Contact sensitization should

be suspected in patients with atypical presentations and in patients failing to respond to appropriate
treatment for stasis dermatitis. The most common contact allergens include balsam of Peru,
fragrances, lanolin, and topical antibiotics and antiseptics. (See 'Contact sensitization' above.)
●The diagnosis of stasis dermatitis is based upon the clinical appearance of the skin lesions
(ranging from erythema, scaling, and hyperpigmentation to edema, erosions, and crusts) (picture 1A-
B, 1E); history of venous insufficiency; and other clinical signs of chronic venous insufficiency,
including varicosities, pitting edema, and hyperpigmentation. In patients with atypical presentations
or solitary lesions, biopsy and histopathologic examination may confirm the diagnosis and/or
exclude other dermatoses or skin cancer. (See 'Diagnosis' above.)
935
●Treatment of the underlying venous insufficiency is the mainstay of therapy for stasis dermatitis.
Treatment of venous insufficiency is discussed separately. (See "Overview of lower extremity
chronic venous disease", section on 'Summary and recommendations' and "Approach to treating
symptomatic superficial venous insufficiency", section on 'Summary and recommendations'.)
●Gentle skin cleansing and emollients are the initial treatment for skin dryness and pruritus in
patients with stasis dermatitis. Petrolatum-based emollients are preferred to preparations containing
lanolin or fragrances to avoid contact sensitization. (See 'Skin care' above.)
●For patients with acute stasis dermatitis who have erythema, pruritus, vesiculation, and oozing, we
suggest topical corticosteroids (Grade 2C). High- or mid-potency corticosteroids (groups III and IV
(table 3)) in an ointment formulation may be applied once or twice daily for one to two weeks to the
affected skin. Wet dressings may be used in conjunction with topical corticosteroids in patients with
exudative eczema and crusting. (See 'Patients with acute stasis dermatitis' above.)
●For patients in whom topical corticosteroids do not adequately relieve symptoms of inflammation
or who have secondary allergic contact dermatitis, a short course of systemic corticosteroids (eg,
prednisone 20 to 30 mg daily for five to seven days) may be indicated. (See 'Patients with
recalcitrant stasis dermatitis' above.)
936
Vulvar dermatitis - UpToDate
uptodate.com/contents/vulvar-dermatitis/print
INTRODUCTION Vulvar dermatitis is the most common type of vulvar

dermatosis. One-third to one-half of vulvar complaints stem from this problem [1-4]. It can develop in
isolation or may occur as part of dermatitis in other areas of the body. Women with vulvar dermatitis
often experience chronic irritation or pruritus, which cause them to persistently rub and scratch the
vulva. These activities lead to histologic changes in the dermis, termed lichen simplex chronicus [5].
This topic will discuss the clinical manifestations, diagnosis, and management of vulvar dermatitis.
Other vulvar dermatoses and vulvar lesions are discussed separately.
●(See "Vulvar lesions: Differential diagnosis based on morphology".)
●(See "Vulvar lichen sclerosus".)
●(See "Vulvar lichen planus".)
●(See "Acute genital ulceration (Lipschütz ulcer)".)
●(See "Vulvar intraepithelial neoplasia".)
937
ENDOGENOUS VERSUS
EXOGENOUS DERMATITIS Vulvar dermatitis has been
traditionally divided into two subtypes, endogenous and exogenous. However, these categories are
not mutually exclusive, and it is possible for both to exist concomitantly in an individual patient.
●Endogenous vulvar dermatitis (eczema) is the term used to describe atopic dermatitis of the vulva.
Atopic dermatitis has a familial predisposition, often begins in childhood, and is characterized by
pruritus. Although some experts feel that vulvar involvement is unusual, even when there is severe
and widespread atopic dermatitis elsewhere, others believe it is more prevalent than previously
acknowledged [6,7]. In women with atopic dermatitis at nongenital sites, the occurrence of erythema
in the labial folds, the perianal region, and in the skin between the buttocks probably represents
endogenous vulvar dermatitis. However, in such cases, it is important to rule out allergic contact
dermatitis as a complicating factor or as the causal diagnosis [8]. (See "Atopic dermatitis (eczema):
●Exogenous vulvar dermatitis results from external factors and is also called contact dermatitis
(picture 1A-B). In allergic contact dermatitis, the trigger (allergen) induces an immune response,
while in irritant contact dermatitis, the trigger (irritant) itself directly damages the skin. Although
exposure to irritants may have been the initial cause of dermatitis, secondary sensitization to
allergens can also occur.
The most common agents that cause irritant or allergic contact dermatitis of the vulva are listed in
the table (table 1). Active and inert constituents of topical medications are a very common etiology
of allergic dermatitis of the vulva in women with persistent vulvar symptoms [9]. Sensitivity to latex
or proteins in seminal plasma are infrequent etiologies [10,11]. (See "Irritant contact dermatitis in
adults" and "Clinical features and diagnosis of allergic contact dermatitis" and "Allergic reactions to
seminal plasma".)
PATHOPHYSIOLOGY Vulvar tissue is more permeable than

exposed skin due to differences in structure, occlusion, hydration, and susceptibility to friction
[11,12]. The vulvar skin is particularly vulnerable to irritants. Compared with other body regions, the
stratum corneum overlying the vulva appears to function less efficiently as a barrier, thereby
permitting increased susceptibility to irritants [13]. As an example, preservatives such as
benzalkonium chloride and maleic acid induce a greater response after application to normal vulvar
skin than when applied to the skin of the forearm [14].
The vulvar skin is also sensitive to allergens. New exposure to an allergen is most likely to induce a
reaction, although patients may also react to products that they have used for months or years. A
delayed hypersensitivity (type IV) reaction takes from 12 to 72 hours to develop, is usually pruritic,
938
and often lasts for several weeks. In acute cases, an exposure occurring up to two weeks prior to the
dermatitis can often be identified. In chronic cases, the dermatitis may have been present for
months or years; identifying the offending trigger in these patients can be difficult.
CLINICAL MANIFESTATIONS In acute vulvar

dermatitis, the skin displays mild to severe erythema of varying extent with some scaling in dry
areas (picture 1B). Fissures may be present along the labial folds. Excoriations from scratching are
common and can be complicated by secondary infection with yeast or bacteria (eg, Staphylococcus
aureus, Streptococcus pyogenes, or Escherichia coli). Although crusts and scales are commonly
observed with dermatitis elsewhere on the body, these signs are often not present in the moist areas
of the vulva.
In chronic cases, the vulvar mucosa is erythematous and may display papillae, a sign of chronic
inflammation (picture 2). The origin of vulvar papillomatosis is uncertain; the papillae can be normal
anatomic variants of the vestibular mucosa or a postinflammatory change [15,16]. Papillomatosis is
not a cause of vulvar pain.
The most common symptom of vulvar dermatitis is pruritus, which can be intense and nocturnal.
Other symptoms include burning, stinging, or rawness. Symptoms may be exacerbated by heat,
sweat, stress, or menstruation. Self-medication and excessive washing of the vulva by women
fearful of a lack of cleanliness often aggravate the dermatitis.
In response to the epithelial irritation and persistent pruritus, the patient may chronically rub and
scratch her skin. Repeated cycles of intense itching and scratching result in the thickening of the
vulvar skin and accentuation of the normal skin markings (lichenification), a condition called lichen
simplex chronicus (picture 3) [4,17]. Labial skin folds appear greatly exaggerated, often edematous,
and pubic hair can be broken or sparse (picture 4A-B) [9,18]. Other changes include
hypopigmentation or hyperpigmentation and hyperkeratosis (picture 5). Due to local moisture, scale
is usually absent and the skin surface appears soft and whitened. (See "Vulvar lesions: Differential
diagnosis based on morphology", section on 'Lichen simplex chronicus'.)
DIAGNOSIS The diagnosis of vulvar dermatitis is in most cases clinical, based

on the clinical presentation, a personal or family history of atopy, or a personal history of vulvar
exposure to medications, perfumes, or other chemicals causing persistent irritation. One should
have a high index of suspicion of contact allergy in any chronic vulvar dermatitis, and patients
should be referred for patch testing. The frequency of clinically relevant patch test results in patients
with vulvar complaints is high, ranging from 16 to 54 percent [8,9,19-23]. A skin biopsy is not
routinely performed in women with vulvar dermatitis; however, histopathologic examination may be
necessary if the diagnosis is uncertain or there is a suspicion of neoplasia. (See 'Differential
diagnosis' below.)
939
History — Women with vulvar complaints should be questioned regarding a personal or
family history of atopy (eg, atopic dermatitis, asthma, rhinitis, conjunctivitis) or autoimmune
diseases. Chronic pruritus should be ascertained. Specific areas to address in the history include:
●What are her major complaints? Pruritus can vary from mild to intolerable, sometimes interfering
with sleep or other activities. When the dermatitis involves mucosal areas, burning, rawness, and
stinging are more common than pruritus and the symptoms are often exacerbated during
menstruation and with coitus.
●What are her hygienic practices (eg, daily use of panty liners, feminine products, baby wipes)?
Women often erroneously regard their personal practices as safe since they have engaged in them
for a long time.
●Does she wear occlusive clothing, such as tight lycra garments, confining undergarments, non-
cotton underwear, or thongs? These types of garments trap sweat, promote candidiasis, and chafe
the skin.
●Does she apply any medications (eg, topical antifungals) or other agents (eg, lubricants,
spermicides, perfumed or deodorant soaps) to the vulva? Women seldom reveal this information
unless asked directly. Patients with vulvar dermatitis have often been treated with multiple
antifungal agents without success. A report that these creams never helped their symptoms is
significant information, indicating that Candida is probably not the source of the complaints.
●Does she have fecal or urinary incontinence? Both feces and urine are skin irritants.
The answers to these questions help to differentiate an endogenous process (eg, atopy) from that
induced by an exogenous agent. Conscientious analysis of the woman's personal practices is the
best way to detect potential irritants and allergens in her environment (table 1) as well as habits
unhealthy for the vulvar skin. In a study of 530 women attending a specialty clinic for vulvar
diseases, over 60 percent of patients described adverse personal hygiene or self-treatment practices
when specifically questioned [24].
Physical examination — Physical examination should include:

●Careful visual inspection of the vulva – Assess for signs of inflammation (erythema, edema,
excoriations, fissures, scaling), changes in vulvar architecture (loss/distal flattening of labia minora,
adhesions of clitoral prepuce to glans, narrowing of introitus) (picture 9B), and signs of atrophy,
which indicate long-standing inflammation or inflammatory vulvar dermatosis, such as lichen
sclerosus (picture 6) or inverse psoriasis (picture 7). (See 'Inflammatory vulvar dermatoses' below.)
●Vaginal examination – Assess for signs of inflammation (erythema, edema erosions, lesions) or
atrophy; perform evaluation of vaginal discharge, including pH, odor, and saline and potassium
hydroxide microscopy to rule out acute vaginitis or desquamative inflammatory vaginitis. Vaginal
940
discharge is usually unremarkable in women with vulvar dermatitis. If Candida is suspected by exam
findings, a vaginal culture should be obtained even if microscopy is negative. (See "Approach to
females with symptoms of vaginitis".)
●Complete skin examination – Examine mouth, nail beds, flexor and extensor surfaces, and scalp
for evidence of nongenital dermatitis. Look for scaly scalp plaques or nail pitting that suggest
psoriasis. Also look for desquamative gingivitis or buccal Wickham striae suggesting lichen planus.
Patch testing — Patch testing is recommended to rule out allergic contact dermatitis
and may be helpful to distinguish between atopic and allergic contact dermatitis. Patch testing
should be performed by a specialist (ie, dermatologist or allergist with access to the appropriate
testing panels). In addition to standard series of allergens, the patient’s own topical medications,
popular remedies, or other suspected products should also be tested [25]. (See "Patch testing".)
Positive patch tests for relevant substances occur in 25 to 60 percent of women with vulvar pruritus;
fragrances, medications, and preservatives are most frequently implicated [9,19,26-30]. In a study
including 282 women with vulvar symptoms undergoing patch testing with a European standard
series and a gynecologic series, 54 percent reacted to one or more allergens [30]. Nickel was the
most commonly found allergen, although the authors felt it was not clinically relevant. In contrast,
positive reactions to fragrances, topical antibiotics or anesthetics, and patients’ own products were
almost always relevant (table 2).
Contact allergy to topical corticosteroids is an important cause of vulvar dermatitis that should not
be overlooked [9,10,19]. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse
effects'.)
A less common but described cause of genital rash is systemic contact dermatitis [20,31]. Patients
sensitized to a topical allergen can develop contact dermatitis if exposed to that allergen
systemically (eg, by ingestion, parenteral administration, or inhalation). Four main groups of
allergens are generally responsible: metals (eg, nickel, cobalt, and chromium); medications (eg,
hydroxyzine, an ethylenediamine-derived antihistamine, or oral medications that contain propylene
glycol); plant and herbal products, fragrances, and flavorings (eg, citrus, wine, beer, cinnamon, cola,
curry, vanilla, or other flavorings); and preservatives (eg, formaldehyde in aspartame). (See
Biopsy — Biopsy is not routinely performed in patients with vulvar dermatitis. However, a
biopsy may be necessary if the diagnosis cannot be made on clinical grounds or there is suspicion
of neoplasia. Histopathologically, vulvar dermatitis is characterized by spongiosis (epidermal
edema) and a dermal infiltrate of lymphocytes with occasional eosinophils [5]. Chronic lesions may
show changes of lichen simplex chronicus, consisting of elongation, widening of the rete ridges and
irregular thickening of the Malpighian layer of rete ridges (acanthosis), hyperkeratosis, and
941
parakeratosis with a modest mid-dermal inflammatory infiltrate [32]. Periodic acid-Schiff stain for
yeasts may be helpful if chronic candidal vulvovaginitis is suspected in patients with negative
microscopy and culture of vaginal discharge.
DIFFERENTIAL DIAGNOSIS Inflammatory vulvar

dermatoses (eg, lichen sclerosus, lichen planus, psoriasis, seborrheic dermatitis), infections (eg,
human papillomavirus [HPV], herpes simplex, Candida), neoplasia, and vulvar pain syndromes are all
sources of vulvar complaints (table 3). These conditions should be ruled out by laboratory tests and
skin biopsy, if necessary. (See "Vulvar lesions: Diagnostic evaluation" and "Vulvar lesions: Differential
diagnosis based on morphology" and "Clinical manifestations and diagnosis of vulvodynia (vulvar
pain of unknown cause)".)
Inflammatory vulvar dermatoses — Common inflammatory

dermatoses involving the vulva include:
●Lichen sclerosus – Lichen sclerosus is a chronic, progressive, inflammatory mucocutaneous

disease of the vulva that occurs in women of all ages, with a peak incidence in prepubertal girls and
perimenopausal or postmenopausal women. Pruritus, irritation, and discomfort are the predominant
symptoms, although women can be totally asymptomatic even in the presence of active disease.
Lichen sclerosus is characterized by "parchment-like" or "cigarette paper" skin, although thickened,
hyperplastic, or lichenified areas are not uncommon (picture 8A-B). Fissures and telangiectasia are
common. Untreated disease leads to loss of the normal architecture of the external genitalia and
constriction of the vaginal orifice (picture 9A-B). The diagnosis can be confirmed by histologic
examination of biopsy specimens if either clinical doubt exists about the diagnosis or if there is
concern about possible neoplasia [33]. Patients with lichen sclerosus may also develop lichen
simplex chronicus from chronic scratching, and more than one biopsy may be necessary for the
correct diagnosis. (See "Vulvar lichen sclerosus".)
●Lichen planus – Vulvar lichen planus may present with erosive, papulosquamous, or hypertrophic
lesions. Erosive lichen planus is the most common type and typically involves the inner aspects of
the vulva and vagina (picture 10). In longstanding disease, loss of the labia minora and narrowing of
the introitus may be seen (picture 11). A skin biopsy for routine histopathologic examination can
confirm the diagnosis. Immunofluorescence studies are useful to differentiate erosive lichen planus
from autoimmune blistering diseases (eg, mucous membrane pemphigoid and pemphigus). (See
"Vulvar lichen planus".)
●Vulvovaginal-gingival syndrome – Vulvovaginal-gingival syndrome is a variant of erosive lichen

planus that can affect the vagina, vulva, and oral cavity (picture 12) either concurrently or
individually [34]. Vulvar lesions are painful, glassy erosions, while those in the vagina are
erythematous and friable (picture 13). Synechiae can develop in the vagina, which may become
obliterated with severe disease. Patients typically have irritation, pain, rawness, and soreness and
may have a serosanguinous discharge from vaginal involvement. (See "Vulvar lichen planus", section
on 'Clinical manifestations'.)
942
●Psoriasis – Psoriasis appears as bright red, sharply demarcated lesions that are raised above the
surrounding normal skin (picture 7). Silver scales, commonly observed in psoriasis, may be seen on
the mons but are not found elsewhere on the vulva. The presence of typical psoriatic lesions on
other body areas suggests the diagnosis. A skin biopsy can be performed for confirmation. (See
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Inverse (intertriginous)
psoriasis'.)
●Seborrheic dermatitis – Seborrheic dermatitis is a chronic inflammatory disorder typically

involving areas of the body that are rich in sebaceous glands, such as the scalp, face, axilla, groin,
and upper trunk. Involvement of the vulva is uncommon. The lesions are erythematous, poorly
defined, and scaling. (See "Seborrheic dermatitis in adolescents and adults".)
Infection — Candida vulvovaginitis causes pruritus, irritation, burning, and soreness of the
vulva. Cutaneous findings of lichen simplex chronicus often accompany Candida infection. Candida
is less common in postmenopausal women but can occur in those on estrogen replacement or
using potent topical corticosteroids (eg, for treatment of lichen sclerosis). Candida infection should
be excluded by culture. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis".)
If there is a malodorous vulvar exudate, bacterial cultures of the vulva should be obtained to aid in
the diagnosis of secondary bacterial infection. Bacterial cultures of the vagina are not
recommended, as the results are usually nonspecific.
Testing for herpes simplex virus is recommended when recurrent ulcerations are noted, as these
may be a sign of genital herpes. (See "Epidemiology, clinical manifestations, and diagnosis of genital
herpes simplex virus infection", section on 'Diagnosis'.)
Vulvar intraepithelial neoplasia — Vulvar intraepithelial

neoplasia related to HPV infection may cause irritation and pruritus of the vulva or raised (picture
14) or macular (picture 15) lesions. Vulvar biopsy is required for the diagnosis. Appropriate sites for
biopsy are identified by physical examination and colposcopy. (See "Vulvar intraepithelial
neoplasia".)
Vulvar cancer — Most patients with vulvar cancer present with a unifocal vulvar
plaque, ulcer, or mass (fleshy, nodular, or warty) on the labia majora (picture 16), whereas the labia
minora, perineum, clitoris, and mons are less frequently involved. Pruritus is the most common
complaint, especially if there is an underlying inflammatory vulvar dermatoses (eg, lichen sclerosus
or lichen simplex chronicus). Bleeding, discharge, or an enlarged inguinal lymph node may also be
present, but patients can be asymptomatic as well. Vulvar biopsy is required for diagnosis. (See
"Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment".)
943
Paget disease (extramammary) — Vulvar Paget disease
typically has an eczematous appearance and may occur anywhere on the vulva. It is well
demarcated, with slightly raised edges and a red background (picture 17). Pruritus is the most
common symptom. Diagnosis is based upon characteristic histopathology. Vulvar biopsy should be
performed in patients with suspicious lesions, including those with persistent pruritic eczematous
lesions that fail to resolve within six weeks of appropriate therapy. Invasive adenocarcinomas may
be present within or beneath the surface lesion or at distant noncontiguous sites, and a work-up for
underlying malignancy should be considered [35,36]. (See "Vulvar cancer: Epidemiology, diagnosis,
histopathology, and treatment".)
Vulvar pain syndromes — Vulvar pain may be related to a specific

disorder (infectious, inflammatory, neoplastic, or neurologic). Vulvodynia refers to vulvar discomfort
of unknown etiology, usually described as burning pain accompanied with allodynia on
vestibular/vulvar Q-tip examination. Pruritus is uncommon; nevertheless, persistent pruritus and
erythema with a negative yeast culture, nonspecific vulvar biopsy, and failure to respond to standard
treatment raises the possibility of vulvodynia. Vulvodynia is a diagnosis of exclusion after specific,
relevant disorders have been ruled out. (See "Clinical manifestations and diagnosis of vulvodynia
(vulvar pain of unknown cause)".)
Vulvovaginal atrophy — Vulvovaginal atrophy is characterized by dryness,

inflammation, and thinning of the epithelial lining of the vagina and lower urinary tract due to loss of
estrogen. Symptoms include vaginal dryness, burning, pruritus, discharge, bleeding, and
dyspareunia. Urinary tract symptoms (eg, frequency, recurrent infection) may also occur. The
diagnosis is clinical, based upon the typical finding of pale, dry, thin vaginal epithelium that is
smooth and shiny with loss of most rugation. Office analysis reveals basic vaginal pH in the
absence of other causes (eg, infection, blood, or semen) and parabasal cells on microscopy. (See
"Clinical manifestations and diagnosis of genitourinary syndrome of menopause (vulvovaginal
atrophy)".)
MANAGEMENT The treatment of vulvar dermatitis requires a multimodal

approach involving habit modification, appropriate skin care and hygiene practices (table 4),
treatment of coexistent infection, control of pruritus, and topical or systemic medication. Various
popular soaps marketed as “fragrance free” or “sensitive skin” contain flower extracts or
fragrances/flavorings and should be avoided. As an example, Dove Sensitive Skin unscented bar
soap contains maltol, a fragrance/flavoring, and Basis Sensitive Skin bar soap contains the
fragrance chemical cyclopentadecanolide. An explanation of the condition, emphasizing the need
for long-term treatment with maintenance regimens, and vigilance to prevent and diagnose recurrent
yeast infections are important factors for success [4]. Therapy that fails to interrupt the itch-scratch
cycle will not lead to consistent, prolonged clinical improvement. For persistent cases, a
multidisciplinary approach involving gynecologists, dermatologists, and allergists may be necessary.
944
In the absence of data from large, randomized trials, we suggest the regimens discussed below
based upon our clinical experience and results from small observational studies.
General measures — Behavior modification and adoption of appropriate

personal care practices are important components of the management of vulvar dermatitis.
●If the patient has clothing or hygiene habits that facilitate dermatitis, these habits must be
modified. Key elements of healthy vulvar hygiene are listed in the table (table 4).
●Patients should be reassured that skin issues are not the result of a lack of cleanliness and that
excessive washing can worsen dermatitis.
●Known or suspected allergens and irritants in the environment should be eliminated.
●Gentle skin care should be encouraged. Soaking in warm water, without additives, for five minutes
in the morning and night hydrates the skin and relieves vulvar discomfort and pruritus. If the patient
does not have access to a bathtub or a sitz bath placed under a toilet seat, a hand-held shower
device can be used for hydration. Moisture is then sealed into the skin with the application of a
nonallergenic emollient (eg, petroleum jelly) or a topical corticosteroid ointment (“soak and seal”).
●The patient’s personal care practices should be reviewed at each visit to ensure ongoing good
practices are being followed.
Diagnosis and treatment of coexistent

infection — Diagnosis of coexistent infections is essential. If a vaginal or vulvar exudate is
present, a vulvar bacterial culture, saline and potassium hydroxide (KOH) preparation, and yeast
culture should be obtained. If herpes simplex infection is suspected, a viral culture, direct fluorescent
antibody (DFA) test, or polymerase chain reaction (PCR) should be performed. (See "Epidemiology,
clinical manifestations, and diagnosis of genital herpes simplex virus infection".)
●Candidiasis – Candidiasis may be present in the absence of the usual vaginal symptoms and may
be the cause of recurrent vulvar fissures. Candidiasis should be excluded in all patients by yeast
culture if the organism is not present on wet mount with 10 percent KOH, which is only 50 percent
sensitive. It is important to repeat the search for Candida with wet mount and cultures at each follow-
up visit, since a previous negative culture does not rule out Candida infection. (See "Candida
vulvovaginitis: Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)
Candidiasis should be treated with oral fluconazole. Oral therapy is preferred to topical therapy
because women with infection superimposed on vulvar dermatitis are at increased risk for
worsening dermatitis from the irritant effects of topical drugs [37]. For uncomplicated Candida
infection, fluconazole 150 mg is given as a one-time dose. Complicated or recurrent infections may
945
require longer courses of therapy or long-term suppression. Nonalbicans yeast do not usually
respond to fluconazole and will require alternative treatment. (See "Candida vulvovaginitis:
Treatment", section on 'Recurrent treatment'.)
●Bacterial infection – Vaginal bacterial cultures are not generally useful because many types of
bacteria normally colonize the vagina. Heavy growth of Staphylococcus or Streptococcus should be
treated [38]. We use cephalexin (500 mg orally three times per day) or cefadroxil (500 mg orally twice
daily) for five to seven days, if appropriate by sensitivity testing. For women allergic to penicillin, we
prescribe azithromycin (250 mg as a single oral dose daily for six days).
●Genital herpes simplex infection – If herpes simplex virus is detected, appropriate antiviral therapy
can be considered in the individual patient based upon the type of infection (primary or recurrent)
and severity of symptoms. (See "Treatment of genital herpes simplex virus infection".)
Control of pruritus — Oral sedating antipruritic agents such as hydroxyzine (a

first-generation H1 antihistamine) or doxepin (a tricyclic antidepressant with antihistamine
properties) given in the evening may be helpful to control nighttime itching and scratching.
Nonsedating antihistamines are of little benefit for vulvar pruritus. (See "Pruritus: Overview of
management".)
Doxepin is also available as a cream formulation; however, it is a known contact sensitizer and
should not be used on inflamed vulvar skin [39]. Additionally, it produced drowsiness in 25 percent of
users due to systemic absorption, which is another limitation to its usefulness [40].
Patients with mild symptoms — Mild vulvar dermatitis usually

responds to low- to medium-potency topical corticosteroid ointments (groups four to seven (table 5))
such as hydrocortisone 1% or 2.5%, desonide 0.05%, or triamcinolone 0.1%. Topical corticosteroids
can be used one or more times daily, for two to four weeks, although a clear benefit has not been
demonstrated with more than once daily application [41-43]. Therapy is continued indefinitely at the
minimum frequency necessary to control pruritus with a goal of less than 14 days per month.
Patients with moderate to severe

symptoms — For patients with moderate to severe vulvar dermatitis, a high-potency
topical corticosteroid in ointment formulation is generally required (groups one to three (table 5)).
We prescribe clobetasol propionate or augmented betamethasone dipropionate 0.05% ointment at
night daily for 30 days and then reevaluate. Ointments are preferred to creams because creams
usually contain moderate sensitizers, such as formaldehyde-releasing preservatives or
methylisothiazolinone. Potent topical steroids have been used for up to 12 weeks on the vulva
without adverse effects [44,45].
946
Another acceptable regimen is to give one of these steroids twice daily for two weeks, then daily for
two weeks, then on Monday and Wednesday and Friday for two weeks, and then reevaluate. If there
is a partial response, we either continue corticosteroids for another two weeks or else switch to
intralesional injections or topical calcineurin inhibitors.
Corticosteroid-dependent vulvar dermatitis — In some

patients, corticosteroid-dependent vulvar dermatitis (ie, dermatitis that relapses rapidly after
stopping or tapering topical corticosteroids) can be controlled with the use of the calcineurin
inhibitors tacrolimus 0.03% ointment or pimecrolimus 1% cream [46,47]. The ointment or cream is
applied sparingly twice daily for 14 to 30 days, followed by maintenance therapy twice per week.
Intermittent prolonged treatment may be necessary because the dermatitis in many cases recurs
upon discontinuation. Some patients cannot tolerate tacrolimus because of burning or stinging.
These side effects may be minimized by applying a film of petroleum jelly before applying the
ointment. Calcineurin inhibitors can also be used in conjunction with steroids to allow for a more
sparing use of steroids.
The US Food and Drug Administration (FDA) has issued a public health advisory regarding a
potential cancer risk (lymphoma, skin cancer) from use of topical calcineurin inhibitors [48]. Despite
the FDA's boxed warning, no clear evidence has been found linking the topical calcineurin inhibitors
to an increased incidence of malignancy in either children or adults [49,50].
Patients with severe refractory disease — For patients

with localized areas of involvement that do not respond to topical therapies, we suggest intralesional
corticosteroids. A total of 1 to 2 mL of triamcinolone acetonide 3.3 to 10 mg/mL is given by injecting
small amounts to include the entire lesion or plaque. If helpful, the injection can be repeated at
monthly intervals for up to four times a year. Prior application of a small amount of a topical
anesthetic, such as EMLA, facilitates injection. Symptomatic localized areas that do not respond to
intralesional corticosteroids should be biopsied to exclude malignancy.
Patients with severe, persistent symptoms may require systemic immunosuppressive therapy.
These patients should be managed in conjunction with appropriate specialists including
gynecologists, dermatologists, and allergists.
Oral or intramuscular (IM) corticosteroids can be used for patients experiencing a severe flare such
that they cannot tolerate topical application or for patients who require a short-term bridge to other
systemic steroid-sparing therapy [51]. The authors prefer the use of oral corticosteroids, so that any
adverse side effects can be minimized by titration of dose, which is not possible after IM
administration. Oral prednisone is given at a dose of 0.5 to 1 mg/kg per day (maximum daily dose 60
mg) for three to seven days and then tapered by 10 to 20 mg every three to seven days. More gradual
tapering of treatment can be required for severe disease, and regimens are often customized based
on the clinical picture.
947
The short- and long-term side effects of systemic steroid therapy are well documented and include
hypertension, hyperglycemia (diabetics may require more frequent blood glucose monitoring),
weight gain, sleep or mood disturbance, gastritis, and adrenal suppression. (See "Major side effects
of systemic glucocorticoids".)
A number of other systemic immunosuppressants, including methotrexate, mycophenolate mofetil,

azathioprine, and cyclosporine, are variably effective in the management of atopic dermatitis,
psoriasis, lichen sclerosus, and lichen planus. All require ongoing monitoring and should be
administered by a clinician experienced in their usage.

provided separately. (See "Society guideline links: Vulvar dermatitis".)

two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient
subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Vulvar itching (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Vulvar dermatitis is the most common cause of vulvar complaints in women. Vulvar dermatitis has
been traditionally divided into two subtypes, endogenous (atopic) and exogenous (irritant or
allergic). However, these categories are not mutually exclusive, and it is possible for both to exist
concomitantly in an individual patient. (See 'Introduction' above and 'Endogenous versus exogenous
dermatitis' above.)
948
●The most common symptom of vulvar dermatitis is pruritus, which can be intense and nocturnal.
Other symptoms include burning, rawness, or stinging. Physical signs depend upon the chronicity of
disease and include erythema (picture 1B), papillomatosis (picture 2), and lichenification (picture 3).
(See 'Clinical manifestations' above.)
●The diagnosis of endogenous or exogenous vulvar dermatitis can usually be made clinically, based
upon characteristic symptoms, a personal or family history of atopy, or personal history of vulvar
exposure to medications, perfumes, or other chemicals. Patch testing is helpful to distinguish
between atopic and allergic contact dermatitis. (See 'Diagnosis' above.)
●Infection should be excluded by vulvar cultures for candidiasis, herpes simplex virus (if ulcers are
noted), and potential bacterial pathogens. In uncertain cases and those not responding to standard
treatment, a biopsy may be necessary to identify an underlying inflammatory dermatosis or
neoplasia. (See 'Differential diagnosis' above.)
●The treatment of vulvar dermatitis requires a multimodal approach involving behavior

modifications, appropriate skin care and hygiene practices (table 4), treatment of coexistent
infections, control of pruritus, and topical or systemic medication. An explanation of the condition,
emphasizing the need for long-term treatment with maintenance regimens, and vigilance to prevent
and diagnose recurrent infections are important factors for success. (See 'Management' above.)
●Soaking in warm water temporarily relieves vulvar discomfort. Sealing in the moisture with
medication prescribed or emollient (eg, plain petroleum jelly) is also a mainstay of therapy. A
sedating antihistamine such as hydroxyzine given in the evening helps to control nighttime itching
and scratching. (See 'General measures' above and 'Control of pruritus' above.)
●For women with mild symptoms, we suggest low- to medium-potency topical corticosteroids
(Grade 2C). Hydrocortisone 1% or 2.5%, desonide 0.05%, or triamcinolone 0.1% ointment is applied
daily for two to four weeks. Therapy is continued indefinitely, at the minimum frequency necessary
to control pruritus, with a goal of less than 14 days per month. (See 'Patients with mild symptoms'
above.)
●For women with moderate to severe symptoms, we suggest high-potency topical corticosteroids,
such as clobetasol propionate 0.05% or betamethasone dipropionate 0.05% (groups one to three
(table 5)) (Grade 2C). Topical corticosteroid are applied at bedtime daily for 30 days. Ointments are
preferred to creams, as they usually do not contain preservatives. (See 'Patients with moderate to
severe symptoms' above.)
●For patients with localized severe vulvar dermatitis that does not respond to high-potency topical
corticosteroids, we suggest intralesional corticosteroids (Grade 2C). A total of 1 to 2 mL of
triamcinolone acetonide 3.3 to 10 mg/mL is given by injecting small amounts to include the entire
involved area. Localized disease that does not respond to intralesional corticosteroids should be
biopsied to exclude malignancy. Patients with severe, persistent symptoms may require systemic
immunosuppressive therapy. (See 'Patients with severe refractory disease' above.)
949
to acknowledge Elizabeth Gunther Stewart, MD, who contributed to earlier versions of this topic
review.
950
Urticarial dermatitis - UpToDate
uptodate.com/contents/urticarial-dermatitis/print
Urticarial dermatitis
Author:
Matthew J Zirwas, MD
Section Editor:
Joseph Fowler, MD
Deputy Editor:
INTRODUCTION The term "urticarial dermatitis" describes an intensely

pruritic, recalcitrant skin eruption characterized by erythematous papules and plaques that resemble
urticaria but last longer than 24 hours and are sometimes accompanied by eczematous lesions [1].
Histologically, urticarial dermatitis is described by most pathologists as a "dermal hypersensitivity
reaction," a nonspecific reaction pattern that is seen in a broad range of skin conditions, including
drug reactions, scabies, and the prodromal phase of bullous pemphigoid [2]. However, in a
substantial subgroup of patients, no underlying cause can be determined, and the diagnosis of
"urticarial dermatitis" is appropriate.
EPIDEMIOLOGY The incidence and prevalence of urticarial dermatitis are

unknown. It occurs most frequently in individuals older than 50 years, with a slight female
predominance [3,4].
PATHOGENESIS The pathogenesis of urticarial dermatitis is

incompletely understood. One hypothesis is that urticarial dermatitis is a lymphocyte mediated (type
IV) hypersensitivity reaction. Clinical and histologic similarities have been noted between urticarial
dermatitis and eruptions that occur in patients treated with anti-cytotoxic T-lymphocyte antigen 4
(CTLA-4) antibodies to break self-tolerance during immunotherapy for cancer [5]. This finding
suggests that urticarial dermatitis may represent a waning of the regulatory function of the immune
system that allows a reaction to develop against a self-antigen. It has been suggested that an intact
basement membrane zone may distinguish urticarial dermatitis from eczematous dermatoses, and
this finding may contribute to our understanding of the difference between these two entities,
although additional confirmation is needed [6].
951
PATHOLOGY The pathologic features of urticarial dermatitis are nonspecific
and include a normal stratum corneum, mild epidermal edema with minimal spongiosis, and a
superficial to mid-dermal perivascular infiltrate of lymphocytes and eosinophils with occasional
neutrophils (picture 1) [2]. A few basal apoptotic keratinocytes are sometimes present. Similar
features may be seen in a variety of skin conditions, including drug reactions, arthropod assault, viral
infections, and prodromal stage of bullous pemphigoid.
CLINICAL MANIFESTATIONS Patients with

urticarial dermatitis typically present with an extremely pruritic, persistent eruption of dull red
papules coalescing into plaques, associated with areas of urticated erythema, sometimes
accompanied by eczematous lesions (picture 2C). In contrast with urticaria, lesions last for more
than 24 hours and often for many days or weeks [1].
The eruption usually involves the trunk and extremities (picture 2A-B). The palms, soles, and face are
typically spared. Lichenification and excoriation from rubbing and scratching is commonly seen in
affected areas.
The eruption follows a chronic relapsing course. Spontaneous regression is unusual.
DIAGNOSIS AND DIFFERENTIAL

DIAGNOSIS Because the clinical and histologic features of urticarial dermatitis
are nonspecific, the diagnosis is one of exclusion. A detailed history, including medication history, a
complete physical examination, and additional testing (eg, complete blood cell count, direct
immunofluorescence, skin scraping, patch testing), should be considered in an attempt to identify
possible triggers and exclude other skin diseases that may present with similar clinical and
pathologic features.
Conditions that may present as urticarial dermatitis include:
●Prodromal bullous pemphigoid – In bullous pemphigoid, the development of bullae may be

preceded by a prodromal phase characterized by intense pruritus and eczematous, papular, or
urticaria-like skin lesions (picture 3) that may persist for weeks to months or, infrequently, may
remain as the only manifestation of the disease. The presence of any vesicles or blisters and the
histologic finding of eosinophilic spongiosis and a mid- to deep-dermal infiltrate of lymphocytes and
eosinophils suggest the diagnosis of bullous pemphigoid. The diagnosis can be confirmed by a skin
biopsy for direct immunofluorescence and serologic test for antibodies against the basement
membrane antigens BP180 and BP230. (See "Clinical features and diagnosis of bullous pemphigoid
and mucous membrane pemphigoid".)
952
●Scabies – Scabies can mimic urticarial dermatitis clinically and histologically. Clinical findings that
favor scabies include an ill-defined eruption, more significant scaling, involvement of the hands
and/or feet, involvement of the male genitalia, and a history of nocturnal pruritus. On histology,
scabies lesions show more spongiosis and a dense inflammatory infiltrate of lymphoid cells and
histiocytes, with an admixture of eosinophils and plasma cells. However, in cases in which the two
entities cannot be confidently differentiated, a positive response to empiric therapy for scabies has
diagnostic value. (See "Scabies: Epidemiology, clinical features, and diagnosis".)
●Hypersensitivity drug reaction – On histologic examination, the finding of significant interface

dermatitis with presence of individual necrotic keratinocytes suggests a drug reaction. A history of
exposure to a high-risk medication in the previous weeks further supports the diagnosis [7]. (See
"Exanthematous (maculopapular) drug eruption" and "Lichenoid drug eruption (drug-induced lichen
planus)".)
●Allergic contact dermatitis – Patch testing may be helpful to confirm or exclude allergic contact
dermatitis, although the histology of the two entities is typically quite distinct, with allergic contact
dermatitis showing a typical spongiotic dermatitis without significant mid-dermal or deep dermal
involvement. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Patch
testing".)
●Occult malignancy – Urticarial dermatitis may rarely be the presentation of occult malignancy [2-
4,8,9]. A complete physical examination with careful review of systems and age-appropriate
malignancy screening may lead to the correct diagnosis (table 1A-B).
MANAGEMENT The initial challenge in the management of patients with

urticarial dermatitis is in deciding when to stop looking for an underlying cause, especially reactions
to medications, and initiate treatment. In our experience, common medications that are not directly
impacting immunologic activity (eg, antihypertensives, proton pump inhibitors, antidiabetic
medications) are very rare as causes of urticarial dermatitis, and we only recommend trial
discontinuations of medications that were initiated within the three months prior to onset of
symptoms. As noted previously, medications that function directly on the immune system, such as
cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors or rituximab, are more likely culprits [10]. (See
Urticarial dermatitis is typically refractory to treatment with topical corticosteroids, oral

antihistamines, and UVB phototherapy [3,4]. Systemic corticosteroids, either oral or parenteral, are
rapidly effective in reducing pruritus and skin inflammation, although recurrence is common as the
dose is tapered. Other systemic immunosuppressive agents, such as mycophenolate mofetil,
methotrexate, cyclosporine, and azathioprine, have also been reported as effective [4,11-13].
Treatment of underlying conditions — In patients in whom

the etiology of urticarial dermatitis has been determined, appropriate treatment of the underlying
condition should be instituted in conjunction with the symptomatic treatment discussed below. (See
953
"Management and prognosis of bullous pemphigoid" and "Scabies: Management".)
If a drug hypersensitivity reaction is suspected, primarily based on histology that shows more
interface reaction than is typical for urticarial dermatitis, all medications that are not essential
should be withdrawn. (See "Exanthematous (maculopapular) drug eruption".)
First-line therapy — For patients with urticarial dermatitis, systemic

corticosteroids are the first-line therapy to achieve rapid relief from the unremitting pruritus.
Prednisone is initiated at 40 mg per day; this dose is maintained for up to one week and then tapered
down to 10 mg every other day or to the lowest dose that maintains symptomatic relief. Our most
common regimen is 40 mg for two days, 20 mg for two days, 10 mg for two days, and then 10 mg
every other day for four to eight weeks.
Intramuscular triamcinolone acetonide given as single 40 mg intramuscular injection at intervals of

6 to 12 weeks may be an alternative to oral corticosteroids. In patients with body weight over 100 kg,
80 mg may be given. This treatment can be repeated up to three to four times.
Most patients experience a prompt recurrence of symptoms when corticosteroids are discontinued
or tapered. To avoid a prolonged therapy with systemic corticosteroids, systemic
immunosuppressive agents (eg, mycophenolate mofetil, azathioprine, or methotrexate) can be
initiated prior to discontinuing corticosteroids. The author prefers mycophenolate mofetil over
azathioprine and methotrexate because of its favorable side effect profile.
After determining the lowest corticosteroid dose necessary to control symptoms, the author initiates
mycophenolate mofetil 30 to 40 mg/kg per day in two divided doses. Treatment is continued at the
same dose for at least two months and then corticosteroids are discontinued. If symptoms do not
recur in the two months following corticosteroid discontinuation, mycophenolate mofetil is tapered
off. The dose can be reduced by 500 mg per day every two to three months. If there is a relapse, the
last effective dose is resumed.
Based on our experience of patients who, despite prior varicella zoster vaccines, developed herpes
zoster while on mycophenolate, literature reports of increased rates of zoster in individuals taking
mycophenolate, and the excellent safety and cost profiles of valacyclovir, the author initiates
prophylactic therapy with 1000 mg daily of valacyclovir in all patients on mycophenolate at a daily
dose of 1000 mg or greater [14]. However, this approach is controversial, and its necessity in all
patients treated with mycophenolate for urticarial dermatitis is unknown.
Data on the efficacy of systemic corticosteroids and immunosuppressive agents for the treatment of
urticarial dermatitis trials are scanty. Their use is based upon limited evidence from small
observational studies and clinical experience [3,4,11,12].
Second-line therapies — For patients who do not respond to

mycophenolate mofetil, methotrexate or cyclosporine may be used as second-line steroid-sparing
agents. Methotrexate is initiated at a weekly dose of 10 to 15 mg in conjunction with the lowest dose
954
of corticosteroids that controls symptoms. Corticosteroids are discontinued after four weeks. If
there is no relapse in the following two months, the weaning of the methotrexate is initiated, with a
dose reduction of 2.5 mg per week every two to three months. In case of relapse, the last effective
dose is resumed.
Low-dose cyclosporine has been reported as an effective therapeutic option for urticarial dermatitis
in a series of 50 patients [13]. Patients were started on an average dose of 3 mg/kg per day for at
least two weeks. Cyclosporine was then gradually tapered over the subsequent weeks and then
discontinued. No relapses were observed. In the author's experience, cyclosporine given at a dose of
3 mg/kg per day is effective in inducing a rapid improvement of symptoms. However, patients
typically need treatment for 6 to 12 months before cyclosporine can be discontinued without a
relapse.
Third-line therapies — Other therapies that are occasionally used in the

treatment of patients with urticarial dermatitis include azathioprine, dapsone, and continued low-
dose systemic corticosteroids. However, data supporting these treatments are lacking.
Azathioprine is given at a starting dose of 2 to 2.5 mg/kg per day in patients with normal levels of
thiopurine methyltransferase. Corticosteroids are discontinued after eight weeks and azathioprine
subsequently tapered off with a dose reduction of 50 mg per day every two to three months, with a
return to last effective dose in the case of relapse.
It is important to remember that approximately 2 percent of patients who initiate azathioprine will
experience a potentially life-threatening hypersensitivity reaction in the first weeks of therapy [15].
Thus, the author only uses this agent if the patient has already failed mycophenolate, methotrexate,
and cyclosporine. (See "Pharmacology and side effects of azathioprine when used in rheumatic
diseases".)
PROGNOSIS Data on the long-term outcomes for patients with urticarial

dermatitis are lacking. It is the author's experience that most patients can discontinue treatment
over a one- to two-year period.
SUMMARY AND
RECOMMENDATIONS
●The term "urticarial dermatitis" describes a recalcitrant pruritic skin eruption characterized
clinically by erythematous papules and plaques that resemble urticaria but last for more than 24
hours and are sometimes accompanied by eczematous lesions. (See 'Introduction' above.)
955
●Patients typically present with an extremely pruritic, persistent eruption of dull red papules
coalescing into plaques that most often involves the trunk and proximal extremities (picture 2A, 2C).
●The diagnosis is based upon clinical and histologic features. Other conditions that mimic urticarial
dermatitis must be ruled out, including prodromal bullous pemphigoid, scabies, and drug
hypersensitivity reactions. (See 'Diagnosis and differential diagnosis' above.)
●Systemic corticosteroids are the first-line therapy to achieve rapid relief of symptoms. Treatment is
started with prednisone 40 mg for one week and then tapered down to 10 mg every other day or the
lowest dose that maintains symptom control. Other systemic immunosuppressants (eg,
mycophenolate mofetil, methotrexate, cyclosporine) may be used as steroid-sparing agents. (See

GRAPHICS
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Histopathologic features of urticarial dermatitis
Urticarial dermatitis is characterized by normal stratum corneum, mild epidermal edema with
minimal spongiosis, and a superficial to mid-dermal perivascular infiltrate of lymphocytes and
eosinophils with occasional neutrophils. However, these features are nonspecific and may be seen
in a variety of skin conditions, including drug reactions, arthropod assault, viral infections, and
prodromal stage of bullous pemphigoid.
Courtesy of Alejandro Gru, MD.
957
Urticarial dermatitis (dermal hypersensitivity reaction)
Small papules coalescing into plaques on the chest and abdomen of a 77-year-old patient with
dermal hypersensitivity.
Courtesy of Matthew J Zirwas, MD.
958
Edematous papules and small plaques along with areas of confluent erythema on the trunk and
arms of a 68-year-old patient with urticarial dermatitis.
959
Dull red plaques on the posterior surface of the thighs in a 68-year-old patient with urticarial
dermatitis.
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Eczematous lesions in bullous pemphigoid
Eczematous and erythematous, urticarial plaques with eroded blisters and excoriations on posterior
trunk and extremity skin.
Screening and prevention, adults younger than 65 years
Priority health Population Preventive intervention(s)*

problem
Cardiovascular disease
Risk Patients ≥20 years CVD risk assessment every three

assessment to five years
Hypertension All patients Blood pressure screening/control
Hyperlipidemia Patients between 17 and 21 years One-time screening for

dyslipidemia
Risk factors: Women ≥35 years, Dyslipidemia screening/control

men ≥25 years
Without risk factors: Women ≥45

years, men ≥35 years
961
Obesity All patients Screen with BMI
Select patients for treatment

based on risk factors
Physical All patients Counseling to exercise

activity
Diabetes Adults with hypertension or Screen for diabetes mellitus

mellitus hyperlipidemia
Adults aged 40 to 70 years with BMI Screen for diabetes mellitus as

≥25 kg/m2 part of cardiovascular risk
assessment
Cancer
Breast cancer Concerning family history Refer for genetic

counseling/testing
Hereditary breast and ovarian Screen per recommendations

syndrome
Women >40 Discuss screening, individual

decision; if screening desired,
screen with mammography
every two years
Cervical Women 21 to 29 years Pap smear every three years

cancer
Women ≥30 years Pap smear every three years
Or
Pap smear + HPV testing

every five years
Colorectal Patients with risk factors Screen per recommendations

cancer
Patients ≥50 years without risk Screening (decide among
factors colonoscopy, flexible
sigmoidoscopy, fecal occult
blood test)
Lung cancer Patients 55 to 74 years, ≥30 pack- Consider screening with low-dose
year smoking history and either helical CT scan
currently smoking or quit in the past
15 years
Prostate High-risk men 40 to 45 years Discuss screening, individual
962
g y g,
cancer decision
Men ≥50 years without risk factors Discuss screening, individual

decision
Melanoma High-risk patients Periodic skin exam
Average-risk patients Remain vigilant for suspicious

lesions
Immunizations
Influenza All patients Annual influenza vaccination
Tdap/Td All patients Tdap at least once
Td every 10 years
Varicella Patients without evidence of Varicella vaccine

immunity
HPV Women until 26 years HPV vaccine
Men until 21 years
MSM until 26 years
Zoster Patients ≥50 years Zoster vaccine
Pneumococcal Patients with risk factors Pneumococcal vaccine*

disease
Meningococcal Patients with risk factors Meningococcal vaccine

disease
Hepatitis B Patients with risk factors Hepatitis B vaccine
Patients with diabetes <60 years

and consider if ≥60 years if risk
factors
Sexually transmitted infections/blood-borne infections
Chlamydia Women <25 years Screening for chlamydia
Women ≥25 at increased risk
Men at increased risk
Gonorrhea Women at increased risk (including Screening for gonorrhea

sexually-active women <25 years)
963
Men at increased risk
Hepatitis B Patients with risk factors Screening for hepatitis B
Hepatitis C Patients born in the United States One-time screening for hepatitis
between 1945 and 1965 C
Patients with risk factors Screening for hepatitis C
HIV All patients One-time screening
Syphilis Patients with risk factors Screening for syphilis
Psychosocial health concerns
Depression All patients Brief screening
Alcohol All patients Screen for alcohol misuse
Tobacco Smokers and tobacco users Smoking/tobacco cessation
Other drug use All patients Assess for unhealthy drug use
Intimate All patients Screen for intimate partner

partner violence on initial visit
violence
Concerning history or physical Screening for intimate partner

exam findings violence
Osteoporosis Postmenopausal women <65 years BMD screening

with risk factors
Men with clinical manifestations of

low bone mass
Refer to individual UpToDate topics for more detailed discussions of screening and preventive
counseling.
CVD: cardiovascular disease; BMI: body mass index; HPV: human papillomavirus; CT: computed
tomography; Tdap: tetanus, diphtheria, and acellular pertussis vaccination; Td: tetanus, diphtheria
vaccine; MSM: men who have sex with men; HIV: human immunodeficiency virus; BMD: bone
mineral density.
* The pneumococcal vaccine (23-valent polysaccharide vaccine or 13-valent conjugate vaccine) and
schedule varies depending upon the risk factor. Refer to UpToDate topic on pneumococcal
vaccination in adults for details.
964
p
Summary of screening, prevention, and counseling recommendations for adults age ≥65 years
Priority Brief recommendation

problem
Historical information and counseling
Exercise Moderate to vigorous aerobic activity 3 to 5 times per week
Weight training or resistance exercises to maintain strength
Flexibility activities to maintain range of motion
Balance training to improve stability and prevent falls
Alcohol use CAGE questionnaire
Counseling to stop drinking
Tobacco use Ongoing regular counseling to stop smoking
Consideration of pharmacotherapy
Medication Regular review of medication list for:

use
Completeness, accuracy, adherence, and affordability
Drug-drug, drug-disease interactions
Careful attention to use of specific drug types/classes including

warfarin, digoxin, antidiabetic, analgesic, antihypertensive, psychotropic,
and anticholinergic drugs
Urinary Inquire about presence and severity biannually

incontinence
(UI) Presence of UI should trigger medication review, GU exam, appropriate
blood and urine tests
Driving Consideration of driving problems in those with problems with vision,

mobility, or cognition
For demented patients, recommend stop driving or refer for detailed

driving assessment
Social support Regular screening for financial and social support
965
Elder Routine direct questioning about problems with abuse or neglect
mistreatment
Advance Discussion and documentation of preferences with living will and

directives designation of health care power of attorney
Physical examination and testing
Blood pressure Measure annually
If treatment initiated, monitor orthostatic blood pressure, renal function,

and electrolytes
Weight Weight loss of 10% or more per year triggers assessment of

undernutrition, possible medical or medication-related causes, dental
status, food security, food-related functional status, appetite and intake,
swallow ability, and previous dietary restrictions
Hearing and Annual screening for hearing loss with patient inquiry and exam
vision (whisper test or handheld audiometry)
Vision assessment as part of the routine workup for older adults with
cognitive decline, functional impairment, or falls
Cognition Targeted screening in patients with memory complaints or new

functional impairment with MMSE, Mini-Cog, Clock Drawing Test,
Memory Impairment Screen, SLUMS, or MoCA
Mood Screen all older adults for depression with two questions:
During the last month:
1) Have you been bothered by feeling down, depressed, or hopeless?
2) Have you often been bothered by having little interest or pleasure in

doing things?
Gait and Get Up and Go Test

balance
Lipids Screen and treat older adults with CAD risk exceeding 10% over 10 years
Bone density Screening densitometry for osteoporosis for women at age 65
Abdominal One-time screening ultrasound in men aged 65 to 75 with any history of

aortic smoking or family history of AAA requiring repair
aneurysm
(AAA)
966
(AAA)
Diabetes Screen adults (to age 70) with BMI ≥25 kg/m2, hypertension, or
hyperlipidemia
Cancer screening
Cancer Key considerations in older adults:

screening
Life expectancy: Will this patient live long enough to benefit?
Potential harms: Procedural complications, anxiety, cost, and

overdiagnosis
Individual patient preference
Breast cancer Shared decision-making; if woman opts to be screened, biennial

mammography if life expectancy is at least 10 years
Colorectal Annual FOBT versus

cancer
Screening colonoscopy every 10 years versus
Flexible sigmoidoscopy every 5 years as long as life expectancy is at

least 5 years
Cervical May safely discontinue Pap smears at or after age 65 after 3

cancer consecutive normals within a 10-year period
May discontinue after hysterectomy for benign indication
Lung cancer Annual low-dose chest CT scan for high-risk individuals to age 80 years;
discontinue if person has not smoked for 15 years or if life expectancy
is limited
Immunization
Tetanus- Booster every 10 years in patients who have received primary series
diptheria (alternative: booster once after age 50); Tdap once
vaccine
Influenza Annual vaccination

vaccine
Pneumococcal Give PCV13 followed by PPSV23 6 to 12 months later, once after age 65
vaccine
(PCV13 Revaccinate PPSV23 once after age 65 if an initial vaccination was
given before age 65 and 5 years have elapsed since the first dose
and PPSV23)
967
Herpes zoster One-time vaccination after age 50
vaccine
Other
Aspirin Consider daily aspirin in patients with 5-year CAD risk of 3% or greater
Weigh risks of gastrointestinal bleeding
Calcium and 1200 mg of elemental calcium (diet and/or supplement) and at least
vitamin D 800 international units of vitamin D
CAGE: Cut down, Annoyed, Guilty, Eye-opener; GU: genitourinary; MMSE: Mini Mental State
Examination; SLUMS: St. Louis University Mental Status Test; MoCA: Montreal Cognitive
Assessment; BMI: body mass index; FOBT: fecal occult blood test; CT: computed tomography; CAD:
coronary artery disease.
Matthew J Zirwas, MDGrant/Research/Clinical Trial Support: LEO Pharma; Pfizer; DS Biopharma;
Incyte; Asana Biosciences; AbbVie; Galderma [Atopic dermatitis (Tralokinumab, DS107, ruxolitinib,
JAK inhibitors, IL-31 inhibitor)]; Janssen Pharmaceuticals; UCB [Psoriasis (Guselkumab,
bimekizumab)]; Foamix Pharmaceuticals [Rosacea, acne (Topical minocycline)]; Eli Lilly and
Company [Atopic dermatitis, psoriasis (Baricitinib, mirikizumab)]; Bausch Health Companies [Acne
(Clindamycin phosphate, clindamycin phosphate and benzoyl peroxide, clindamycin phosphate and
tretinoin)]; Aclaris Therapeutics [Atopic dermatitis, warts (JAK1/JAK3 inhibitor, topical solution)];
Arcutis Biotherapeutics [Atopic dermatitis, seborrheic dermatitis (Topical PDE inhibitor)]. Speaker's
Bureau: Regeneron Pharmaceuticals; Sanofi [Atopic dermatitis (Dupilumab)]; Genentech; Novartis
[Chronic urticaria (Omalizumab)]. Consultant/Advisory Boards: Bausch Health Companies;
Medimetriks Pharmaceuticals; Promius Pharma; Exeltis; Smart Practice; Anacor Pharmaceuticals;
Sun Products [Nummular eczema (Cleansers, moisturizers, healing ointments, sunscreen,
hydrocortisone butyrate, neomycin-fluocinolone, betamethasone valerate, patch testing materials,
crisaborole, laundry detergent, fabric softeners)]; Genentech [Urticarial dermatitis
(Omalizumab)].Joseph Fowler, MDGrant/Research/Clinical Trial Support: Novartis; Eli Lilly and
Company; Asana BioSciences [Eczema, psoriasis (Secukinumab, ixekizumab, dual Janus
kinase/spleen tyrosine kinase inhibitor)]. Speaker's Bureau: SmartPractice [Allergic contact
dermatitis (Epicutaneous patch test)].Rosamaria Corona, MD, DScNothing to disclose
968
969
Radiation dermatitis - UpToDate
uptodate.com/contents/radiation-dermatitis/print
INTRODUCTION Radiation dermatitis is one of the most common side

effects of radiotherapy for cancer, affecting approximately 95 percent of patients receiving
radiotherapy [1-6]. Cutaneous adverse effects of radiation therapy can be divided into early/acute
reactions, occurring within 90 days of initiating treatment, and late effects, which often become
apparent months to years after radiation treatment has been completed (table 1).
This topic will discuss the pathogenesis, clinical manifestations, and treatment of radiation
dermatitis. The complications of breast and chest wall irradiation and radiation-induced fibrosis are
discussed separately. (See "Clinical manifestations, prevention, and treatment of radiation-induced
fibrosis" and "Patterns of relapse and long-term complications of therapy in breast cancer survivors",
section on 'Chest wall and breast complications'.)
EPIDEMIOLOGY
Incidence — Radiation dermatitis occurs in approximately 95 percent of patients
receiving radiotherapy, especially patients with skin cancer, breast cancer, head and neck cancer,
lung cancer, or sarcoma [1,7-9]. The reason for the higher incidence in these cancer patient
populations is due to a higher radiation dose to the skin. In most cases, the skin reaction is mild or
moderate (table 2). Approximately 20 to 45 percent of patients experience moist desquamation and
ulceration [10,11].
970
Risk factors — Risk factors for radiation dermatitis include patient-related factors, use
of concurrent chemotherapy, and radiation dosing and schedule (table 3).
Patient-related
Body areas — Different areas of the body have different sensitivities to radiation (table 3). The
most sensitive regions of the body are the anterior of the neck, extremities, chest, abdomen, and
face [3]. Hair follicles on the scalp as well as the breast tissue are also radiosensitive. In addition,
breast reconstructions and implants are associated with increased risk of severe radiation
dermatitis due to the skin's inability to dissipate heat after reconstruction. These reactions are
usually confined to surfaces of transposed flaps or to mastectomy flaps [12,13].
Comorbidities and lifestyle factors — Obesity, poor nutritional status, chronic

sun exposure, and smoking appear to increase the risk of radiation dermatitis [2-4,14,15]. Based
upon limited evidence from case reports and small case series, patients with connective tissue
diseases, and in particular those with scleroderma, were considered in the past to be at increased
risk of severe acute and chronic radiation dermatitis [16]. However, data from large case series and a
few case-control studies do not show an increased frequency of acute or late complications in
patients with connective tissue diseases undergoing radiation therapy [17-19]. Skin thickening
localized to the field of irradiation has been reported to occur in approximately 50 percent of patients
with scleroderma [20]. (See "Overview of the management and prognosis of systemic lupus
erythematosus in adults", section on 'Issues with specific medications and therapies' and
"Malignancy and rheumatic disorders", section on 'Safety of radiation therapy for malignancy in
patients with rheumatologic disease'.)
Genetic susceptibility — Patients with inherited diseases associated with impaired

DNA repair capacity, such as ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, Gorlin
syndrome, or xeroderma pigmentosum, are at risk of developing severe radiation dermatitis [2].
However, even in the absence of a known genetic disease, some individuals may have an increased
susceptibility to radiation dermatitis. DNA sequencing studies have identified a number of single
nucleotide polymorphisms (SNPs) associated with the development of radiation dermatitis [21-24].
One study of 114 patients with locally advanced nasopharyngeal carcinoma found an association
between the codon 399 Arg/Arg SNP in the X-ray repair cross-complementing gene 1 (XRCC1) and
risk of acute radiation dermatitis [23]. Another study of 446 women receiving radiation therapy after
lumpectomy for breast cancer found that women with polymorphisms encoding reduced or absent
activity in the glutathione S-transferases function had a greater than twofold increase in risk for
acute radiation dermatitis [21]. In another study of 156 patients with breast cancer, SNPs that
mapped to two genes, ABCA1 and IL12RB2, were associated with a nearly threefold increased risk of
radiation-induced dermatitis [24].
971
Radiation dosing and schedule — The total dose, dose per fraction, and
volume and surface area exposed to radiation influence the risk of radiation dermatitis. In addition,
the use of bolus material to ensure full skin dose in certain clinical scenarios (eg, skin cancer, scar
recurrence) has enhanced the development of radiation dermatitis. Among patients with early breast
cancer undergoing adjuvant radiation therapy, evidence from observational studies and randomized
trials indicates that hypofractionated radiotherapy (40 to 42.5 Gy given in three to four weeks) is
associated with a lower risk of acute toxic effects compared with conventionally fractionated
radiotherapy (50 Gy in 25 fractions) [25,26]:
●In a multicenter, cohort study including 2309 patients with breast cancer treated with adjuvant
radiotherapy, the frequency of moist desquamation, dry desquamation, and grade ≥2 dermatitis was
significantly lower among patients treated with hypofractionated radiation therapy compared with
those treated with conventional radiation therapy (6.6 versus 28.5 percent, 18.7 versus 58.8 percent,
and 27.4 versus 62.6 percent, respectively) [26].
●Similar results were obtained in a randomized trial including 287 patients with breast cancer
treated with hypofractionated or conventional radiation therapy [25]. In this study, the rate of grade
≥2 dermatitis was 47 percent among patients treated with hypofractionated radiation therapy and 78
percent among those treated with conventional radiotherapy.
However, possible delayed acute cutaneous toxic effects of hypofractionated radiotherapy occurring
after completion of treatment were not systematically ascertained in these studies. Further studies
with a longer follow-up are necessary to evaluate the full extent of radiation-induced skin changes
from hypofractionated radiation therapy.
Concurrent chemotherapy — Patients receiving conventional chemotherapy

agents (eg, anthracyclines, taxanes) or targeted anticancer therapy with epidermal growth factor
receptor (EGFR) inhibitors plus radiation therapy are at increased risk of developing severe radiation
dermatitis [27,28] (see "Locally advanced squamous cell carcinoma of the head and neck:
Approaches combining chemotherapy and radiation therapy"):
●In a meta-analysis of 15 randomized trials comparing chemoradiotherapy versus radiation therapy

alone for the treatment of nasopharyngeal carcinoma, chemoradiotherapy was associated with a
nearly doubled risk of severe (grade 3 or 4) radiation dermatitis (relative risk [RR] 1.80, 95% CI 1.13-
2.88) [28].
●In a systematic review of 48 studies including 2152 patients with locally advanced head and neck
squamous cell carcinoma treated with concurrent radiotherapy and cetuximab, grade 3 or 4
radiation dermatitis developed in 32.5 percent of patients (95% CI 28.5-36.5 percent) [29]. In a
subsequent report of 51 patients treated with radiotherapy and cetuximab, grade 3 or 4 radiation
dermatitis occurred in 43 percent of patients [30].
PATHOGENESIS
972
Acute effects — Basal keratinocytes, stem cells in the hair follicles, and melanocytes
are highly radiosensitive [7,31,32]. During radiation therapy, the first fractionated dose of radiation
causes immediate structural tissue damage, ionization of cellular water and generation of short-
lived free radicals, irreversible double-stranded breaks in nuclear and mitochondrial DNA, and
inflammation [2,33-35]. The destruction of a large proportion of basal keratinocytes results in the
disruption of the self-renewing property of the epidermis. Repeated exposures do not allow time for
basal skin cells to replenish in order to maintain optimal renewal of the epidermis.
The mechanism of radiation-induced inflammation is incompletely understood. Ionizing radiation

incites signaling between the epidermis and dermis through resident skin cells. The hallmark of
radiation-induced skin injury is the transendothelial migration of leukocytes and other immune cells
from circulation to irradiated skin [36,37]. Keratinocytes, Langerhans cells, fibroblasts, and
endothelial cells in the skin stimulate resident and circulating immune cells [37,38]. Numerous
cytokines and chemokines are produced in response to these activation signals, which act on the
endothelial cells of local vessels, causing the upregulation of adhesion molecules (intercellular
adhesion molecule 1 [ICAM1], vascular cell adhesion molecule 1 [VCAM1], E-selectin) [36,37,39].
Acute radiation skin toxicity has been correlated with increased formation of various cytokines and
chemokines, in particular interleukin (IL) 1-alpha, IL-1-beta, tumor necrosis factor (TNF)-alpha, IL-6,
IL-8, chemokine ligand (CCL)4, cysteine-X-cysteine motif chemokine ligand (CXCL)10, and CCL2
[36,40,41]. In addition, ionizing radiation induces degranulation of mast cells in the dermis [38].
Research suggests that fibroblasts are a key cell type responsible for the late/delayed effect of
radiation (ie, fibrosis) [3,37,38].
Radiation skin injury also involves imbalances in antioxidant status and redox control of wound
healing [35-38,42]. Specific enzymes that have been implicated in oxidative stress following radiation
exposures include superoxide dismutases, glutathione peroxidases, thioredoxins, heme-oxygenases,
heat shock protein 27 (HSP27), and nitric oxide synthase [35,42]. A T helper type 2 (Th2)-mediated
immune response may also be responsible for nonresolution of inflammatory response and delayed
wound healing following irradiation [42].
Late effects — Transforming growth factor (TGF)-beta, whose levels are increased
within hours of radiation exposure, is thought to be implicated in the late radiation-induced fibrotic
changes [43]. TGF-beta is a regulatory protein that controls cell proliferation and differentiation,
wound healing, and synthesis of extracellular matrix components in normal tissue inflammatory
response [44]. (See "Clinical manifestations, prevention, and treatment of radiation-induced
fibrosis".)
ACUTE RADIATION DERMATITIS
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Clinical manifestations — Acute radiation dermatitis, defined as
dermatitis occurring within 90 days of starting treatment, typically occurs gradually during a
fractionated course of radiation therapy. The skin changes (table 1 and picture 1) depend upon the
radiation dose and include erythema, edema, pigment changes, hair loss, and dry or moist
desquamation [45,46]. During a fractionated course of 2 Gy per fraction of radiation therapy,
erythema occurs at doses of 12 to 20 Gy, dry desquamation at ≥20 Gy, and moist desquamation at
>50 Gy or higher [31].
In patients receiving cetuximab — In patients treated with concurrent

cetuximab and radiotherapy, the clinical presentation of radiation dermatitis may be different from
that seen in patients treated with radiotherapy alone. It results from the combination of radiation-
induced dry or moist desquamation with the xerosis and papulopustular inflammatory reaction
associated with epidermal growth factor receptor (EGFR) inhibition [47]. The skin reaction develops
earlier and is more often severe (grade 3 or 4), with marked xerosis, intense inflammation, and
epidermal necrosis, resulting in superficial ulceration, spontaneous bleeding, and crusting (picture 2)
[48,49]. These lesions are at increased risk of bacterial superinfection.
Grading — The severity of radiation dermatitis can be assessed by several grading systems
(table 2 and picture 1) [2,7,8]. The most commonly used are the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) (table 4) and the Radiation Therapy Oncology
Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) toxicity criteria
[50,51]. The RTOG/EORTC follows the same grading criteria described below for NCI CTCAE:
●NCI CTCAE grade 1 – Faint erythema with dry desquamation. Mild dermatitis is characterized by
mild, blanchable erythema or dry desquamation. The onset is typically within days to weeks of
initiating therapy, and symptoms may fade within a month. Pruritus, hair loss, and decreased
sweating are common associated symptoms. It is generally of no long-term consequence.
●NCI CTCAE grade 2 – Moderate dermatitis is characterized by moderate to brisk erythema and
patchy, moist desquamation mostly confined to skin folds and creases. It may be associated with
moderate edema. Moist desquamation is characterized by epidermal necrosis, fibrinous exudates,
and often considerable pain [2].
●NCI CTCAE grade 3 – There is confluent, moist desquamation in locations other than skin folds.
There may be bleeding when associated with trauma.
●NCI CTCAE grade 4 – This is characterized by skin necrosis or ulceration of full-thickness dermis.
Spontaneous bleeding from the involved site can occur. Skin graft may be indicated, and it can have
life-threatening consequences.
●NCI CTCAE grade 5 – Death due to dermatitis alone is a very rare event.
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Although commonly used in clinical and research settings, these grading systems are highly
subjective. Real-time laser Doppler flowmetry has been proposed as a quantitative method to detect
changes in cutaneous microcirculation that relate to increased radiation-induced skin injury [52]. A
grading atlas has also been developed, based upon a selection of representative digital photographs
of radiation dermatitis graded according to the CTCAE by an expert panel [53]. Additionally, the NCI
has established a Patient-Reported Outcomes version of the CTCAE, which can aid in assessment of
symptomatic adverse reactions from radiation therapy [54-56].
Clinical course and complications — The acute dermatitis

typically continues to progress up to 10 to 14 days after completion of radiation therapy. Re-
epithelialization usually begins within 10 days after radiation exposure in the absence of infection
[7]. Severe dermatitis (grade 4) with necrosis of the epidermis or underlying dermis is associated
with prolonged inflammation and healing time, resulting in fibrosis and loss of adnexal elements.
In addition, radiation exposure reduces the skin's antimicrobial defenses, leading to an increased risk
of bacterial infections in irradiated skin, most often from Staphylococcus aureus [57]. Bacterial
cultures are indicated if there are clinical signs of infection.
The severity of dermatitis and healing time are significantly increased in patients taking
radiosensitizing drugs, such as doxorubicin or EGFR inhibitors [27]. Patients receiving EGFR
inhibitors may concurrently develop a papulopustular, acneiform eruption [58]. (See "Acneiform
eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
Radiation dermatitis has a negative impact on patients' quality of life, with larger effects in higher-
grade dermatitis [59]. The worsening of quality of life is especially marked for the physical domain
(due to itching, burning, and irritation), followed by the emotional and functional domains.
Diagnosis — The diagnosis of acute radiation dermatitis is clinical, based upon the
finding of skin changes in a patient with a recent history of radiation therapy (picture 1). The sharp
demarcation of the skin changes and their limitation to the irradiated areas are important clues to
the diagnosis. Key elements of history are the duration of treatment and the cumulative dose of
radiation. A skin biopsy is usually not necessary for the diagnosis of radiation dermatitis. However,
histopathologic examination of a skin biopsy may be helpful if the diagnosis is uncertain.
Histopathology — Acute radiation dermatitis is characterized by apoptotic

keratinocytes, vacuolization of the basal layer, and epidermal edema. Depending upon the radiation
dose, epidermal necrosis with blister formation and sloughing of the epidermis may be seen [60].
These changes manifest clinically as "moist desquamation." Hyperkeratosis is seen with dry
desquamation. Dermal changes include dermal and endothelial cell edema, vasodilation, erythrocyte
extravasation, and fibrin thrombi in vessels. An inflammatory infiltrate is noted throughout the
dermis.
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Differential diagnosis — The differential diagnosis of radiation dermatitis
includes other skin conditions that can develop during or after completing the treatment:
●Allergic contact dermatitis – Allergic contact dermatitis to cosmetics, adhesive bandages, or

simulation markings may mimic radiation dermatitis. (See "Clinical features and diagnosis of allergic
contact dermatitis".)
●Intertrigo – Intertrigo is a common inflammatory condition of skin folds characterized by moist

erythema, malodor, weeping, pruritus, and tenderness, often associated with candidal or bacterial
secondary infection (picture 3). (See "Intertrigo".)
●Radiation port dermatophytosis – Dermatophyte infection rarely can occur at the site of irradiation
[61,62]. It presents as single or multiple, annular, erythematous plaques with a well-defined, scaling
border (picture 4). A potassium hydroxide preparation can confirm the diagnosis.
●Herpes zoster – Herpes zoster (shingles) presents with grouped, erythematous papules, vesicles,
and pustules typically located in a single dermatome, most often thoracic or lumbar (picture 5). Pain,
described as burning, throbbing, or stabbing, is the most common symptom. (See "Epidemiology,
clinical manifestations, and diagnosis of herpes zoster".)
●Graft-versus-host disease (GVHD) – Acute GVHD presents with a maculopapular rash that initially
involves the nape of the neck, ears, shoulders, and the palms of the hands. The rash may become
generalized, with bullae and extensive skin sloughing (picture 6). The histopathologic features are
similar to those of radiation dermatitis and include vacuolization of the basal layer, apoptotic
keratinocytes, satellite cell necrosis, and a superficial perivascular lymphocytic infiltrate (picture 7).
(See "Cutaneous manifestations of graft-versus-host disease (GVHD)" and "Clinical manifestations,
diagnosis, and grading of acute graft-versus-host disease".)
●Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – Severe radiation dermatitis

shares clinical and histopathologic features with SJS/TEN, a severe skin reaction typically induced
by medication (picture 8A-B). In SJS/TEN, histopathologic examination of a skin biopsy reveals
subepidermal bullae and full-thickness epidermal necrosis. (See "Stevens-Johnson syndrome and
toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Prevention
Modern radiation therapy techniques — Intensity-modulated
radiation therapy (IMRT) and volumetric-modulated arc radiation therapy (VMAT), advanced forms of
radiation therapy that deliver radiation to the planned treatment volume while minimizing radiation to
normal tissue outside the target, have been reported to reduce the occurrence of skin reactions. In a
multicenter, randomized trial, 331 breast cancer patients were treated postoperatively with adjuvant
radiotherapy using either a standard wedge missing-tissue compensation technique or breast IMRT
[63]. Fewer patients in the IMRT group than in the conventional radiotherapy group experienced
976
moist desquamation (31 versus 48 percent). In a multivariate analysis, breast IMRT decreased the
risk of moist desquamation by nearly 60 percent (odds ratio [OR] 0.42, 95% CI 0.23-0.75). (See
"Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation
therapy'.)
Furthermore, hypofractionated irradiation has become increasingly popular for breast radiation
therapy [51]. Hypofractionation delivers a higher fractionated radiation dose daily for an equivalent
total dose over a shorter period of time (ie, fewer number of sessions). A prospective evaluation of
hypofractionated versus standard fractionated therapy suggests that rates of dermatitis, pruritus,
hyperpigmentation, and pain are decreased with hypofractionated therapy [25].
General skin care — The skin in the treatment area needs to be protected from
irritation and friction during and for two to four weeks after radiotherapy treatment has finished.
General skin care measures for patients undergoing radiation therapy include [7,8,14,64]:
●Maintaining the irradiated area clean and dry.
●Washing with lukewarm water and mild soap (synthetic soaps are preferable).
●Using unscented, lanolin-free, water-based moisturizers two to three times per day, including
nontreatment day on the weekend.
●Avoiding skin irritants, such as perfumes and alcohol-based lotions.
●Wearing loose-fitting clothes to avoid friction injuries.
●Avoiding corn starch or baby powder in skin folds.
●Avoiding sun exposure.
●Avoiding wet shaving within the treatment area; an electric razor is a safe alternative.
It is important to instruct patients to gently clean and dry the skin in the radiation field before each
irradiation session.
The benefit of a washing routine during treatment has been evaluated in a few randomized trials
involving breast cancer patients and in one meta-analysis [57,65,66]. Although washing practices do
not seem to reduce the overall risk of developing radiation dermatitis, washing with soap and water
or water alone is associated with a significant reduction in itching, erythema, and desquamation
compared with no washing [57]. Moreover, allowing patients their normal hygiene routine may
prevent unnecessary distress and social isolation.
Patients are typically advised to avoid applying topical moisturizers, gels, emulsions, or dressings
shortly before radiation treatment, as they can cause a bolus effect (ie, increase in the radiation dose
delivered to the epidermis) [10,67]. However, a study that evaluated the dosimetric effect of topical
agents commonly used for radiation dermatitis (ie, petrolatum-based ointment, silver sulfadiazine
977
cream) by using optically stimulated luminescent dosimeters found that the surface radiation dose
increased when a very thick layer (≥3 mm) of the topical agent was applied but did not increase if
only a moderately thick layer (1 to 2 mm) was applied [67].
The use of deodorants, and in particular metallic deodorants, during radiation therapy has been
debated due to concerns that the deposition of aluminum salts may influence the superficial
radiation dose or cause a bolus effect [68]. However, a randomized trial including 333 breast cancer
patients using aluminum-containing deodorants, nonaluminum-containing deodorants, or no
deodorants during conventionally fractionated postoperative radiation therapy did not find any
significant difference among the three groups in the incidence or severity of radiation dermatitis [69].
Patients in the aluminum-containing deodorant group experienced significantly less sweating than
the control; the odds of their sweating being barely tolerable and frequently or always interfering
with their daily activities was decreased by 85 percent (OR 0.15, 95% CI, 0.03-0.91).
Topical corticosteroids — We suggest topical corticosteroids for the prevention

of severe radiation dermatitis and the reduction of discomfort and itching [64]. Low- to medium-
potency topical corticosteroids (groups 4 to 6 (table 5)), such as mometasone furoate 0.1% or
hydrocortisone 1% cream, are applied to the treatment field once or twice daily, after each
radiotherapy session.
Evidence from several randomized trials and one meta-analysis indicates that the regular use of
topical corticosteroids during the radiation therapy and for a few additional weeks after the
completion of treatment may reduce the incidence of severe dermatitis (moist desquamation)
[57,70-74]:
●A 2017 meta-analysis including 10 randomized trials (919 participants with breast cancer) found
that topical corticosteroids applied once or twice daily to the breast or chest wall from the first day
of radiotherapy to up to three weeks after completion of radiotherapy reduced the risk of wet
desquamation compared with placebo creams (OR 0.29, 95% CI 0.19-0.45) [75]. All studies showed
that the mean radiation dermatitis score assessed by RTOG or CTCAE version 3.0 was lower in the
corticosteroid group than in the control group. Moreover, in six studies, patients' subjective report of
pruritus and burning was less in the topical corticosteroid group than in the control group.
●In a 2018 randomized trial, 124 patients with breast cancer undergoing postmastectomy radiation
therapy were treated with mometasone furoate 0.1% cream or an emollient cream twice daily,
starting on the first day of radiation therapy and continuing until either the development of moist
desquamation or two weeks after the completion of radiation therapy. Moist desquamation occurred
in fewer women in the mometasone furoate group than in the emollient group (44 versus 67 percent)
[74].
Other topical agents/dressings — Evidence from a limited number of

randomized trials does not support the use of aloe vera, trolamine (triethanolamine), sucralfate, or
hyaluronic acid for the prevention of radiation dermatitis [76-83]:
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●In a randomized trial including 225 patients with breast cancer, more patients in the aloe vera gel
group than in the aqueous cream group developed dry desquamation, dermatitis of grade 2 or
higher, and greater pain [78]. A subsequent systematic review did not find evidence for efficacy of
aloe vera in preventing or minimizing radiation dermatitis in cancer patients [80]. A subsequent
randomized trial found that the use of either an aloe cream or placebo cream during radiation
therapy increased the incidence and severity of radiation dermatitis compared with a dry powder
regimen (nonmetallic baby powder or cornstarch) [82].
●In a randomized trial, 166 patients with advanced squamous cell carcinoma of the head and neck
were assigned to prophylactic trolamine, 175 patients to interventional trolamine, and 165 patients to
institutional preference product [76]. Grade ≥2 dermatitis was reported in 79, 77, and 79 percent of
the three groups, respectively. In another trial including 254 breast cancer patients, trolamine cream
or calendula cream was applied after each session [77]. The occurrence of acute radiation
dermatitis of grade 2 or higher was significantly lower with the use of calendula than with trolamine
(41 versus 63 percent). However, in a subsequent study including 420 breast cancer patients, the
incidence of grade ≥2 dermatitis was similar in patients using a calendula cream and in those using
a water-based emollient cream [79].
●Sucralfate cream for the prevention of radiation dermatitis was compared with aqueous cream or
no treatment in a randomized trial including 357 patients undergoing radiotherapy to the head and
neck, breast, or anorectal area. After five weeks, the severity of erythema, desquamation, itch, pain,
and discomfort, as reported by patients, was similar in the three groups [81].
●In a left-right randomized trial, 74 breast cancer patients applied topical hyaluronic acid on the
medial or lateral half of the irradiated breast and a petrolatum-based emollient to the other half of
the breast [84]. Breast skin treated with the hyaluronic acid gel developed a significantly higher rate
of grade ≥2 dermatitis than the skin treated with petrolatum (61.5 versus 47.7 percent).
●Topical regenerating agents using engineered biopolymers, such as glycosaminoglycans, have

been compared with placebo in a phase 3 randomized trial of 76 patients with head and neck cancer
undergoing radiation therapy with concurrent cetuximab [85]. The incidence of grade ≥2
radiodermatitis was similar in the two groups, as evaluated by two external experts using
photographs (76 versus 74 percent). In addition, no difference was noted in the Dermatology Life
Quality Index score (score >10, 15 versus 20 percent).
A variety of other agents and dressings have also been evaluated in single randomized trials and in
systematic reviews, including silver sulfadiazine (SSD), petroleum-based ointments, ascorbic acid,
allantoin, almond oil, olive oil, dexpanthenol, calendula, barrier film, silver nylon dressings, and
silicone-based film-forming gel dressing [64,86-90]. However, there is limited or no evidence for
efficacy of any of these topical agents in preventing or reducing the severity of radiation dermatitis:
●SSD is known to have anti-inflammatory and barrier-enhancing properties, which may protect
radiation-damaged skin from other infectious agents [91]. In a randomized trial including 102
patients with breast cancer, SSD 1% cream applied three times a day, three days a week, for five
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weeks during radiotherapy and one week thereafter was compared with general skin care in the
prevention of radiation dermatitis [87]. Patients in the SSD group experienced a less severe
dermatitis than patients in the control group (mean dermatitis score 5.49 versus 7.21, respectively).
●Silver nylon dressings, which have traditionally been used as burn wound dressings, have
demonstrated some efficacy in reducing radiation-induced skin toxicity. In a small, randomized trial
including 42 patients with anal or rectal cancer treated with radiation therapy, the use of silver nylon
dressings was associated with a lower radiation dermatitis severity score compared with standard
skin care [92]. In contrast, in a randomized trial including 196 patients with breast cancer, silver
nylon dressings did not reduce the incidence or severity of radiation dermatitis compared with
standard skin care [93]. However, patients in the silver nylon dressing group experienced less itching,
pain, and burning compared with those in the standard care group.
●In a single-blind, randomized trial, 197 patients with head and neck cancer were treated with a
silicone-based film-forming gel dressing or a moisturizer (sorbolene) at the start of radiotherapy,
twice a day until the skin reaction subsided, up to four weeks post-treatment [94]. The rates of grade
2 and grade 3 radiation dermatitis were lower in the active treatment group than in the control group
(80 and 28 percent versus 91 and 45 percent, respectively). The risk of developing grade 2 or grade 3
radiation dermatitis was reduced by 40 and 50 percent, respectively, in the active treatment group
compared with the control group, after adjusting for cetuximab treatment (hazard ratio [HR] 0.59,
95% CI 0.44-0.80, and HR 0.51, 95% CI 0.32-0.80, respectively).
Systemic agents — Several oral agents have been evaluated in single small,
randomized trials, including proteolytic enzymes (a combination of papain, trypsin, and
chymotrypsin) [95], pentoxifylline [96], antioxidant supplements, zinc supplementation [97],
sucralfate [98], and curcumin [99]. However, there is little or no evidence for efficacy of any of these
systemic treatments. Examples of studies that examined the role of systemic agents in the
prevention of radiation dermatitis include:
●In a small, randomized study including 78 patients treated with postoperative radiation therapy for
squamous cell carcinoma of the head and neck, oral pentoxifylline (400 mg three times daily) was
not more effective than placebo in the prevention of acute radiation dermatitis [96]. However, the
authors noted a beneficial effect of pentoxifylline in reducing late skin changes, fibrosis, and skin
necrosis.
●In a multicenter, randomized trial including 686 breast cancer patients undergoing radiation
therapy, curcumin 1.5 g per day taken throughout the prescribed course of radiotherapy and then for
an additional week was not more effective than placebo in reducing the severity of radiation
dermatitis [100].
Management — The management of radiation dermatitis is guided by the severity of

skin damage and involves general skin care measures, prevention and treatment of secondary skin
infection, and the use of dressings [64,91]. It is important to educate the patient and family about the
980
care of their skin during treatment to reduce irritation and trauma, relieve discomfort, and promote
healing.
Patients with grade 1 dermatitis — Patients with mild dermatitis (RTOG

and NCI CTCAE grade 1 dermatitis (table 2)) have faint erythema and dry desquamation. For most
patients, no specific treatment is required in addition to general skin care measures. (See 'General
skin care' above.)
Dry desquamation may be treated with hydrophilic (oil-in-water) moisturizers. Mid-potency topical
corticosteroids (groups 4 and 5 (table 5)) may be useful to control itch or irritation. Antihistamines
are generally not effective in reducing pruritus related to radiation dermatitis.
In patients with grade 1 radiation dermatitis, the use of special dressings does not seem to be
effective in halting the progression of dermatitis. In a four-week randomized trial, 278 breast cancer
patients with grade 1 radiation dermatitis were treated with a hydrocolloid dressing or placebo (a
water-based spray) [101]. At four weeks, the rates of local treatment failure, defined as skin
deterioration or interruption of radiation therapy due to radiation dermatitis, were similar in the active
treatment and placebo groups (49 versus 51 percent, respectively); the intensity of erythema and
pain and quality-of-life scores were also similar in the two groups.
Patients with grade 2 to 3 dermatitis — Patients with grade 2 and 3

dermatitis (table 2) present with moist desquamation involving the skin folds or other skin areas.
Treatment involves measures aimed at preventing secondary skin infection and the use of dressings
over the areas of skin sloughing [10,64]. If infection occurs, standard therapy for bacterial infections
should be initiated with topical and/or systemic antibiotics.
For moist desquamation, we typically use soft, absorbent, silicone foam bandages (eg, Mepilex Lite,
Biatain). This type of dressing is atraumatic to the wound and surrounding skin when removed. The
bandage can be applied with or without topical agents. The dressing should be changed daily or
more frequently, depending upon the severity of weeping.
The use of dressings in the management of moist desquamation is based upon the observation that
a moist environment promotes the rate of re-epithelization and increases the speed of wound
healing [102] (see "Basic principles of wound management", section on 'Wound dressings'). In
clinical practice, a variety of wound dressings are used, including nonadherent, hydrogel, or
hydrocolloid dressings [7]. However, there is little evidence to aid in the choice among the various
types of dressings. A few randomized trials have compared different dressings or dressings versus
other topical agents with inconclusive results [103-105]:
●In one study, 100 patients with moist desquamation received dry nonadherent dressing or hydrogel
dressing [103]. The time to healing was longer in the hydrogel group than in the dry dressing group.
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●Two small trials compared hydrogel or hydrocolloid dressing with gentian violet 0.5% aqueous
solution [104,105]. In one study, patients in the hydrogel group were more likely to heal than patients
in the gentian violet group; the median time to healing was 12 days for hydrogel dressing and more
than 30 days for gentian violet [104]. In another study, the healing time was similar for patients
receiving hydrocolloid dressing and those receiving gentian violet (11.4 versus 11.7 days,
respectively) [105]. However, dressing comfort and acceptability were higher for hydrocolloid
dressing than gentian violet. Grade 3 radiodermatitis with moist desquamation may require
interruption of radiation therapy, depending upon the body location and the patient's discomfort.
Patients with grade 4 dermatitis — Grade 4 dermatitis (table 2) is rare.

Patients presenting with full-thickness skin necrosis and ulceration should be treated on a case-by-
case basis. They may require discontinuation of radiation therapy and a multidisciplinary approach,
involving a wound specialist, radiation oncologist, dermatologist, and nurse [10]. Treatment may
include surgical debridement, full-thickness skin graft, or myocutaneous or pedicle flaps. For
infected or at-risk wounds, systemic or topical antibacterial agents should be considered. (See
"Basic principles of wound management".)
Patients receiving cetuximab — In patients receiving concurrent

cetuximab therapy who develop grade 1, 2, or 3 radiation dermatitis, interruption or dose reduction of
cetuximab is not generally necessary [47,106-108]. However, some experts suggest a dose reduction
of cetuximab in patients with severe grade 3 reaction [108]. Interruption of both radiation therapy
and cetuximab is advised in patients with grade 4 reaction. Cetuximab should be interrupted until the
skin reaction has resolved to at least grade 2 [47,106].
Patients treated with cetuximab may need additional treatment or prophylaxis for the
papulopustular, acneiform eruption commonly associated with EGFR inhibitors. (See "Acneiform
eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors", section on
'Management' and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and
MEK inhibitors", section on 'Prevention'.)
Future therapies — Preclinical studies have identified promising targeted

therapies for radiation injury, including transforming growth factor (TGF)-beta 1 pathway inhibitor
[109,110], synthetic superoxide dismutase/catalase mimetics [111], recombinant interleukin (IL) 12
[112], toll-like receptor-2 and -5 agonists [32,113], and inhibitors of cyclin-dependent kinases [113].
In single case reports of patients with severe radiation burns, mesenchymal stem cells injected into
and around the wound bed following excision of necrotic skin promoted tissue regeneration and
wound healing [114,115]. In animal models, pravastatin reduced radiation-induced skin injury by
maintaining endothelial cell function via upregulation of endothelial nitric oxide synthase [36].
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RADIATION BURNS Radiation burns may occur rarely as a result
from high exposure to radiographs during repeated diagnostic medical imaging, interventional
radiology procedures, or radiation therapy [116]. The most distinctive feature of radiation burns
compared with thermal burns is the difficulty in delineating radiation-injured tissue from uninjured
tissue [114,115]. This difficulty stems from the unpredictable progression of tissue injury, which can
occur weeks to years after irradiation and often results in necrosis of skin grafts [114,115].
Additional unique characteristics of radiation burns include a dose-dependent clinical pattern and
opiate-resistant pain [2,3,14,31,114,117].
RADIATION RECALL REACTION Radiation

recall is an acute inflammatory reaction confined to an area of previous radiation exposure that is
triggered by chemotherapeutic agents or other drugs [118]. The reaction occurs in approximately 6
to 9 percent of patients receiving chemotherapy after radiation therapy, is drug-specific for each
individual, and can occur weeks to months to years after radiation therapy [118,119]. The diagnosis
is based on the appearance within the previous radiation therapy field (picture 9). (See "Cutaneous
side effects of conventional chemotherapy agents", section on 'Radiation recall and enhancement'.)
Radiation recall occurs most frequently with conventional chemotherapy agents, in particular
anthracyclines (doxorubicin), taxanes (docetaxel, paclitaxel), and antimetabolites (gemcitabine,
capecitabine, pemetrexed) [118]. However, it has also been reported in association with targeted
anticancer agents, such as epidermal growth factor receptor (EGFR) inhibitors, BRAF inhibitors, and
anti-PD-1 monoclonal antibodies [120-124].
The clinical manifestations of radiation recall include mild rash, dry desquamation, pruritus, swelling,
maculopapular eruptions, and ulceration [118]. In approximately one-third of cases, recall reactions
occur in other sites, such as lung, oral mucosa, and gastrointestinal system. After withdrawal of the
drug, the reaction usually resolves within one to two weeks. The management is similar to that of
acute radiation dermatitis.
EOSINOPHILIC, POLYMORPHIC,
AND PRURITIC ERUPTION Eosinophilic, polymorphic,
and pruritic eruption associated with radiotherapy (EPPER) is an uncommon reaction to radiation
therapy that most commonly develops in patients with cervical cancer and breast cancer. EPPER
presents with erythematous papules, pustules, excoriations, and occasionally wheals, vesicles, and
bullae, accompanied by localized or generalized pruritus (picture 10) [125,126]. The eruption is not
confined to the irradiated area but may involve the adjacent areas and the upper and lower
extremities. Biopsy shows a superficial and deep, perivascular, lymphohistiocytic infiltrate with
eosinophils. Treatment includes topical and systemic corticosteroids and antihistamines. EPPER
usually resolves in a few weeks after completing radiation therapy.
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FLUOROSCOPY-INDUCED
SUBACUTE RADIATION
DERMATITIS Subacute radiation dermatitis is an uncommon form of radiation
dermatitis that typically presents weeks to a few months after the initial exposure to ionizing
radiation during a diagnostic or interventional radiologic procedure [127]. The clinical appearance is
that of an erythematous patch or plaque over the irradiated area that may become indurated,
hyperpigmented, and ulcerate [128-130]. The diagnosis may be delayed given the delayed
presentation and rarity.
Histologically, fluoroscopy-induced subacute radiation dermatitis is indistinguishable from acute

graft-versus-host disease or fixed drug reaction [129]. Histologic findings include atypical
keratinocytes, hypergranulosis, and compact hyperkeratosis. An interface dermatitis with
keratinocyte necrosis is usually present. In addition, clefting along the dermal-epidermal junction,
fibroblast proliferation, and telangiectatic vessels may be seen. The papillary dermis may show a
variable lymphocytic infiltrate with histiocytes around the papillary dermal plexus but no eosinophils,
in contrast to fixed drug reactions.
LATE-EFFECT (CHRONIC)
RADIATION DERMATITIS
Clinical manifestations — Late-effect or chronic radiation dermatitis
typically presents months to years after radiation exposure [8]. It is characterized by dermal fibrosis
and poikilodermatous skin changes, including hyper- and hypopigmentation, atrophy, and
telangiectasias (table 1) [3,31,131].
Histopathology — Histologically, late-stage radiation dermatitis is characterized by

eosinophilic, homogenized sclerosis of dermal collagen; scattered, large, atypical fibroblasts;
absence of pilosebaceous units; and vascular changes. The deep vessels show fibrous thickening,
sometimes with luminal obliteration and recanalization, whereas telangiectases are prominent in the
upper dermis.
Management — Several small, randomized trials suggest that prolonged treatment

with pentoxifylline in combination with vitamin E for up to >3 years may be helpful for the treatment
of subcutaneous radiation-induced fibrosis [132-134]. However, the optimal dose and duration of
therapy and the role of tocopherol have not been determined. It is also unclear whether this therapy
should be continued indefinitely to maintain benefit. Pentoxifylline and vitamin E can reverse
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superficial radiation-induced fibrosis, but the optimal dose and duration of therapy are unknown at
this time. Physical therapy may include active and passive range of motion exercises, which may
help to improve range of motion and reduce contractures. (See "Clinical manifestations, prevention,
and treatment of radiation-induced fibrosis", section on 'Pentoxifylline plus tocopherol'.)
Hyperbaric oxygen has been evaluated as a treatment for radiation-induced fibrosis; however, there
is currently insufficient evidence to show efficacy [135].
There are a few reports of successful treatment of radiation therapy-induced telangiectasias and
hyperpigmentation with laser therapy [136,137]. (See "Laser and light therapy for cutaneous vascular
lesions" and "Laser and light therapy for cutaneous hyperpigmentation".)
POSTIRRADIATION MORPHEA Postirradiation

morphea is a rare late complication of radiotherapy occurring months to years after treatment and is
characterized by the development of sclerotic plaques that resemble idiopathic morphea in the
irradiated area. In some patients, sclerotic changes may also involve the adjacent nonirradiated skin
[138,139]. Postirradiation morphea occurs in most cases in women undergoing radiation therapy for
breast cancer, is associated with considerable morbidity and pain, and is cosmetically disfiguring
(picture 11) [140]. In a retrospective study of 25 patients (23 women) with postirradiation morphea,
11 had a coexistent autoimmune disorder [139].
Treatment of postirradiation morphea is similar to that of idiopathic morphea and includes topical
and intralesional corticosteroids, phototherapy, and systemic immunosuppressive agents in various
combinations [138]. (See "Treatment of morphea (localized scleroderma) in adults".)

provided separately. (See "Society guideline links: Radiation dermatitis".)
SUMMARY AND
RECOMMENDATIONS
●Radiation dermatitis is one of the most common side effects of radiotherapy for cancer, affecting
approximately 95 percent of patients receiving radiotherapy, especially patients with breast cancer,
head and neck cancer, lung cancer, or sarcoma. Risk factors for radiation dermatitis include body
site, older age, female sex, and obesity (table 3). (See 'Introduction' above and 'Epidemiology' above.)
●Acute radiation-induced skin changes (table 1) depend upon the radiation dose and include
erythema, edema, pigment changes, epilation, and dry or moist desquamation (picture 1). Severity of
radiation dermatitis is commonly assessed by using the National Cancer Institute Common
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Terminology Criteria for Adverse Events (NCI CTCAE) or the Radiation Therapy Oncology Group
(RTOG) toxicity scoring system and ranges from mild (grade 1) to severe (grade 3 and 4) (table 2).
(See 'Acute radiation dermatitis' above.)
●The diagnosis of acute radiation dermatitis is clinical, based upon the finding of erythema, dry
desquamation, or moist desquamation in a patient with a recent history of radiation therapy. (See
'Diagnosis' above.)
●Modern radiation therapy techniques, such as intensity-modulated radiation therapy (IMRT) and
volumetric-modulated arc radiation therapy (VMAT), which deliver radiation to the planned treatment
volume while minimizing radiation to normal tissue outside the target, may reduce the occurrence of
radiation dermatitis. (See 'Prevention' above.)
●For patients undergoing radiation therapy, we suggest prophylactic topical corticosteroids in

addition to general skin care measures for the prevention of radiation dermatitis (Grade 2B). Low- to
medium-potency topical corticosteroids (groups 4 to 6 (table 5)) are applied to the treatment field
once or twice daily, after each radiotherapy session. Agents of unproven efficacy include aloe vera,
trolamine, sucralfate, hyaluronic acid, silver sulfadiazine, and silver nylon dressings. (See
'Prevention' above and 'Topical corticosteroids' above.)
●The management of radiation dermatitis is guided by the severity of skin damage (table 2). Patients
with grade 1 radiation dermatitis usually do not require any specific treatment in addition to general
skin care measures. (See 'Patients with grade 1 dermatitis' above.)
●For patients with grade 2 to 3 radiation dermatitis and moist desquamation, we typically use soft,
absorbent, silicone foam bandages. Bacterial superinfection is treated with topical and/or systemic
antibiotics. (See 'Patients with grade 2 to 3 dermatitis' above.)
●Patients with grade 4 radiation dermatitis who present with full-thickness skin necrosis may require
surgical debridement and full-thickness skin graft or myocutaneous or pedicle flaps. (See
●Late-stage or chronic radiation dermatitis typically presents months to years after radiation
exposure with subcutaneous fibrosis. The management of radiation-induced fibrosis is discussed in
detail elsewhere. (See 'Late-effect (chronic) radiation dermatitis' above and "Clinical manifestations,
prevention, and treatment of radiation-induced fibrosis", section on 'Pentoxifylline plus tocopherol'.)
●Postirradiation morphea is a rare late complication of radiotherapy presenting with sclerotic

plaques in the irradiated area that resemble idiopathic morphea (picture 11). Treatment includes
topical and intralesional corticosteroids, phototherapy, and systemic immunosuppressive agents.
(See 'Postirradiation morphea' above and "Treatment of morphea (localized scleroderma) in adults".)

to acknowledge Marilyn Ling, MD, who contributed to an earlier version of this topic review.
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Pathogenesis, clinical manifestations, and diagnosis of acne
vulgaris
uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-acne-vulgaris/print
988
INTRODUCTION Acne vulgaris is a common cutaneous disorder

characterized by chronic or recurrent development of papules, pustules, or nodules on the face,
neck, trunk, or proximal upper extremities. The pathogenesis of acne vulgaris involves the
interaction of multiple factors that result in the formation of comedones and the development of
inflammation.
Acne vulgaris is most frequent among adolescents and young adults but is not limited to these ages.
The severity of skin involvement varies from minimal involvement to disfiguring and highly
inflammatory presentations. Hyperpigmentation, scarring, and negative psychosocial effects are
common complications.
The pathogenesis, clinical manifestations, and diagnosis of acne vulgaris will be reviewed here. The
treatment of acne vulgaris is discussed separately. (See "Treatment of acne vulgaris" and "Hormonal
therapy for women with acne vulgaris" and "Oral isotretinoin therapy for acne vulgaris" and "Light-
based, adjunctive, and other therapies for acne vulgaris" and "Management of acne scars".)
EPIDEMIOLOGY Acne vulgaris is common and occurs most frequently in

adolescents and young adults. Estimates of the prevalence of acne vulgaris in adolescents range
from 35 to over 90 percent [1-3].
Acne often begins in the preadolescent period (ages 7 to 12 years) and resolves in the third decade,
but may persist into adulthood or develop de novo in adulthood. Adolescent acne exhibits a male
predominance; in contrast, postadolescent acne predominantly affects women [4]. (See
"Postadolescent acne in women".)
The prevalence of acne decreases with increasing age. A survey of over 1000 adults in the United
States found the following rates of self-reported acne in men and women [2]:
●20 to 29 years: 43 and 51 percent, respectively
●Ages 50 and older: 7 and 15 percent, respectively
Of note, studies using a clinical examination typically find a lower prevalence than survey studies
that document self-reported acne.
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Infantile acne, a variant of acne vulgaris, may begin in infancy. Mid-childhood acne (acne that
develop in children ages one to six years) is uncommon and may be an indicator of an underlying
condition. (See 'Infantile acne' below and "Premature adrenarche".)
PATHOGENESIS Acne vulgaris is an inflammatory disorder of the

pilosebaceous unit, which is comprised of the hair follicle and sebaceous gland. The pathogenesis
of acne involves a complex interplay of host factors, such as androgen-mediated stimulation of
sebaceous glands, dysbiosis within the microbiome of the pilosebaceous follicle, and innate and
cellular immune responses, and may be influenced by factors such as genetics and, possibly, diet
[5].
Lesion development — The microcomedo (a small, hyperkeratotic plug

composed of corneocytes in the lower portion of the follicular infundibulum; plural
"microcomedones") is considered the precursor for the clinical lesions of acne vulgaris, which
include closed comedones (often colloquially called "whiteheads"), open comedones (often
colloquially called "blackheads"), and inflammatory papules, pustules, and nodules. The process by
which microcomedones develop and evolve into other acne lesions remains to be elucidated but
may involve interaction of four main pathogenic factors:
●Follicular hyperkeratinization
●Increased sebum production by sebaceous glands
●Cutibacterium acnes (C. acnes, formerly Propionibacterium acnes), an anaerobic diphtheroid that is a
normal component of skin flora
●Inflammation
The temporal sequence of events leading to formation of acne lesions is unknown. The following
events have been proposed (figure 1):
●Accumulation of sebum and keratinous material converts a microcomedo into a closed comedo
(picture 2D).
●The follicular orifice is opened with continued distension, forming an open comedo (picture 1).
Densely packed keratinocytes, oxidized lipids, and melanin contribute to the dark color of the open
comedo.
●Immune responses to C. acnes contribute to the development of inflammatory papules and

pustules. Follicular rupture releases bacteria, proinflammatory lipids, and keratin into the
surrounding dermis, leading to exacerbation of inflammation and/or nodule formation (picture 2A-B).
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Sebaceous glands and the role of
androgens — Androgens contribute to the development of acne by stimulating the
growth and secretory function of sebaceous glands, leading to increased sebum production.
Increased sebum production is thought to provide a growth medium for C. acnes. C. acnes utilizes
triglycerides in sebum as a nutrient source by hydrolyzing them into free fatty acids and glycerol.
The anaerobic, lipid-rich environment in microcomedos allows these bacteria to thrive.
Most circulating androgens are produced by the adrenal gland and the gonads (figure 2). Androgen
production also occurs within the sebaceous glands, which convert dehydroepiandrosterone sulfate
(DHEAS), an adrenal androgen precursor, to testosterone via the action of several enzymes (table 1).
Testosterone is subsequently converted to 5-alpha-dihydrotestosterone (DHT) via the action of type I
5-alpha reductase in the sebaceous gland.
The effects of androgens are mediated through androgen receptors. Androgen receptors that bind
DHT and testosterone are present in the sebaceous glands and the outer root sheath keratinocytes
of the follicular epithelium. DHT has greater affinity for androgen receptors than testosterone.
Clinical observations support the importance of androgens for the development of acne. Although
the majority of patients with acne have normal androgen levels, androgen excess due to conditions
such as polycystic ovarian syndrome, congenital adrenal hyperplasia, or adrenal or ovarian tumors
can cause acne. In addition, acne typically does not develop prior to adrenarche (the prepubertal
period in which levels of DHEAS rise), with the exception of infantile acne, a condition seen in infants
that results from excess androgen production by immature adrenal glands or gonads. Moreover,
men with androgen insensitivity do not produce sebum and do not develop acne [6]. (See "Definition,
clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents" and
"Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults" and "Diagnosis
and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase
deficiency" and "Adrenal hyperandrogenism" and 'Infantile acne' below and "Pathogenesis and
clinical features of disorders of androgen action".)
Cutibacterium acnes and inflammation — The ability

of C. acnes, the prominent commensal bacteria within the microbiome of pilosebaceous follicles [7-
9], to activate innate and adaptive immune responses may contribute to the inflammatory response
observed in acne. Sequencing of the C. acnes genome has led to the identification of bacterial
properties that may contribute to inflammation and virulence [10,11]. Critical factors may include
virulence-associated genes in certain C. acnes strains, C. acnes production of enzymes that promote
degradation of the follicular wall and follicular rupture, and C. acnes surface proteins that trigger
humoral and cell-mediated immune responses.
Strains of C. acnes associated with either acne (phylotype IA) or healthy skin (phylotypes II and III)
have been identified [12]. The acne-associated strains are more likely to carry genes associated with
antibiotic resistance [8]. Acne-associated strains also have a greater propensity to stimulate TH17
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cells to secrete interferon (IFN)-gamma and proinflammatory interleukin (IL) 17, whereas healthy
skin-associated strains stimulate TH17 cells to produce anti-inflammatory IL-10 [13,14]. Vitamin A
and vitamin D may play regulatory roles in the C. acnes-induced IL-17 response; in an in vitro study,
C. acnes-mediated IL-17 induction was inhibited by exposure of peripheral blood mononuclear cells
to vitamin A or vitamin D [13].
C. acnes activates the innate immune response to produce proinflammatory IL-1 via activation of the
nod-like receptor P3 (NLRP3) inflammasome in human sebocytes and monocytes [15,16]. It also
binds and activates toll-like receptor 2, located on perifollicular macrophages, and triggers the
release of proinflammatory cytokines (including IL-8 and IL-12) [17,18]. These cytokines contribute
to the attraction of neutrophils and the release of neutrophil lysosomal enzymes that promote
follicular rupture (see "Toll-like receptors: Roles in disease and therapy"). Differences in the host
inflammatory response to C. acnes or the pathogenicity of specific strains of C. acnes that colonize
skin may contribute to the variation in the prevalence and severity of acne [12,19]. C. acnes may also
form biofilms within follicles that could contribute to resistance to therapy [20].
Gene expression studies have been performed in the skin of patients with acne to further elucidate
the inflammatory response. Upregulation of matrix metalloproteinases 1 and 3, inflammatory
cytokines (IL-8), and antimicrobial peptides (human beta-defensin 4 and granzyme B) have been
detected in inflammatory acne lesions [21]. In addition, human beta-defensin 2 immunoreactivity is
highly upregulated in acne-affected skin, with human beta-defensin 1 also upregulated to a lesser
degree [22].
Genetics — Individuals with close family members with acne are at increased risk for the
disorder, supporting a genetic component to the disease [3,23-25]. Case-control studies have
demonstrated a more than threefold risk among individuals with affected first-degree family
members [23,25,26]. A large twin study of monozygotic and dizygotic twins also supported the
heritable nature of acne [27]. An important role for genetics in mild acne is less certain due to the
almost ubiquitous occurrence in young adolescents.
ASSOCIATED FACTORS Proposed contributory factors for

acne have included skin trauma, dietary habits, stress, insulin resistance, and body mass index.
Skin trauma — Repetitive mechanical trauma caused by scrubbing affected skin with
soaps, detergents, astringents, or other agents may worsen acne by rupturing comedones,
promoting the development of inflammatory lesions [28].
Diet — The role of diet in acne is an evolving concept [29-33]. Several studies suggest an
association between acne and increased milk consumption and high glycemic load diets. Increased
levels of insulin-like growth factor (IGF) related to dairy consumption or high glycemic load diets and
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natural hormonal components of milk or other bioactive molecules in milk are hypothesized to play a
role [34-37] (see 'Insulin resistance' below):
●Milk consumption – A study of 47,355 women in the Nurses' Health Study that used retrospective
data collection to determine diet during high school found an association between acne and intake
of milk [34]. Two subsequent, large, prospective, cohort studies (one involving boys and the other
involving girls) also reported an association of milk ingestion and acne [38,39]. All three studies were
questionnaire-based, requiring subjects to recall their dietary intake and self-diagnose acne and
disease severity.
A case-control study of 205 patients with clinician-confirmed moderate to severe acne and 358
controls with mild or nonexistent acne also found an association between milk consumption (more
than three portions per week) and moderate to severe acne (odds ratio [OR] 1.78, 95% CI 1.22-2.59)
[23]. Similar to the other studies, food intake history was assessed via a retrospective patient
questionnaire.
A case-control study that used three 24-hour diet recall phone interviews to assess typical food
intake in 120 teenagers (ages 14 to 19 years) with moderate facial acne and 105 teenagers without
acne suggests that the association of acne with higher milk consumption may be limited to low-fat
and skim milk [40]. The study did not find an association between acne and consumption of full-fat
milk.
A longitudinal, questionnaire-based, population study of Norwegian adolescents demonstrated an

association between high intakes of dairy products and acne in adolescence [41].
●High glycemic load diets – A 12-week, randomized trial that compared low and high glycemic load
diets in 43 male patients with acne found a greater reduction in lesion counts with the low glycemic
load diet [42]. However, the participants on that diet also lost more weight than those on the high
glycemic load diet, so it is possible that the results were due to changes in weight rather than the
composition of the diet. Additionally, a study of 20 subjects with altered metabolic profiles,
randomized to a low glycemic diet and metformin versus control, resulted in statistically significant
improvements in both acne and metabolic parameters in the intervention group [43].
●Other factors – Although it is a common assumption that chocolate consumption increases

severity of acne, a relationship between chocolate consumption and the prevalence or severity of
acne has not been proven [32].
Data on favorable effects of dietary factors, such as zinc, omega-3 fatty acids, antioxidants, vitamin
A, and dietary fiber, on acne vulgaris are limited [44]. Further studies are necessary to determine the
roles of these supplements in acne vulgaris.
Stress — Psychologic stress is often proposed as a potential exacerbating factor for acne
[45,46]. Some studies have found an association between stress and increased acne severity.
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A prospective cohort study in 94 secondary school students compared acne severity and sebum
production at times of high stress (midterm examinations) and low stress (summer holidays) [47].
Sebum production did not appear to be related to stress, but increased acne severity, as assessed by
an examiner blinded to the hypothesis of the study, did appear to be associated with stress,
particularly in boys.
Similarly, a study of 22 university students found that greater acne severity appeared to correlate
with increased perceived stress around the time of school examinations [48].
Insulin resistance — Insulin resistance may play a role in acne. Insulin

resistance may stimulate increased androgen production and is associated with increased serum
levels of insulin-like growth factor-1 (IGF-1), a finding linked to increased facial sebum excretion [49].
There is a normal rise in insulin resistance and IGF-1 during puberty, the typical time of onset of
acne. In addition, some studies have found higher serum IGF-1 levels in women with postadolescent
acne than in women without acne [50] or a positive correlation between serum IGF-1 levels and acne
lesion counts in women [36]. Moreover, a cross-sectional study of 100 postadolescent males with
acne found a higher prevalence of insulin resistance in males with acne than in 100 age-matched
controls (22 versus 11 percent) [51].
Body mass index — Studies evaluating the relationship between acne vulgaris
and weight have yielded varied results, resulting in uncertainty regarding the relationship between
these conditions [23,52-56]. One of the largest studies, a population-based study of over 600,000
Israeli adolescents and young adults (mean age 19 years), found an inverse relationship between
excess weight and acne. As body mass index (BMI) increased, risk for acne progressively decreased,
with diagnoses of acne in 20 and 16 percent of underweight (BMI <18.5) males and females,
respectively, compared with 13 and 11 percent of severely obese (BMI >35) males and females,
respectively [55]. The adjusted OR for acne in severely obese individuals was 0.53 (95% CI 0.42-0.64)
for males and 0.5 (95% CI 0.37-0.62) for females. Individuals with a BMI of 18.5 to 22 were defined
as the reference group.
In contrast, a case-control study of approximately 200 adolescents and young adults (ages 10 to 24)
with moderate to severe acne and approximately 350 controls with no acne or mild acne found a
correlation between low BMI and a reduced risk for moderate to severe acne that was most evident
among males [23]. In addition, a cross-sectional, survey-based study of approximately 3600 young
adults (ages 18 and 19) in Norway found an association between rising BMI and increased risk for
acne among females [53].
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Classic features — The typical distribution of acne vulgaris correlates with areas
of the body with large, hormonally responsive sebaceous glands, including the face, neck, chest,
upper back, and upper arms. One or more types of active lesions may be present, including:
●Closed comedones – Noninflammatory; <5 mm; dome-shaped; smooth; skin-colored, whitish, or

grayish papules (picture 2D)
●Open comedones – Noninflammatory, <5 mm papules with a central, dilated, follicular orifice
containing gray, brown, or black, keratotic material (picture 1)
●Papulopustular acne – Inflamed, relatively superficial papules and pustules, typically <5 mm in
diameter (picture 2B-C)
●Nodular acne – Deep-seated, inflamed, often tender, large papules (≥0.5 mm) or nodules (≥1 cm)
(picture 3A-B)
Nodular acne is sometimes inaccurately referred to as "cystic" or "nodulocystic" acne. In reality, true
cysts are rare.
Skin pigmentation may mask the characteristic erythema of inflamed lesions in patients with highly
pigmented skin (picture 3B).
The extent and severity of skin involvement varies widely, ranging from the periodic appearance of a
few small comedones to the chronic presence of numerous inflamed nodules involving the majority
of skin in an affected region (picture 3A, 3C). Patient characteristics may influence the likelihood of
certain presentations. Young adolescents often primarily have comedonal acne involving the
forehead, nose, and chin. As the acne progresses, adolescents may develop inflammatory lesions
(picture 2B, 2D). Adult women may present with acne involving the lower face and neck that is often
associated with premenstrual flares (picture 2C, 2E) [57,58]. Premenstrual flares of acne appear to
be more common in women over the age of 33 than in women aged 20 to 33 years [59]. (See
"Postadolescent acne in women".)
Estimations of acne severity are patient-specific and depend on a number of factors. The clinical
type of lesions, presence of scarring, presence of draining lesions or sinus tracts, lack of therapeutic
response, and the psychologic impact of acne are some of the features taken into account [60]. As
an example, patients with inflammatory, nodular acne are often considered to have severe acne.
Similarly, a patient without nodules but who has numerous inflammatory papules and pustules and
notable scarring could also be classified as having severe disease.
Common sequelae — Resolution of individual acne lesions may leave

transient or permanent changes on the skin. Postinflammatory hyperpigmentation and scarring are
common sequelae that can be highly distressing for patients.
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Postinflammatory hyperpigmentation — As with other
inflammatory skin conditions, acne vulgaris may lead to the development of hyperpigmentation at
the site of an active or resolving lesion. The risk for hyperpigmentation increases with increasing
baseline skin pigmentation and is particularly common in individuals with skin phototypes IV to VI
(table 2). (See "Postinflammatory hyperpigmentation".)
Postinflammatory hyperpigmentation typically resolves spontaneously, but an individual

hyperpigmented macule may persist for several months or longer without treatment. As a result,
even patients with relatively mild, active acne can exhibit postinflammatory hyperpigmentation as a
prominent disfiguring feature (picture 4).
Scarring — Acne scarring is a common consequence of acne vulgaris that occurs in some
patients. Inflammatory acne is considered more likely to result in scarring than noninflammatory
acne. Why scarring occurs in some patients and not others despite similar manifestations of acne
vulgaris is not clear. (See "Management of acne scars", section on 'Pathogenesis'.)
Various types of scars can result from acne vulgaris, including atrophic scars (ice pick scars, rolling
scars, and boxcar scars), hypertrophic scars, and keloids (picture 5A-B). The features of acne scars
are reviewed separately. (See "Management of acne scars", section on 'Classification'.)
Variants — Occasional variants of acne vulgaris include acne conglobata and acne
excoriée.
Acne conglobata — Acne conglobata is a severe form of nodular acne that most
often occurs in young males (picture 3C). Skin involvement tends to be most prominent on the back,
chest, and buttocks but can also appear on the face or other sites. Large, draining lesions; sinus
tracts; and severe scarring may occur. Sinus tracts manifest as fluctuant, linear lesions and are
formed when nodules merge. Systemic symptoms are absent.
Acne conglobata is distinct from acne fulminans, an acute condition characterized by nodules,
friable plaques, erosions, and ulcers. (See 'Acne fulminans' below.)
The treatment of acne conglobata is reviewed separately. (See "Treatment of acne vulgaris", section
on 'Acne conglobata'.)
Acne excoriée — Acne excoriée typically presents with relatively mild acne comedones
or inflammatory papules that are chronically and obsessively picked and excoriated, leading to
erosions and scarring (picture 6). This condition is often, but not always, seen in young women. An
underlying psychiatric disorder can be associated, and treatment may involve antidepressants and
psychotherapy. (See "Skin picking (excoriation) disorder and related disorders".)
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Infantile acne — Infantile acne typically begins between ages three to six months and
results from elevated levels of androgens produced by the immature adrenal gland in girls and the
immature adrenal gland and testes in boys. Androgen levels fall by age one to two and is
accompanied by improvement in acne. (See "Vesicular, pustular, and bullous lesions in the newborn
and infant", section on 'Infantile acne'.)
COMPLICATIONS Potential complications of acne vulgaris include

psychosocial dysfunction, gram-negative folliculitis, acne fulminans, and solid facial edema.
Psychologic effects — Acne vulgaris can contribute to significant

psychologic morbidity and, rarely, to mortality due to suicide [61,62]. Embarrassment, anxiety, and
lowered self-esteem related to the appearance of affected skin or disfiguring scars can impact the
social lives and employment of affected individuals.
Gram-negative folliculitis — Patients with acne vulgaris who have been

treated with long-term systemic antibiotics (usually tetracyclines) may develop gram-negative
folliculitis. These patients exhibit an initial response to the oral antibiotic, followed by apparent
resistance to the treatment and worsening of acne.
Inflammatory papules, pustules, and nodules typically appear on perinasal skin and the central face.
A culture of lesions will yield gram-negative organisms, such as Enterobacter, Klebsiella,
Pseudomonas, Proteus, or Escherichia species. (See "Infectious folliculitis", section on 'Bacterial
folliculitis'.)
Acne fulminans — Acne fulminans is a disorder characterized by an acute

eruption of large, inflammatory nodules and friable plaques with erosions, ulcers, and hemorrhagic
crusts (picture 7). This rare condition primarily affects adolescent males with pre-existing acne
vulgaris. Acne fulminans may be triggered by isotretinoin therapy or may occur spontaneously. The
pathogenesis is unclear. Lesions usually involve the trunk but may be present elsewhere.
Acne fulminans may occur in association with systemic symptoms (eg, fever, malaise, bone pain,
arthralgias), erythema nodosum, and laboratory and radiologic abnormalities [63]. Potential
laboratory abnormalities include leukocytosis, anemia, and an elevated erythrocyte sedimentation
rate or C-reactive protein. Radiographs may reveal osteolytic lesions of the bone, particularly in the
sternum, clavicles, sacroiliac joints, or hips.
A proposed classification system for acne fulminans divides the condition into four variants [63]:
●Acne fulminans with systemic symptoms –Skin manifestations (abrupt, dramatic flare of
inflammatory acne with erosions, crusts, ulcers, and hemorrhagic nodules or plaques) are
accompanied by systemic symptoms, laboratory abnormalities, or osteolytic bone lesions.
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●Acne fulminans without systemic symptoms – Skin manifestations are similar to acne fulminans
with systemic symptoms, but systemic findings are absent.
●Isotretinoin-induced acne fulminans with systemic symptoms – Drug-induced form of acne

fulminans with systemic findings; skin manifestations are similar to the other variants.
●Isotretinoin-induced acne fulminans without systemic symptoms – Drug-induced form of acne

fulminans without systemic findings; skin manifestations are similar to the other variants.
Isotretinoin-induced acne fulminans without systemic symptoms is the most common type of acne
fulminans [63].
The evaluation and treatment of patients with acne fulminans are reviewed separately. (See
'Additional tests' below and "Treatment of acne vulgaris", section on 'Acne fulminans'.)
Solid facial edema — Solid facial edema (Morbihan's disease) is a rare

complication of acne that presents as facial soft tissue edema and erythema. The condition may
wax and wane in severity but usually does not spontaneously resolve without treatment.
Improvement with isotretinoin with or without ketotifen, systemic glucocorticoids, or clofazimine has
been reported [64].
ASSOCIATED DISEASES Hyperandrogenism, a condition

that may occur in disorders such as polycystic ovarian syndrome, late-onset adrenal hyperplasia,
and adrenal or ovarian tumors, may cause acne. Polycystic ovarian syndrome is the most common
cause of hyperandrogenism in women. (See "Definition, clinical features, and differential diagnosis
of polycystic ovary syndrome in adolescents" and "Epidemiology, phenotype, and genetics of the
polycystic ovary syndrome in adults" and "Diagnosis and treatment of nonclassic (late-onset)
congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Adrenal hyperandrogenism"
and "Pathogenesis and clinical features of disorders of androgen action".)
Examples of rare syndromes that may include acne as a feature include SAPHO (synovitis, acne,
pustulosis, hyperostosis, and osteitis) syndrome and PAPA (sterile pyogenic arthritis, pyoderma
gangrenosum, and acne) syndrome. Patients with SAPHO syndrome exhibit features of
inflammatory arthritis or osteitis, particularly of the anterior chest wall. (See "SAPHO (synovitis,
acne, pustulosis, hyperostosis, osteitis) syndrome" and "Periodic fever syndromes and other
autoinflammatory diseases: An overview".)
DIAGNOSIS AND EVALUATION The diagnosis of

acne vulgaris is generally made based upon the physical examination. There are no laboratory tests
that confirm a diagnosis of acne vulgaris. The need for laboratory or radiologic tests is generally
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limited to patients for whom the clinical evaluation suggests underlying hyperandrogenism or other
specific conditions warranting additional testing. Skin biopsies are not typically necessary. (See
"Treatment of acne vulgaris".)
History — The patient history is an important component of the evaluation. The history is
particularly helpful for identifying patients with acne caused or exacerbated by an exposure (eg,
drug-induced acne) or who may need further evaluation for associated disease (eg,
hyperandrogenism, SAPHO [synovitis, acne, pustulosis, hyperostosis, and osteitis] syndrome, acne
fulminans). Information gleaned from the patient history may also be helpful for guiding treatment.
(See "Treatment of acne vulgaris", section on 'Pretreatment assessment'.)
Helpful information includes:
●Age of onset and current age
●Medication history (table 3)
●Menstrual history in females (frequency, association with acne flares)
●Medical history
●Family history of acne
●Signs of virilization in young children or females (hirsutism, male pattern hair loss, genital
enlargement, deepening of voice)
●Joint, bone, or systemic symptoms in patients with severe acne
●Skin care regimen (use of occlusive or comedogenic products)
●Current and prior treatments and response
●Psychologic impact of acne
Physical examination — The diagnosis is based upon the recognition of

characteristic lesions (closed comedones, open comedones, inflammatory papules, inflammatory
pustules, inflamed nodules) in a characteristic distribution (eg, face, chest, shoulders, back, or upper
arms) during the skin examination.
Helpful factors to assess on the skin examination include:
●Lesion type and distribution
●Lesion stages (monomorphous versus polymorphous)
●Signs of hyperandrogenism in young children and females (hirsutism, male pattern hair loss)
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●Presence of sequelae of acne vulgaris, including postinflammatory hyperpigmentation and
scarring
The identification of comedones with or without other lesion types strongly supports the diagnosis.
In addition, acne lesions are generally in various stages of development and resolution, in contrast to
some presentations of drug-induced acne, which exhibit the acute development of monomorphous
lesions. Pityrosporum folliculitis, a condition in the differential diagnosis of acne vulgaris, also often
presents with monomorphous inflammatory lesions. (See 'Trunk and extremities' below and
"Infectious folliculitis", section on 'Fungal folliculitis'.)
Additional tests — Laboratory tests and radiologic imaging is not indicated for the
vast majority of patients with acne vulgaris. Indications for testing are primarily limited to patients
who exhibit signs of associated disease or acne fulminans.
Populations in whom testing is advised include:
●Patients with signs of hyperandrogenism – Assessment for hyperandrogenism is indicated for

patients exhibiting additional signs suggestive of androgen excess, such as may occur in polycystic
ovarian syndrome, congenital adrenal hyperplasia, and adrenal or ovarian tumors [65]. Clinical
findings that support an evaluation include:
•Irregular or infrequent menses in females
•Hirsutism
•Signs of virilization in females or prepubertal males (male pattern hair loss, clitoromegaly, increased
muscle mass, deepening of voice (picture 8))
•Development of mid-childhood acne (onset between one and six years of age)
•Abrupt onset of severe, atypical, recalcitrant acne
Other signs that may suggest androgen excess in prepubertal children include early-onset body odor,
early development of axillary or pubic hair, accelerated growth, advanced bone age, and genital
maturation [65]. An endocrinologic work-up is usually not necessary for children with preadolescent
acne (ages 7 to 12 years) in the absence of other clinical signs of hyperandrogenism [66,67]. (See
"Premature adrenarche".)
Recommendations for the evaluation for hyperandrogenism vary based upon the clinical
presentation:
•Premenopausal adolescent or adult females with oligomenorrhea without virilization:
-(See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Basic

diagnostic approach'.)
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-(See "Diagnosis of polycystic ovary syndrome in adults", section on 'Evaluation'.)
•Premenopausal adolescent or adult females with hirsutism without oligomenorrhea or virilization:
-(See "Evaluation of premenopausal women with hirsutism", section on 'Hirsutism and normal
menstrual cycles'.)
-(See "Evaluation and management of postmenopausal hyperandrogenism".)
•Premenopausal adolescent or adult females with virilization:
-(See "Evaluation of premenopausal women with hirsutism", section on 'Severe hyperandrogenism'.)
-(See "Evaluation of premenopausal women with hirsutism", section on 'Additional evaluation for
severe hyperandrogenemia'.)
•Postmenopausal women with hirsutism or virilization:
-(See "Evaluation and management of postmenopausal hyperandrogenism".)
•Children with mid-childhood acne or features suggestive of androgen excess:
-(See "Premature adrenarche".)
The abrupt onset of severe, atypical, or recalcitrant acne should prompt consideration of
hyperandrogenism induced by adrenal or ovarian tumors. Laboratory tests and radiologic imaging
may be necessary. (See "Clinical presentation and evaluation of adrenocortical tumors", section on
'Diagnostic evaluation' and "Evaluation of premenopausal women with hirsutism" and "Evaluation
and management of postmenopausal hyperandrogenism" and "Ovarian hyperthecosis" and "Sex
cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)
Patients in whom initial tests reveal abnormalities may be referred to endocrinology, gynecology, or
other specialists, as needed.
●Patients with acne fulminans – The following evaluation is suggested for patients with clinical
findings consistent with acne fulminans to assess for systemic involvement and in preparation for
isotretinoin therapy [63]:
•Complete blood count with differential
•Liver function tests
•Erythrocyte sedimentation rate and C-reactive protein in patients with systemic findings
•Serum cholesterol and triglycerides
•Urine or serum pregnancy test (in women)
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•Radiograph (if symptoms suggestive of bone or joint involvement are present)
●Patients with musculoskeletal symptoms suggestive of SAPHO syndrome – SAPHO syndrome

should be suspected in patients in whom moderate to severe nodular acne is accompanied by
symptoms of arthritis or osteitis, particularly when involving the chest wall. The assessment of
patients with SAPHO syndrome is reviewed separately. (See 'Associated diseases' above and
"SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS Although acne vulgaris is

a common and often easily diagnosed condition, the possibility of other disorders, including other
skin diseases and acneiform eruptions, should always be considered. Important diagnoses to
consider include other skin diseases that induce inflammatory or noninflammatory skin lesions and
acneiform eruptions, nonacne disorders that closely resemble acne.
Inflammatory facial lesions — Examples of disorders in the

differential diagnosis of facial inflammatory acne lesions include:
●Rosacea – Common features of rosacea include erythema, telangiectasias, and papules or

pustules on the central face (picture 9). Acne vulgaris is distinguished from acne rosacea by the
presence of comedones and the absence of telangiectasias. (See "Rosacea: Pathogenesis, clinical
features, and diagnosis".)
●Periorificial dermatitis – Periorificial dermatitis (also known as perioral dermatitis) is characterized

by small, grouped, erythematous papules in a perioral (or occasionally perinasal or periorbital)
distribution (picture 10A-B). When the perioral skin is involved, a rim of spared skin is usually seen
around the vermilion border of the lip. (See "Perioral (periorificial) dermatitis".)
●Pseudofolliculitis barbae – Pseudofolliculitis barbae occurs most commonly in individuals with

Afro-textured hair. Inflammatory papules and pustules occur in the beard area and may result in
keloidal scarring. It is thought that short, shaved or clipped hairs in the beard area curl back towards
the skin, penetrate the skin, and cause a foreign body inflammatory reaction (picture 11A-B). (See
"Pseudofolliculitis barbae" and "Keloids and hypertrophic scars".)
●Facial angiofibromas in tuberous sclerosis – Facial angiofibromas associated with tuberous

sclerosis usually appear in childhood. These lesions commonly present as persistent, 1 to 3 mm,
pink or red papules on the nose and medial cheeks (picture 12). (See "Tuberous sclerosis complex:
Genetics, clinical features, and diagnosis".)
Noninflammatory facial lesions — Examples of disorders in the

differential diagnosis of facial noninflammatory acne lesions include:
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●Sebaceous hyperplasia – Visible enlargement of sebaceous glands is termed "sebaceous
hyperplasia." It most commonly occurs in adults with a history of oily skin. These growths are
umbilicated, yellowish papules most commonly found on the forehead and cheeks (picture 13A-B).
These lesions may resemble basal cell carcinomas. (See "Cutaneous adnexal tumors", section on
'Sebaceous hyperplasia'.)
●Nevus comedonicus – Nevus comedonicus appears at birth or in childhood and exhibits a grouped
or linear arrangement of comedones.
●Adnexal tumors – Benign follicular tumors, such as trichoepitheliomas, trichodiscomas, or

fibrofolliculomas, typically present as flesh-colored facial papules. (See "Cutaneous adnexal
tumors".)
●Favre-Racouchot syndrome – Favre-Racouchot syndrome is a condition resulting from cutaneous

photodamage (sun damage) seen in middle-aged or older adults. Open and closed comedos are
found in areas of photodamage, usually on the lateral upper cheeks (picture 14).
Trunk and extremities — Examples of disorders that may present with

lesions resembling acne vulgaris on the trunk or extremities include:
●Folliculitis – Staphylococcal, eosinophilic, pseudomonal, or Pityrosporum folliculitis may mimic

inflammatory acne (picture 15A-D). Comedos are absent, and lesions are usually monomorphous,
unlike the polymorphous lesions in different stages of development that are typical of acne. (See
"Infectious folliculitis".)
●Keratosis pilaris – In this common condition caused by keratotic, follicular plugging, patients
typically present with small, follicular papules on the extensor surfaces of the upper arms or thighs
(picture 16A-B). Erythema may be present. Lesions can also occur on the face, particularly in
children. (See "Keratosis pilaris".)
●Hidradenitis suppurativa – Hidradenitis suppurativa is a chronic inflammatory skin disorder

characterized by recurrent, inflamed nodules and abscesses with a predilection for intertriginous
skin areas, such as the axilla, groin, perianal, perineal, and inframammary regions (picture 17).
Additional features include comedones, sinus tracts, and scarring. (See "Hidradenitis suppurativa:
●Steatocystoma multiplex – Steatocystoma multiplex is an autosomal dominant or sporadic genetic

disorder in which multiple yellow or skin-colored, sebum-filled cysts are found on the trunk, upper
arms, or chest (picture 18). (See "Overview of benign lesions of the skin", section on 'Steatocystoma
multiplex'.)
Acneiform eruptions — There are multiple disorders in which acne-like

eruptions occur, unassociated with true acne vulgaris. These include:
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●Drug-induced acne – Drug-induced acne typically presents with a monomorphous, inflammatory,
papular eruption (as opposed to the polymorphous eruption with lesions in varying stages seen with
acne vulgaris) (picture 19A-B). Medications associated with drug-induced acne are listed in a table
(table 3). Glucocorticoid-induced eruptions are also referred to as "steroid folliculitis." (See "Topical
corticosteroids: Use and adverse effects", section on 'Cutaneous'.)
●Neonatal cephalic pustulosis – Neonatal cephalic pustulosis (previously called neonatal acne)
presents with inflammatory papules and pustules on the face in the absence of comedones.
Neonatal cephalic pustulosis is distinct from infantile acne. Neonatal cephalic pustulosis appears
within the first few weeks of life (picture 20); infantile acne usually appears around three to six
months of age. (See "Skin lesions in the newborn and infant", section on 'Neonatal cephalic
pustulosis (neonatal acne)'.)
●Acne cosmetica – Cosmetic products that contain comedogenic ingredients can induce the
formation of acne lesions. This type of acne has lessened as products designed to be less
comedogenic have become widely available. Heavy, oil-based hair products are still commonly used
and may contribute to the development of acne on the forehead (pomade acne).
Irritant reactions to cosmetic products can also produce eruptions that resemble acne vulgaris.
Inflammatory papules or pustules may occur within hours after the application of the inciting
product.
●Acne mechanica – Worn items, such as turtlenecks, bra straps, shoulder pads, orthopedic casts,
and sports helmets, may irritate pilosebaceous follicles, stimulating comedo formation.
●Occupational acne and chloracne – Comedones, inflammatory papules, pustules, nodules, or cysts
can occur in response to exposure to certain chemicals, including insoluble cutting oils, coal tar
derivatives, and chlorinated hydrocarbons. "Chloracne" is the term used to describe acne that occurs
with exposure to chlorinated hydrocarbons (eg, dioxin) via percutaneous contact, inhalation, or
ingestion. Clinically, chloracne is characterized by large, monomorphic comedos with evolution into
severely inflammatory and scarring lesions. Chloracne is most common on the face, neck,
postauricular skin, axillae, and scrotum, although other sites may be involved.

provided separately. (See "Society guideline links: Acne vulgaris".)

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●Basics topics (see "Patient education: Acne (The Basics)")
●Beyond the Basics topics (see "Patient education: Acne (Beyond the Basics)")
SUMMARY
●Acne vulgaris is a common skin condition in adolescents and young adults that may also occur at
other ages. The clinical manifestations of acne vulgaris vary widely, and the psychologic impact can
be significant. (See 'Epidemiology' above.)
●Acne vulgaris is a disorder of the pilosebaceous follicles. Follicular hyperkeratinization, sebum

production, Cutibacterium acnes, and inflammation are involved in the pathogenesis. The temporal
sequence of events leading to the formation of acne lesions is unknown but likely involves both host
factors and dysbiosis within the microbiome of the pilosebaceous follicle. (See 'Pathogenesis'
above.)
●Androgens induce sebum production and are an important factor in the development of acne
vulgaris. Hyperandrogenism may cause acne, but most patients with acne vulgaris do not have
androgen excess. (See 'Sebaceous glands and the role of androgens' above.)
●The role of diet in acne vulgaris is an evolving concept. A contributory effect of milk and high
glycemic index diets has been proposed, but prospective trials are necessary to clarify the
relationship between diet and acne. (See 'Diet' above.)
●Typically, acne vulgaris occurs on areas of the body with hormonally sensitive sebaceous glands,
including the face, neck, chest, upper back, and upper arms. Open comedones, closed comedones,
and inflammatory papules, pustules, or nodules are the characteristic lesions. (See 'Clinical
●Common sequelae of acne vulgaris include postinflammatory hyperpigmentation and scarring.

Acne fulminans is a serious complication of acne vulgaris that may present as an acute eruption of
inflamed nodules and friable plaques and systemic symptoms. Other cutaneous complications of
acne vulgaris include gram-negative folliculitis and solid facial edema. (See 'Common sequelae'
above and 'Complications' above.)
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●The diagnosis of acne vulgaris rests upon the patient's history and physical examination.
Laboratory tests are not necessary for most patients. Patients with additional clinical findings
suggestive of hyperandrogenism should be tested for androgen excess. (See 'Diagnosis and
evaluation' above.)
●Although acne vulgaris is often easily diagnosed, the differential diagnosis includes a wide variety
of skin diseases and acneiform eruptions. (See 'Differential diagnosis' above.)
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Postadolescent acne in women - UpToDate
uptodate.com/contents/postadolescent-acne-in-women/print
INTRODUCTION Acne vulgaris is a skin disorder characterized by the

presence of comedones and inflammatory lesions on the face, neck, shoulders, or trunk (picture 1A-
B). Although the high prevalence of acne in the adolescent population has contributed to a
perception that acne is a disorder of youth, acne remains a significant problem for many adults.
The unique features of postadolescent acne in women will be discussed here. General information
on the pathogenesis, clinical features, diagnosis, and management of acne is reviewed separately.
(See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Treatment of acne
vulgaris" and "Hormonal therapy for women with acne vulgaris" and "Oral isotretinoin therapy for
acne vulgaris" and "Light-based, adjunctive, and other therapies for acne vulgaris".)
1007
EPIDEMIOLOGY Postadolescent acne is a common disorder that is often
defined as acne that occurs in individuals aged 25 years or older. The disorder appears to occur
more frequently in women than men [1-8]. As an example, in a population-based study of more than
17,000 individuals in China, acne was more common in men prior to the age of 30 but was more
prevalent in women thereafter [2]. Similarly, in a community-based study of 749 adults aged 25 years
or older in the United Kingdom, clinically significant acne (defined as Leeds acne grade ≥1) was
detected in 12 percent of women but only 3 percent of men [7,9].
In addition, women may be more likely to visit health care providers for the evaluation and treatment
of postadolescent acne [4,10]. In a retrospective study performed in the United Kingdom, 152 out of
200 patients (75 percent) over the age of 25 who were referred to a dermatology department for
acne were female [4].
The prevalence of acne in women steadily decreases with age. This was evident in a prospective
study of 2895 women (aged 10 to 70 years) performed in the United States, England, Italy, and Japan
[11]. Although acne was most prevalent at age 16 (present in almost 70 percent of subjects) and
proceeded to decline after the age of 18, approximately one-half of women in their 20s, one-quarter
of women in their 30s, and more than 10 percent of women in their 40s still had clinically significant
acne (defined as more than four inflammatory lesions or comedones present on one side of the
face). Acne occurred less frequently in postmenopausal women; among women aged 51 years and
older, clinically significant acne was detected in less than 5 percent.
Ethnicity may play a role in the risk for postadolescent acne in women. In the study population of
2895 women described above, clinically significant acne was slightly more prevalent in African-
American and Hispanic females (37 and 32 percent, respectively), than in Continental Indian,
Caucasian, or Asian women (23, 24, and 30 percent, respectively) [12].
PATHOGENESIS Similar to acne in other populations, multiple factors

contribute to the development of acne lesions in women. The four local events in the skin that are
linked to the formation of acne lesions are the following:
●Abnormal keratinization of the pilosebaceous follicles
●Excess sebum production
●Cutibacterium (formerly Propionibacterium) acnes colonization
●Inflammation
Excess sebum production and abnormal follicular keratinization contribute to the formation of
comedones, which are considered the primary lesions of acne. Rupture of the comedones and
inflammatory reactions to C. acnes, an organism that feeds on sebum, are associated with the
1008
development of inflammatory lesions. (See "Pathogenesis, clinical manifestations, and diagnosis of
acne vulgaris", section on 'Pathogenesis'.)
Endogenous or exogenous androgens, the menstrual cycle, smoking, and cosmetic use may
contribute to comedone formation in women and may play a role in the development of acne:
●Androgens – Androgens are capable of stimulating the growth of sebaceous glands in the skin and
can augment sebum production, characteristics that may contribute to lesion formation [13]. A role
for androgens in the development of acne in women is supported by the observation that
endogenously or exogenously derived increases in serum androgen levels have been linked to the
development of acne [13-16]. In addition, acne in women often improves during treatment with
antiandrogenic therapies [17,18]. (See "Hormonal therapy for women with acne vulgaris".)
The most common cause of endogenous hyperandrogenemia in women is polycystic ovarian

syndrome; less common causes include late-onset adrenal hyperplasia, ovarian hyperthecosis, and
virilizing ovarian or adrenal tumors [18,19]. Hyperandrogenemic states may also result from the
administration of anabolic steroids or testosterone supplementation. In addition, progestin-only
contraceptives that contain proandrogenic progestins and lack antiandrogenic estrogens may
contribute to the development of acne [20,21]. (See "Clinical manifestations of polycystic ovary
syndrome in adults" and "Genetics and clinical presentation of nonclassic (late-onset) congenital
adrenal hyperplasia due to 21-hydroxylase deficiency" and "Ovarian hyperthecosis" and "Sex cord-
stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Adrenal
hyperandrogenism".)
However, most adult women with acne have normal androgen levels and do not receive exogenous
androgens [19,22]. The relationship between circulating androgen levels and acne in these women is
uncertain [18,23]. Proposed mechanisms through which androgens may contribute to acne in these
patients include the effects of increased conversion of androgen precursors to androgens within the
sebaceous glands and elevated sensitivity of sebaceous glands to androgens [18,24].
●Menstrual cycle – Many women with acne note correlation of acne severity with their menstrual
cycle. Up to 83 percent of women with acne note premenstrual flares [3,5,25-28]. In one series of 41
women between the ages of 18 and 44 with acne, 63 percent showed a premenstrual increase in the
number of inflammatory lesions, and the number of inflammatory lesions present increased by 25
percent [25].
Accumulation of sebum within the sebaceous glands due to a reduction in the size of the
pilosebaceous orifice during the premenstrual period has been proposed as a potential contributor
to premenstrual flares [29,30]. However, the mechanism responsible for this phenomenon remains
unknown.
●Smoking – Several studies have linked smoking to adult female acne, including one study that
specifically linked smoking with the presence of noninflammatory acne lesions [31-33]. Effects of
nicotine on sebum production or keratinization have been proposed as potential contributing factors
1009
[31,32]. Yet, other studies have found conflicting results, and the existence of a causative
relationship remains uncertain [34-37].
●Cosmetic products – The terms "acne cosmetica" and "pomade acne" have been used to describe
an association between the use of cosmetic skin or hair products and acne, a phenomenon that was
attributed to follicular plugging induced by certain agents [38-40]. This phenomenon may contribute
to the insidious, slow development of comedones and, eventually, inflammatory lesions. In addition,
follicular irritation related to the application of cosmetics may result in the rapid appearance of an
eruption characterized by small, inflammatory papules that closely resembles acne vulgaris (vellus
hair folliculitis). (See 'Skin care' below and "Pathogenesis, clinical manifestations, and diagnosis of
acne vulgaris", section on 'Pathogenesis'.)
The degree to which cosmetic use contributes to acne in the adult female population is unclear
[5,23,24,28,41]. The methods used to test comedogenicity of products vary considerably across the
cosmetic industry, and products that contain comedogenic ingredients are not necessarily
comedogenic when applied to human skin [41,42]. In addition, individual responses to certain
products may vary [41].
●Other factors – Other factors that may play a role in acne include stress, diet, and genetic factors
[24,27,43]. Data on risk factors specifically for postadolescent acne in women are limited. A case-
control study of 248 women with acne and 270 controls found associations between adult female
acne and a history of adolescent acne, family history of acne, no prior pregnancies, hirsutism, office
work, high level of reported psychologic stress, and low weekly consumption of fruits, vegetables, or
fish [44]. Additional studies are required to confirm these findings. (See "Pathogenesis, clinical
manifestations, and diagnosis of acne vulgaris", section on 'Diet'.)
A more detailed discussion of the pathogenesis of acne is included elsewhere. (See "Pathogenesis,
clinical manifestations, and diagnosis of acne vulgaris".)
CLINICAL FEATURES
Onset — Acne in the adult woman may present as a continuation of adolescent acne
(persistent acne), which represents the most common presentation, or as a newly developing
disorder (late-onset acne) [4,5,7,22,45]. In a prospective study of patients over the age of 25 who
presented to a dermatology department in the United Kingdom for acne, only 28 of 152 women (18
percent) had late-onset acne (onset after the age of 25 years) [4]. An international prospective study
of 374 adult females (≥25 years of age) who presented to a dermatologist for the evaluation of acne
found similar results; only 10 percent of women recalled the onset of acne after age 25 years [22].
Physical findings — As with acne in adolescents, acne in adult women

commonly presents with both small, noninflammatory papules (comedones (picture 2A-B)) and
inflammatory acne lesions (papules, pustules, or nodules (picture 1A)). Acne presenting as only
1010
noninflammatory or only inflammatory lesions is less common [22]. The face is a common site for
involvement, but lesions on the neck and trunk may also occur frequently [4,28]. In the study
evaluating acne in 374 adult females with acne, approximately 50 percent of women had truncal
involvement [22].
Some authors have divided facial acne in adult females into two clinical presentations [5,31]. One
clinical presentation is characterized by multiple comedones that may be accompanied by a few
inflammatory lesions. In this variant, comedones may occur on multiple areas, including the upper
face. The other presentation is an inflammatory form characterized by papules, pustules, or nodules
that primarily occur on the lower face (eg, chin, perioral skin, and mandible) (picture 1A-B). The
reason for this particular distribution is unknown.
Although lower facial acne has often been viewed as a characteristic presentation of adult female
acne (picture 1B), the findings of the prospective study of 374 adult females with acne described
above suggest that lesions limited to this area actually may occur in only a small subset of patients
[22]. Only 11 percent of women in the study had lesions limited to the mandibular area.
The severity of acne in women is typically mild to moderate [3,5,22,31]. It is common for adult
patients with inflammatory acne to have only several active lesions at the time of evaluation.
DIAGNOSIS The diagnosis of acne is made based upon the physical

examination. Supportive clinical features are comedones and/or inflammatory papules or pustules
involving the face, neck, chest, back, and/or shoulders.
ADDITIONAL EVALUATION The evaluation of women

with acne should include an assessment for signs of underlying hyperandrogenism and exposure to
medications that may cause acne or acneiform eruptions.
Hyperandrogenism — Laboratory evaluation for a hyperandrogenic state is

indicated in women who exhibit symptoms or signs suggestive of hyperandrogenism [46]. Examples
of such features include [24]:
●Signs of virilization, such as hirsutism (male pattern hair growth), frontotemporal hair loss, or
clitoromegaly
●Irregular/infrequent menses
●Infertility
●Polycystic ovaries
●Abrupt onset of severe acne
1011
●Acne that is severe or resistant to therapy
●Cushingoid features
●Acanthosis nigricans
●Obesity
Of note, since hair removal may make signs of hirsutism undetectable, physical examination is not
sufficient for ruling out a hirsute state. Patients should be specifically questioned about male pattern
hair growth and hair removal practices. (See "Evaluation of premenopausal women with hirsutism".)
Oral contraceptive agents should be discontinued at least four to six weeks prior to laboratory
testing for hyperandrogenism. The laboratory evaluation of patients with acne and suspected
hyperandrogenism is reviewed separately. (See "Pathogenesis, clinical manifestations, and
diagnosis of acne vulgaris", section on 'Additional tests'.)
Medications — The medication history should be reviewed to identify any medications

and supplements that may induce acne or acneiform eruptions (table 1). In particular, progestin-only
contraceptive agents, including oral, injected, and implanted agents, have been associated with
exacerbation of acne. (See "Hormonal therapy for women with acne vulgaris", section on 'Progestin-
only contraceptives' and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris",
section on 'Acneiform eruptions'.)
DIFFERENTIAL DIAGNOSIS Multiple disorders may

present with clinical features that resemble acne vulgaris. In particular, in adult women, the following
disorders should be considered:
●Rosacea – Rosacea is a common inflammatory disorder that may present with inflammatory
papules, pustules, telangiectasias, or erythema involving the central face (picture 3). The absence of
comedones and the centrofacial location of rosacea help to distinguish rosacea from acne. (See
"Rosacea: Pathogenesis, clinical features, and diagnosis".)
●Perioral dermatitis – Perioral dermatitis (also known as periorificial dermatitis) is a disorder most
commonly seen in young women that presents with clusters of small papules around the mouth
(picture 4A-B). The skin immediately adjacent to the vermilion border of the lip is typically spared.
This disorder may also occur in a periocular distribution. (See "Perioral (periorificial) dermatitis".)
●Pseudofolliculitis barbae – Pseudofolliculitis barbae is a condition most commonly seen in black

men that occurs as a result of re-entry of the free ends of short, cut beard hairs into the skin (picture
5A-C). Women with terminal hair growth on the face may also develop this condition. (See
"Pseudofolliculitis barbae".)
1012
●Pathologic skin picking – Pathologic skin picking is a behavioral disorder characterized by
deliberate and repeated picking or scratching at skin. The term "acne excoriée" has been used to
describe patients who repeatedly pick, scratch, or squeeze relatively minor acne lesions, resulting in
visible tissue damage that often greatly exceeds the severity of acne (picture 6A-C). (See "Skin
picking (excoriation) disorder and related disorders".)
●Drug-induced acne (acne medicamentosa) – Multiple drugs may precipitate acneiform eruptions,
including topical or systemic corticosteroids, lithium, epidermal growth factor inhibitors, and other
agents (table 1). (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section
on 'Acneiform eruptions'.)
Other disorders to be considered in the differential diagnosis of postadolescent acne in women

include bacterial folliculitis or furunculosis, eosinophilic folliculitis (picture 7), acne mechanica
(development of inflammatory papules at sites of friction or pressure on the skin), and lupus miliaris
disseminata faciei (picture 8). The differential diagnosis of acne vulgaris is discussed in greater
detail separately. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris",
section on 'Differential diagnosis'.)
TREATMENT Treatment of acne is not mandatory but is often beneficial for

patients for whom acne causes distress, cosmetic concerns, or otherwise negatively impacts quality
of life and patients who desire to minimize common sequelae, such as postinflammatory
hyperpigmentation and scars (picture 1A, 1C). Even acne that appears mild to the clinician may have
significant negative psychosocial effects on the patient [47,48].
Pretreatment assessment — As with all patients with acne,

assessment of the type of acne lesions present (comedones versus inflammatory lesions), the
severity of acne, and the presence of acne sequelae (eg, hyperpigmentation, scarring) is of value for
the selection of an appropriate therapeutic regimen (table 2). In addition, treatable contributors to
acne (eg, hyperandrogenemic states, acne-inducing medications) should be addressed. (See
"Treatment of acne vulgaris", section on 'Pretreatment assessment'.)
Considerations that are particularly relevant for postadolescent acne in women include:
●Prior therapies – Postadolescent acne in women can be difficult to treat, and patient complaints
regarding prior ineffective therapies are not uncommon [4]. A history of previous therapeutic
interventions should be carefully obtained prior to treatment selection to determine whether specific
treatments were truly ineffective. A failure to respond to therapy is sometimes due to a lack of
adherence to the treatment regimen for an appropriate amount of time or early discontinuation of an
agent due to adverse effects [49]. At least 8 to 12 weeks of consistent treatment is required to judge
the effectiveness of many acne medications. (See "Treatment of acne vulgaris".)
1013
●Childbearing status – Avoidance of many acne therapies is preferable in pregnancy (table 3).
Women who are candidates for these therapies should be asked about the possibility of existing
pregnancy and plans for childbearing in the near future. The results guide appropriate patient
counseling and selection of therapy. (See "Treatment of acne vulgaris", section on 'Pregnancy and
acne therapy' and "Oral isotretinoin therapy for acne vulgaris", section on 'Teratogenicity'.)
Active acne — The therapeutic approach to postadolescent acne in women is similar to

the approach to acne in other adults and adolescents (table 2). In addition to the standard acne
therapies available to the general population of acne patients (eg, topical retinoids, azelaic acid,
salicylic acid, antimicrobial agents, and oral isotretinoin), hormonal therapy is an option for women
with acne that can yield clinical improvement even in the absence of hyperandrogenism [17,18]. Oral
contraceptives with or without antiandrogenic progestins and spironolactone are the most common
hormonal therapies prescribed. A more detailed discussion of hormonal therapy in the management
of acne is presented separately. (See "Treatment of acne vulgaris", section on 'Approach to
treatment' and "Oral isotretinoin therapy for acne vulgaris" and "Hormonal therapy for women with
acne vulgaris".)
Acne sequelae — Features such as postinflammatory hyperpigmentation and

scarring may persist long beyond the successful suppression of active lesions and can be highly
distressing for patients (picture 1C-D). Thus, interventions that improve these features can be of
value and are reviewed in detail separately. (See "Treatment of acne vulgaris", section on 'Therapy for
postinflammatory hyperpigmentation' and "Postinflammatory hyperpigmentation" and "Management
of acne scars".)
SKIN CARE Many women also desire advice on skin care regimens. Picking or
squeezing lesions, which can increase the risk for scar formation, should be discouraged, and gentle
skin cleansing practices are recommended [50]. Many topical acne medications can be particularly
irritating in adult skin, and the daily application of moisturizers can limit transepithelial water loss
and decrease skin inflammation [50]. Daily sunscreen use is also recommended. (See "Treatment of
acne vulgaris", section on 'Home skin care recommendations'.)
Although the methods for determining comedogenicity in skin care and cosmetic products vary and
the importance of cosmetic products as contributors to acne is uncertain [41,42], most
dermatologists, including ourselves, continue to favor the use of skin care products (eg,
moisturizers, cleansers, cosmetics, etc) labeled as "noncomedogenic" and "nonacnegenic" for
patients with acne and suggest the avoidance of occlusive agents. In addition, we advise patients
who desire to use foundation as part of their makeup routine to select "oil-free" liquid silicone
(dimethicone or cyclomethicone) matte foundations over oil-containing products, as the silicone-
based products may be less likely to cause follicular occlusion.
1014
PROGNOSIS Although the progressive decrease in the prevalence of acne with
increasing age indicates that spontaneous resolution is likely to occur [11], women may suffer from
acne for many years. In one survey study of adult women with acne, the mean age of disease onset
was 16 years, and patients reported an average duration of acne of 20 years [27].
The effect of pregnancy on acne vulgaris is variable. Acne may improve, remain unchanged, or
worsen during pregnancy [27].

SUMMARY AND
RECOMMENDATIONS
●Acne is a common disorder that affects both adolescents and adults. Although the prevalence of
acne vulgaris decreases with age, acne is a significant concern for many adult women. (See
●The factors that contribute to acne in adult women and other populations are similar. Sebum
production, keratinization abnormalities, Cutibacterium (formerly Propionibacterium) acnes
colonization, and inflammation involving the pilosebaceous follicle contribute to the development of
acne vulgaris. (See 'Pathogenesis' above and "Pathogenesis, clinical manifestations, and diagnosis
of acne vulgaris", section on 'Pathogenesis'.)
●Although hyperandrogenemia promotes the occurrence of acne vulgaris, many women with acne
have normal serum androgen levels. Local production of androgens within the pilosebaceous
follicles or an increased sensitivity of sebaceous glands to tissue androgens may contribute to acne
in these women. (See 'Pathogenesis' above.)
●Many women with postadolescent acne experience premenstrual flares. The reason for this
observation is unknown. (See 'Pathogenesis' above.)
●Postadolescent acne most commonly occurs as a consequence of the persistence of adolescent

acne. Women often present with both inflammatory and noninflammatory acne lesions. A subset of
women with acne may present with lesions primarily distributed on the lower face (picture 1B). (See
'Clinical features' above.)
●The possibility of a hyperandrogenemic state should be considered in women who present with
acne. If signs or symptoms of hyperandrogenism are present, laboratory evaluation is indicated.
(See 'Hyperandrogenism' above and "Pathogenesis, clinical manifestations, and diagnosis of acne
1015
vulgaris", section on 'Acneiform eruptions'.)
●The treatment of adult women with acne involves a review of prior therapies, assessment of lesion
types, and the evaluation for conditions that may influence the selection of therapy. Topical
retinoids, antimicrobial agents, and hormonal drugs are often used for the management of acne.
Gentle skin care practices are also recommended. (See 'Treatment' above and "Treatment of acne
vulgaris".)
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1017
INTRODUCTION Although acne is not physically disabling, its

psychologic impact can be striking, contributing to low self-esteem, depression, and anxiety [1-3]. As
a result, there is a significant demand for effective acne therapies (table 1).
The lack of standardization for grading acne severity and measuring treatment outcomes has made
systematic interpretation of the literature difficult [4]. However, quality evidence-based literature in
the field of acne is increasing [5-7].
Medical therapies for acne and therapeutic principles that support the selection of treatments will be
discussed here. A table summarizing treatment recommendations for patients with acne vulgaris is
provided (table 2). Procedural therapies for acne, oral isotretinoin therapy for severe acne, hormonal
therapy for women with acne, and interventions for acne scars are reviewed in detail separately. (See
"Light-based, adjunctive, and other therapies for acne vulgaris" and "Oral isotretinoin therapy for
acne vulgaris" and "Hormonal therapy for women with acne vulgaris" and "Management of acne
scars".)
PRETREATMENT ASSESSMENT Deciding on

the appropriate course of treatment for acne requires a comprehensive assessment that includes:
●Clinical type and severity of acne (eg, comedonal, papulopustular, mixed, nodular)
•Determines the types of treatments needed (see 'General approach' below)
●Skin type (eg, dry, oily)
•Influences choice of topical drug vehicle (see 'General approach' below)
●Presence of acne scarring
•Indicates need to consider more aggressive acne therapy and treatments for scarring (see 'Oral
isotretinoin' below and "Management of acne scars")
●Presence of postinflammatory erythema or postinflammatory hyperpigmentation
•Indicates need to consider therapies for hyperpigmentation or erythema as well as the need to
resolve and prevent inflammatory acne lesions (see 'Therapy for postinflammatory
hyperpigmentation' below)
●Menstrual cycle history and history of signs of hyperandrogenism in women
1018
•Identifies need to consider laboratory workup and hormonal therapies (see "Hormonal therapy for
women with acne vulgaris" and "Pathogenesis, clinical manifestations, and diagnosis of acne
vulgaris", section on 'Additional tests')
●Current skin care regimen and acne treatment history
•Identifies successful and unsuccessful previous treatments
•Identifies skin care practices that should be adjusted or discontinued during acne therapy (see
'Home skin care recommendations' below)
●History of acne-promoting cosmetic products and medications
•Identifies potential for improvement with discontinuation of topical cosmetic products (acne
cosmetica) and medications (acne medicamentosa) that may contribute to acne (table 3)
●Psychologic impact of acne on the patient
•Identifies need for a more aggressive treatment approach or psychologic services
TREATMENT PRINCIPLES Medical therapies for acne

target one or more of four key factors that promote the development of acne lesions: follicular
hyperproliferation and abnormal desquamation, increased sebum production, Cutibacterium
(formerly Propionibacterium) acnes proliferation, and inflammation (figure 1). (See "Pathogenesis,
clinical manifestations, and diagnosis of acne vulgaris", section on 'Pathogenesis'.)
These factors are targeted as follows [8]:
●Follicular hyperproliferation and abnormal desquamation
•Topical retinoids
•Oral retinoids
•Azelaic acid
•Salicylic acid
•Hormonal therapies
●Increased sebum production
•Oral isotretinoin
•Hormonal therapies
●C. acnes proliferation
1019
•Benzoyl peroxide
•Topical and oral antibiotics
•Azelaic acid
●Inflammation
•Oral isotretinoin
•Oral tetracyclines
•Topical retinoids
•Azelaic acid
In addition, the procedural therapies used as adjunctive therapies for acne target one or more
contributory factors. The mechanisms of these interventions are reviewed separately. (See "Light-
based, adjunctive, and other therapies for acne vulgaris".)
Knowledge of mechanisms of action of acne therapies is combined with recognition of specific

clinical features to determine the best approach to treatment. The following concepts guide the
selection of therapy:
●Topical retinoids are beneficial for both comedonal (noninflammatory) (picture 1A-B) and
inflammatory acne (picture 2A) and should be included in the initial management of most patients.
Topical retinoids are effective in the treatment of comedonal acne due to their ability to normalize
follicular hyperkeratosis and prevent formation of the microcomedo, the primary lesion of acne [9].
The efficacy of topical retinoids for inflammatory acne [10,11] may be due to a combination of
intrinsic anti-inflammatory properties of topical retinoids and their ability to prevent the formation of
microcomedones. Topical retinoids can be used as monotherapy in individuals with exclusively
comedonal acne.
●Patients with an inflammatory component often benefit from antimicrobial therapies (eg, benzoyl
peroxide or topical antibiotics). Antimicrobial agents reduce the number of proinflammatory C. acnes
colonizing the skin. (See 'Topical antimicrobials' below.)
●Patients with moderate to severe inflammatory acne often warrant more aggressive treatment with
oral antibiotics [8]. Antibiotics in the tetracycline class are most frequently used, and appear to have
both antibacterial and anti-inflammatory properties. (See 'Oral antibiotics' below.)
●The use of benzoyl peroxide with topical or oral antibiotics decreases the emergence of antibiotic
resistant bacteria. Therefore, use of benzoyl peroxide is recommended in patients receiving
antibiotic therapy [7]. (See 'Oral antibiotics' below.)
1020
●Androgens stimulate increased sebum production, which contributes to the formation of acne [9].
Hormonal therapy may benefit women with moderate to severe acne, even in the absence of a
hyperandrogenic state. (See "Hormonal therapy for women with acne vulgaris".)
●Patients should be given realistic expectations regarding timelines for improvement. Improvement
in acne is dependent upon both the prevention and resolution of acne papules, pustules, and
nodules. At least two to three months of consistent adherence to a therapeutic regimen is often
necessary prior to concluding that treatment is ineffective. Adjustments to the regimen also may be
needed.
●Acne typically recurs over years, and maintenance therapy is an important component of acne
management. (See 'Maintenance therapy' below.)
APPROACH TO TREATMENT
General approach — An example of an initial approach to acne based upon the
principles above is outlined below. Additional therapeutic options are reviewed in a table derived
from the 2016 acne treatment guidelines from the American Academy of Dermatology (table 2) [7].
●Comedonal (noninflammatory) acne (picture 1A-B)
•Topical retinoid (alternatives include azelaic acid and salicylic acid)
●Mild papulopustular and mixed (comedonal and papulopustular) acne (picture 2A-B)
•Topical antimicrobial (eg, benzoyl peroxide alone or benzoyl peroxide +/-topical antibiotic) AND
•Topical retinoid
OR
•Benzoyl peroxide AND topical antibiotic (for patients who cannot tolerate a retinoid or who require a
simplified treatment regimen)
●Moderate papulopustular and mixed acne (picture 3)
•Topical retinoid AND
•Oral antibiotic AND
•Topical benzoyl peroxide
●Severe acne (eg, nodular acne) (picture 4A-C)
•Topical retinoid AND
1021
•Oral antibiotic AND
•Topical benzoyl peroxide
OR
•Oral isotretinoin monotherapy (see 'Oral isotretinoin' below and "Oral isotretinoin therapy for acne
vulgaris")
Of note, oral hormonal therapy is an alternative to oral antibiotic therapy in postmenarchal females
with moderate to severe acne (table 2). (See "Hormonal therapy for women with acne vulgaris".)
Consistent adherence to acne therapy is critical for achieving clinical improvement. When
recommending topical therapy, the clinician should design a regimen that is feasible for the patient.
This should involve a discussion with the patient to ensure that each component of the treatment
regimen is acceptable to the patient. We typically design regimens that require the patient to treat no
more than once or twice daily.
A sample regimen for a patient with mild inflammatory facial acne who is using a topical retinoid,
topical benzoyl peroxide, and topical clindamycin is as follows:
●Morning: Wash face with a gentle facial cleanser. Apply a thin layer of a fixed-dose combination
benzoyl peroxide/clindamycin gel to the entire face. (An alternative regimen could require the patient
to wash the face with a benzoyl peroxide cleanser followed by application of a thin layer of topical
clindamycin to the entire face.)
●Night: Wash face with a gentle facial cleanser. Apply a thin layer of the topical retinoid to the entire
face.
Some patients may prefer the use of fixed-dose combination products to simplify treatment (table 4).
However, the cost of such treatments may be higher than single-active ingredient agents. (See
'Combination therapy' below.)
The selection of the delivery system for topical acne medications also may help to improve the
likelihood of adherence to treatment. The choice depends upon the patient's skin type (dry versus
oily) and preference. Some gels have a drying effect; they may be preferred by patients with oily skin.
Creams and lotions tend to be moisturizing. Solutions are drying but they cover large areas more
easily than other preparations, and foams are easy to apply to hair-bearing areas. Pledgets are
single-use absorbent pads impregnated with medication. They are convenient to use and facilitate
the spreading of medication over large areas.
Clinicians should be aware that further modifications to the vehicle of a drug may also affect
characteristics such as efficacy, tolerability, or stability. As an example, the microsphere formulation
of tretinoin consists of tretinoin contained in microscopic biodegradable spherical particles. As the
1022
microspheres are degraded, tretinoin is slowly and progressively delivered to the skin. This
formulation is associated with improved drug stability and decreased irritation [12,13]. (See 'Topical
retinoids' below.)
Procedural therapies are sometimes used in conjunction with conventional medical therapy. These
interventions are reviewed separately. (See "Light-based, adjunctive, and other therapies for acne
vulgaris", section on 'Light/laser therapies' and "Light-based, adjunctive, and other therapies for acne
vulgaris", section on 'Adjunctive therapies'.)
Truncal acne — Although the treatment of both facial and truncal acne can be
approached similarly, a challenge for the treatment of truncal acne is the difficulty associated with
applying topical treatments to the entire affected area. Given the difficulty that patients may have
applying medications to areas such as the back compared with the face and the large quantity of
topical medication required for use on large areas, we have a lower threshold for incorporating oral
antibiotic or oral hormonal therapies into the treatment regimen. Pharmacy-provided medication
applicators designed to aid with application of medication or emollients to the back are sometimes
helpful for topical treatment.
Children — The medical therapies used for the treatment of acne in children are similar to
the management of acne in adolescents and adults. A significant exception is the need to avoid the
use of tetracyclines in children under the age of nine years [14]. (See 'Tetracyclines' below.)
An additional important consideration for acne therapy in children and adolescents is the
implementation of measures to optimize adherence to therapy. Careful efforts should be made to
recognize when the complexity of the regimen, the child or adolescent's dislike of the vehicle
prescribed (eg, cream, lotion, gel), or drug side effects inhibit consistent use of acne medication [14].
Discussing adherence to the treatment regimen and obstacles to adherence at each visit allows for
therapeutic adjustments that may lead to more consistent treatment and a better clinical response.
In addition, thorough discussions of realistic expectations for treatment may help to prevent
premature discontinuation of therapy by a child or adolescent who is discouraged by the lack of an
immediate and complete disappearance of acne lesions.
Recommendations on the management of pediatric acne vulgaris formulated by a panel of experts

and endorsed by the American Academy of Pediatrics have been published [14]. The management of
neonatal and infantile acne is reviewed separately. (See "Vesicular, pustular, and bullous lesions in
the newborn and infant", section on 'Neonatal cephalic pustulosis' and "Vesicular, pustular, and
bullous lesions in the newborn and infant", section on 'Infantile acne'.)
Acne fulminans — Acne fulminans is a rare, severe form of acne vulgaris

characterized by the abrupt development of large inflammatory nodules and friable plaques with
erosions, ulcers, and hemorrhagic crusts, with or without associated systemic findings. Acne
fulminans may occur following the initiation of isotretinoin or spontaneously. (See "Pathogenesis,
clinical manifestations, and diagnosis of acne vulgaris", section on 'Acne fulminans'.)
1023
Oral glucocorticoids (typically, prednisone 0.5 to 1 mg/kg per day) and oral isotretinoin are the
mainstays of treatment for acne fulminans. There is a paucity of high-quality data to guide the
approach to treatment. Recommendations from a panel of clinicians with expertise in severe acne
vulgaris include the following (algorithm 1) [15]:
●For patients with isotretinoin-induced acne fulminans (with or without systemic symptoms),
discontinue isotretinoin immediately and treat similarly to patients without isotretinoin-induced
disease.
●For patients with acne fulminans with systemic symptoms, initiate oral glucocorticoid
monotherapy at least four weeks prior to starting oral isotretinoin to prevent a flare of the condition.
●For patients with acne fulminans without systemic symptoms, initiate oral glucocorticoid
monotherapy at least two weeks prior to starting oral isotretinoin.
●Start low-dose isotretinoin (0.1 mg/kg per day) and continue with prednisone for at least four
weeks; after this period, the dose of isotretinoin can be gradually increased as tolerated and the oral
glucocorticoid can be slowly tapered over four to eight weeks, as tolerated.
●If flares occur during treatment, extending the course of oral glucocorticoid therapy or temporary
discontinuation of oral isotretinoin may be required (algorithm 1).
The typical goal cumulative dose of isotretinoin for acne vulgaris is 120 to 150 mg/kg. Greater
cumulative doses may be required for patients with refractory acne fulminans [15]. (See "Oral
isotretinoin therapy for acne vulgaris".)
Combination therapy with oral glucocorticoids and oral tetracyclines (eg, doxycycline or minocycline
[100 mg twice daily] or tetracycline [500 to 1000 mg twice daily]) has also been used for treatment
but may not be as effective as oral glucocorticoids and isotretinoin and is not recommended as first-
line treatment [15]. Other alternative treatments that have seemed beneficial in case reports include
high-potency topical corticosteroids [16], cyclosporine [17], dapsone [18,19], levamisole [15], and
pulsed dye laser [20].
There is a lack of data on the effects of biologic therapies for recalcitrant acne fulminans. Based
upon reports of benefit of anti-tumor necrosis factor (TNF) biologic therapy in patients with acne
conglobata and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, it is
conceivable that such treatment may be beneficial. (See 'Acne conglobata' below and "SAPHO
(synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome", section on 'Treatment'.)
Acne conglobata — Acne conglobata is a severe form of nodular acne vulgaris

that may result in drainage, sinus tracts, and severe scarring. (See "Pathogenesis, clinical
manifestations, and diagnosis of acne vulgaris", section on 'Acne conglobata'.)
1024
Treatments have included systemic antibiotics, intralesional glucocorticoids, systemic
glucocorticoids, and surgical intervention [21]. Patients can respond well to isotretinoin, although
they may experience severe flares at the start of isotretinoin therapy. For this reason, lower doses of
isotretinoin (0.5 mg/kg per day or less) plus systemic glucocorticoids before or during isotretinoin
therapy are often required [21].
A few case reports have documented improvement in acne conglobata during treatment with
biologic TNF-alpha inhibitors (etanercept [22], adalimumab [23], and combination therapy with
infliximab and isotretinoin [24]). However, further study is necessary before treatment with these
agents can be recommended.
TOPICAL RETINOIDS Topical retinoids are used for the

treatment of both noninflammatory and inflammatory acne, and should be included in the initial
management of most patients. The first topical retinoid for the treatment of acne, topical all-trans
retinoic acid (topical tretinoin), is still extensively used. Adapalene, tazarotene, and trifarotene are
other effective topical retinoids. Topical isotretinoin is not available in the United States, but is
utilized in other countries. Properties of the individual preparations and comparisons of the available
drugs are discussed below (table 1). (See 'Administration' below and 'Comparative studies' below.)
In the United States, a prescription is required to obtain most topical retinoids. The exception is
adapalene 0.1% gel, which can be purchased without a prescription.
Efficacy — Topical retinoids are vitamin A derivatives that act by binding to two nuclear
receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors
(RXR) [25]. Tretinoin, adapalene, and tazarotene target both RAR-beta and RAR-gamma receptors;
trifarotene is selective for the RAR-gamma receptor. The retinoid-receptor complexes are
transported into the nucleus, where they activate specific regulatory DNA sequences called retinoid
hormone response elements, thereby stimulating the transcription of target genes. These events
contribute to the normalization of follicular keratinization and decreased cohesiveness of
keratinocytes, resulting in reduced follicular occlusion and microcomedone formation [26]. Salicylic
acid and azelaic acid are alternative comedolytic therapies for patients who are unable to tolerate
topical retinoids, but may be less effective. (See 'Salicylic acid' below and 'Azelaic acid' below.)
In addition to this direct effect of retinoids on comedogenesis, retinoids may also improve
inflammatory acne through other mechanisms. The retinoid-receptor complex competes for
coactivator proteins of AP-1, a key transcription factor involved in inflammation [25,27]. Retinoids
also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the
inflammatory response in acne [28,29]. Moreover, retinoids may enhance the penetration of other
topical acne medications [9,30].
Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris [11,31-40].
Most high-quality trials have focused on the response of facial acne; efficacy for truncal acne has
been demonstrated in trials evaluating trifarotene [41]. Representative trials of topical retinoids
1025
versus placebo include:
●A 12-week randomized trial of 60 patients with acne vulgaris treated with tretinoin 0.05% solution,
tretinoin 0.025% solution, or placebo showed greater reductions in acne lesions with the tretinoin
formulations than with placebo [31].
●In a 12-week randomized controlled trial, 200 patients were given either adapalene 0.1% gel or
vehicle. Treatment with adapalene led to significantly greater reductions in total, inflammatory, and
noninflammatory lesions [39]. The mean percent reduction in total lesion counts at the end of
therapy was 63.2 percent for patients who received adapalene gel versus 36.9 percent for patients
treated with vehicle.
●A 12-week trial involved 653 patients who were randomly assigned to treatment with adapalene
0.3% gel, adapalene 0.1% gel, or vehicle [35]. Adapalene 0.3% gel, adapalene 0.1% gel, and vehicle gel
yielded 55.6, 48.2, and 36.4 percent reductions in total lesion counts, respectively. Thus, adapalene
products were more effective than vehicle alone.
●Pooled results of two randomized controlled trials of a total of 847 patients with acne vulgaris
treated with tazarotene 0.1% cream or vehicle for 12 weeks showed a significantly greater reduction
in noninflammatory, inflammatory, and total lesion counts in patients treated with tazarotene
compared with patients who received the vehicle [38]. The median percent reduction in total lesion
counts for patients treated with tazarotene was 43 percent compared with 23 percent for patients
treated with vehicle.
●Two 12-week trials (PERFECT 1 [n = 1208] and PERFECT 2 [n = 1212) in which patients with
moderate facial and truncal acne were randomly assigned to once-daily application of either
trifarotene 0.005% cream or vehicle found trifarotene an effective treatment [41]. In PERFECT 1 and
PERFECT 2, 29 and 42 percent of patients who applied trifarotene achieved treatment success for
facial acne (investigator global assessment rating of clear or almost clear and at least a two-grade
change from baseline), respectively, compared with 20 and 26 percent of patients in the vehicle
groups. Trifarotene was also effective for truncal acne, demonstrating treatment success in 36 and
43 percent of patients in the PERFECT 1 and PERFECT 2 trifarotene groups, respectively, compared
with 25 and 30 percent of patients in the vehicle groups. A 52-week, open-label study (n = 453)
suggests efficacy of trifarotene may increase with long-term use [42].
In addition to treating active acne, retinoids accelerate the resolution of acne-induced

postinflammatory hyperpigmentation [25]. This complication occurs more frequently in patients with
darker skin pigmentation and is often a significant concern. (See 'Therapy for postinflammatory
hyperpigmentation' below.)
Topical retinoids are also useful as maintenance therapy for patients who have responded to initial
treatment [43-46]. The use of retinoids as maintenance therapy can diminish the prolonged use of
antibiotics [7]. (See 'Maintenance therapy' below.)
1026
Administration — Topical tretinoin, isotretinoin, adapalene, and tazarotene are
available in a variety of vehicles and concentrations. Trifarotene cream is expected to become
commercially available in 2019. Combination gels containing a retinoid and an antimicrobial are also
available (table 4). (See 'Combination therapy' below.)
The topical retinoids are applied once daily and traditionally at night due to photolability reported
with tretinoin [47]. Adapalene and trifarotene are more light-stable [48,49]. In addition, newer
formulations of tretinoin, tretinoin gel microsphere, and micronized tretinoin 0.05% in a hydrogel
vehicle, are less affected by light exposure than their precursors [50-52]. For example, in a study in
which tretinoin gel microsphere 0.1% and tretinoin 0.025% gel were exposed to simulated solar
ultraviolet radiation, 94 percent of tretinoin in the microsphere formulation remained stable after two
hours, compared with only 19 percent of tretinoin in the 0.025% gel [50].
Topical tretinoin should not be applied at the same time as benzoyl peroxide. Tretinoin is less stable
when exposed to benzoyl peroxide due to oxidation, an effect magnified during light exposure
[47,50]. Adapalene, tretinoin gel microsphere, micronized tretinoin gel, tazarotene, and trifarotene
remain more stable than tretinoin in the presence of benzoyl peroxide [7,47-50,53]. A combination
product, containing adapalene and benzoyl peroxide, is available (table 4).
Patients should be directed to apply a thin layer of the topical retinoid to the affected areas; a pea-
sized amount of medication is usually sufficient to cover the face. Due to the preventive effect of
topical retinoids on acne, the medication should be applied to the entire affected area, not as spot
treatment of individual lesions. Skin should be dry at the time of application.
Skin irritation is a common and expected side effect of topical retinoid therapy. Irritation may be
minimized by starting with the lowest concentration of a topical retinoid product and then increasing
the potency as tolerated (table 1). Of note, the type of vehicle may influence the potential for
irritation. In one study in which different formulations of tretinoin were applied under occlusion to
the backs of 28 healthy subjects, the irritation potential of tretinoin in ascending order was: 0.025%
cream and 0.01% gel, followed by 0.025% gel, followed by 0.05% cream and 0.1% cream [54]. (See
'Adverse effects' below and 'Comparative studies' below.)
A microencapsulated (microsphere) form of tretinoin gel is less irritating and is available as a 0.04%,
0.08%, and 0.1% gel. Similarly, reduced irritation has been noted with a polyolprepolymer-2 base [55]
and micronized tretinoin 0.05% gel [53,56]. Low rates of irritation have been reported with tretinoin
0.05% lotion, a newer formulation [57,58]. Adapalene 0.1% gel produces less irritation than tretinoin
0.025% gel and cream [59,60] (table 1).
In general, tazarotene has been considered more effective but also more irritating than adapalene
and tretinoin [61]. A short-contact regimen with tazarotene is another treatment option, and can
decrease irritation. Patients apply tazarotene for up to five minutes daily, then wash off the
medication [62].
The irritation potential of trifarotene has not been directly compared with other retinoids.
1027
Adverse effects — Topical retinoids cause irritation, dryness, and flaking of the
skin, an effect most notable during the first month of therapy [25]. To minimize irritation, patients
should avoid the concomitant use of over-the-counter irritating products, such as harsh soaps,
toners, astringents, and alpha hydroxy acid or salicylic acid products [63]. A gentle non-soap
cleanser should be recommended. Delaying application of the retinoid for at least 20 minutes after
washing and drying the face may also be helpful. (See 'Home skin care recommendations' below.)
If irritation is a problem, a decrease in the frequency of application to every other or every third night
can be considered, and the frequency of application can be increased as tolerance improves. The
fine skin flaking that is often seen can be gently exfoliated with a washcloth [61]. A noncomedogenic
facial moisturizer can also be applied if needed.
Topical retinoids are not true photosensitizing drugs, but patients using topical retinoids have
described symptoms of increased sun sensitivity. This is thought to be due to thinning of the
stratum corneum leading to a decreased barrier against ultraviolet light exposure, as well as an
enhanced sensitivity due to the presence of cutaneous irritation [61]. The use of sun-protective
clothing and/or sunscreen is recommended, particularly when prolonged sun exposure is
anticipated [61].
Micronized tretinoin 0.05% gel contains soluble fish proteins. The drug should be used with caution
in patients with a known allergy to fish [64].
A large randomized trial evaluating the use of long-term topical tretinoin 0.1% cream for the
prevention of basal cell and squamous cell carcinoma reported an increase in mortality in older adult
men [65]. However, there is a possibility that these findings may have been due to chance in the
population studied, and the applicability of these findings to the use of tretinoin in younger patients
for the treatment of acne is uncertain.
The use of topical retinoids is not recommended in pregnancy. In particular, tazarotene is a

pregnancy category X drug (table 5). A systematic review and meta-analysis did not find significant
increases in risk for major congenital abnormalities with first trimester topical retinoid exposure,
providing information that may be reassuring for women who have inadvertent topical retinoid
exposure during early pregnancy [66]. However, the study was insufficiently powered to conclude
that topical retinoid use is safe in pregnancy. There are case reports documenting fetal
malformations in infants of women exposed topical retinoid therapy during pregnancy [67-71]. (See
'Pregnancy and acne therapy' below.)
Comparative studies — Randomized trials and their meta-analyses have

compared the efficacy and tolerability of topical retinoids. Interpretation of results needs to take into
account the drug concentrations and formulations. The trials do not definitively support the use of
one topical retinoid over another.
1028
A meta-analysis of five randomized trials found that adapalene 0.1% gel and tretinoin 0.025% gel had
similar efficacy, but adapalene was somewhat better tolerated and produced more rapid
improvement [59]. Adapalene 0.1% gel also appeared to have equivalent efficacy and greater
tolerability when compared with tretinoin microsphere 0.1% gel or tretinoin 0.05% cream [72,73].
A multicenter randomized trial found that the reduction in noninflammatory lesions was greater with
tazarotene 0.1% gel than tretinoin 0.025% gel (55 versus 42 percent reduction) [74]. The preparations
were similarly effective in reducing inflammatory lesions; tazarotene caused more skin irritation.
Randomized trials found that tazarotene cream and gel were more efficacious than adapalene
cream and gel at the same concentrations (0.1%); the creams had similar tolerability, but adapalene
gel was better tolerated than tazarotene gel during the first few weeks of treatment [75,76]. In
another trial, adapalene 0.3% gel was noninferior to tazarotene 0.1% gel and remained better
tolerated [77].
From these studies, it appears that advantages of adapalene and tazarotene are tolerability and
efficacy, respectively.
TOPICAL ANTIMICROBIALS Topical antimicrobials

are used to decrease the number of C. acnes colonizing the skin, with the goal of reducing the
inflammatory response that occurs in acne. The most commonly used topical antimicrobials include
benzoyl peroxide, clindamycin, and erythromycin. Sulfacetamide and dapsone are additional
treatment options. Minocycline 4% foam is expected to become available in early 2020. A list of
topical antimicrobial preparations for the treatment of acne is provided (table 1).
Combination therapy with a topical antimicrobial plus a topical retinoid appears to be more effective
than either agent alone, and adding an antimicrobial agent is recommended when retinoids are used
for the treatment of patients with inflammatory acne [9,78]. (See 'Combination therapy' below.)
Benzoyl peroxide — In addition to its antibacterial properties, benzoyl peroxide is

also comedolytic. The drug is available in the United States in both prescription and nonprescription
products as 2.5 to 10% gels, lotions, creams, pads, masks, and cleansers, and is usually applied
twice daily. Concentrations of benzoyl peroxide that are higher than 2.5% may not contribute to
increased benefit. In one study, 2.5% benzoyl peroxide was as effective as 10% benzoyl peroxide in
reducing the number of inflammatory acne lesions [79]. In addition, the time required for onset of
action for varying concentrations of benzoyl peroxide appears to be similar [80]. Visible
improvement typically occurs within three weeks, with maximum results evident after 8 to 12 weeks
[7].
Increased concentrations of benzoyl peroxide can lead to increased skin irritation. Irritation may
appear as erythema, scaling, xerosis, or stinging, tightening, or burning sensations [81]. Although
irritation is common, true allergic contact dermatitis to benzoyl peroxide is rare. Only 0.25 to 2.5
1029
percent of patients develop a true allergic contact sensitivity [82,83]. Patients should also be advised
that benzoyl peroxide can cause bleaching of the hair and clothing.
Of note, there are rare reports of serious and potentially life-threatening hypersensitivity reactions to
nonprescription topical acne products containing benzoyl peroxide or salicylic acid [84]. Whether
these active ingredients or other ingredients are responsible for the reactions is unclear. The US
Food and Drug Administration recommends limiting application of these products to one or two
small affected areas during the initial three days of use to test for hypersensitivity [84]. (See "Light-
based, adjunctive, and other therapies for acne vulgaris", section on 'Other topical medications'.)
Antibiotics may promote the appearance of resistant strains of C. acnes when used alone.
Resistance is diminished by combination use with benzoyl peroxide. (See 'Combination therapy'
below.)
Tretinoin and benzoyl peroxide should not be applied simultaneously to the skin due to the oxidizing
effect of benzoyl peroxide on tretinoin. If both agents are prescribed, benzoyl peroxide should be
applied in the morning and tretinoin in the evening. Adapalene, the microsphere formulation of
tretinoin, and tazarotene are stable in the presence of benzoyl peroxide. (See 'Administration' above.)
Topical antibiotics — Topical antibiotics reduce the numbers of C. acnes in the

sebaceous follicles and thereby suppress inflammation in patients with inflammatory acne. In
addition to erythromycin and clindamycin, topical preparations of sulfacetamide and dapsone are
available. All topical antibiotics may occasionally cause skin irritation.
Erythromycin and clindamycin — Topical erythromycin and clindamycin

are the most common topical antibiotics used for the treatment of acne. Erythromycin is available in
gel and solution formulations; clindamycin is available as a gel, solution, lotion, foam, or as pledgets
(antibiotic impregnated wipes). Erythromycin and clindamycin are often used in 2% and 1%
concentrations, respectively.
Topical erythromycin and clindamycin should not be used as monotherapy for acne, as evidence
shows better treatment efficacy when these drugs are combined with retinoids or benzoyl peroxide
[85]. In addition, the use of benzoyl peroxide with antibiotics decreases the occurrence of bacterial
resistance. (See 'Combination therapy' below.)
Combination gels containing benzoyl peroxide or tretinoin combined with an antibiotic are available
(table 4).
Sulfacetamide — Sulfacetamide is an antibacterial agent that inhibits C. acnes. It is

often combined with 5% sulfur. (See "Light-based, adjunctive, and other therapies for acne vulgaris",
section on 'Sulfur'.)
1030
Sulfacetamide should not be used in patients with sulfa or sulfonamide allergies [81]. Data regarding
the effectiveness of sulfacetamide in the treatment of acne are limited [86-88], and other
antimicrobials are preferred as first-line therapy.
Dapsone — Dapsone 5% and 7.5% gels are an effective treatment for acne vulgaris. Oral
dapsone is known to have anti-inflammatory and antimicrobial properties, although the mechanism
through which dapsone gel improves acne has not been confirmed. Both inflammatory and
noninflammatory acne lesions improve with treatment, with the greatest improvement occurring in
inflammatory lesions [89,90]. The 5% formulation is applied twice daily, while the 7.5% formulation is
applied once daily.
In two phase 3 randomized trials of dapsone 5% gel with a total of 3010 patients, the percent
reduction of inflammatory lesions after 12 weeks of twice daily treatment was significantly greater in
patients treated with topical dapsone than in those treated with vehicle (48 versus 42 percent) [89].
An open-label long-term study of patients treated with the same regimen for up to 12 months (mean
253 days) found a reduction in inflammatory lesions of 58 percent [90]. Benefit of dapsone 5% gel
may be slightly greater in females than in males [91].
A 12-week randomized trial (n = 2102) found dapsone 7.5% gel superior to vehicle, with mean
percent reductions in inflammatory lesions of 56 and 49 percent, respectively [92]. A second
identical trial (n = 2238) found similar results, with mean percent reductions in inflammatory lesions
for dapsone 7.5% gel and vehicle of 54 and 48 percent, respectively [93].
An increased risk of hemolytic anemia is seen in patients with glucose-6-phosphate dehydrogenase

(G6PD) deficiency taking oral dapsone. However, patients with G6PD deficiency and acne have
tolerated topical dapsone gel [89,94]. Testing for G6PD deficiency is not necessary for use of the
topical preparation of dapsone. In addition, dapsone is a sulfone, not a sulfonamide, and topical
dapsone is not contraindicated in sulfonamide ("sulfa") allergic patients [95].
Temporary yellow to orange discoloration of the skin and hair may occur when dapsone gel and
topical benzoyl peroxide are applied concomitantly [96,97]. In one study, 7 out of 100 patients
experienced this adverse effect when the two drugs were applied 10 minutes apart; discoloration
resolved between 4 and 57 days after discontinuation of therapy [96]. If both drugs are prescribed
for the treatment of acne, applying the drugs at separate times of the day and washing skin between
applications may reduce the risk of this side effect.
Methemoglobinemia, a known complication of systemic dapsone therapy, is a rare side effect of

topical dapsone [98]. (See "Methemoglobinemia".)
Minocycline — Minocycline 4% foam has demonstrated efficacy for acne vulgaris. The
drug is applied once daily.
1031
Two identical phase 3 trials in which a total of 961 patients (ages nine years and older) with
moderate to severe acne vulgaris were randomly assigned in a 2:1 ratio to either minocycline 4%
foam or vehicle applied once daily for 12 weeks found minocycline 4% foam effective for reducing
inflammatory and noninflammatory lesion counts in both studies and for achieving treatment
success (a score of 0 or 1 [clear or almost clear] on the six-point Investigator's Global Assessment
scale with at least a two-grade improvement) in the second study [99]. Rates of treatment success
for minocycline and vehicle groups were 15 versus 8 percent (risk ratio [RR] 1.88, 95% CI 1.02-3.46)
in the first study and 8 versus 5 percent (RR 1.72, 95% CI 0.73-4.05) in the second study, respectively.
In addition, a larger, 12-week phase 3 trial found minocycline 4% foam effective for reducing
inflammatory and noninflammatory lesion counts and achieving the same measure of treatment
success. In the trial, 1488 patients (ages nine years and older) with moderate to severe acne vulgaris
were randomly assigned (in a 1:1 ratio) to once-daily application of minocycline 4% foam or vehicle
[100]. In the minocycline group, 31 percent achieved treatment success compared with 20 percent of
the vehicle group (RR 1.58, 95% CI 1.32-1.88).
Minocycline foam was generally well tolerated in the randomized trials. The most common
treatment-emergent adverse effects included headache and increased creatinine phosphokinase
levels [99,100].
COMBINATION THERAPY For patients with

inflammatory acne, combining a topical retinoid with antimicrobial agent(s) optimizes therapy [6,7].
Combination therapy with a topical antibiotic plus a topical retinoid appears to be more effective
than either agent alone. The use of benzoyl peroxide with topical or oral antibiotics is also
recommended. Adding benzoyl peroxide reduces the development of antibiotic resistance.
Several fixed-dose combination products are available in the United States (table 4).
Topical retinoid and topical antimicrobial — Multiple

studies comparing monotherapy versus combination therapy with topical retinoids and
antimicrobials (erythromycin, clindamycin, or benzoyl peroxide) have demonstrated improved
treatment efficacy with combination therapy [43,78,101-112]. Representative trials include:
●A randomized controlled trial of 249 patients with mild to moderate acne vulgaris evaluated
treatment with adapalene 0.1% gel plus clindamycin 1% lotion versus clindamycin plus vehicle [104].
Significantly greater reductions in total lesions were seen in patients who received combination
therapy (46.7 versus 25.5 percent). Improvement was seen in both inflammatory and
noninflammatory lesions.
●Two 12-week randomized controlled trials involving a total of 2219 patients with acne vulgaris
compared treatment with a combination hydrogel containing 1% clindamycin and 0.025% tretinoin to
one of three treatments: each agent as monotherapy or vehicle [78]. The efficacy of the combination
hydrogel was superior to monotherapy and vehicle in the reduction of inflammatory,
1032
noninflammatory, and total lesions. The reductions in total lesion counts for the combination
hydrogel, clindamycin gel, tretinoin gel, or vehicle were 48.7, 38.3, 40.3, and 23.2 percent,
respectively.
●A 12-week randomized controlled trial with 517 subjects compared treatment of acne vulgaris with
an adapalene 0.1% and benzoyl peroxide 2.5% combination gel to monotherapy with each drug and
to vehicle [103]. Treatment with the combination gel was more effective, with a significantly greater
reduction in total lesion counts noted as early as one week after starting therapy. At the end of
treatment, the combination gel, adapalene, benzoyl peroxide, and vehicle groups exhibited 51, 35.4,
35.6, and 31 percent reductions in total lesion counts.
The use of multiple anti-acne active ingredients may cause skin irritation. In one small trial,
adapalene 0.1% gel was less irritating than tazarotene 0.05% cream or tretinoin microsphere 0.04%
gel when used in combination regimens [113].
The topical retinoid and topical antimicrobial fixed-dose combination products available in the
United States include:
●Clindamycin 1.2% and tretinoin 0.025% gel
●Benzoyl peroxide 2.5% and adapalene 0.1% gel
●Benzoyl peroxide 2.5% and adapalene 0.3% gel
Antibiotics and benzoyl peroxide — As a result of the

widespread use of topical antibiotics, resistance to these agents has increased [114]. Unlike the
topical antibiotics erythromycin and clindamycin, C. acnes resistance to benzoyl peroxide has not
been identified. Combining antibiotic therapy with the use of benzoyl peroxide decreases the
development of antibiotic resistance and improves treatment efficacy [85,114-118].
One randomized trial found that a combination 3% erythromycin and 5% benzoyl peroxide gel was
superior to either agent alone in terms of antibacterial activity [119]. The combination gel also led to
clinical improvement in an open-label study of patients with pretreatment erythromycin-resistant C.
acnes strains [119].
Combination therapy with clindamycin and benzoyl peroxide is also more potent than monotherapy
with either agent. In an open-label study, the combination of benzoyl peroxide and clindamycin
decreased the numbers of C. acnes found on healthy skin more effectively than clindamycin alone
[120]. The clinical efficacy of combination benzoyl peroxide and clindamycin gel was assessed in a
meta-analysis of randomized trials [121]. The meta-analysis found that gels containing benzoyl
peroxide and clindamycin were modestly superior to benzoyl peroxide alone for the treatment of
inflammatory acne lesions (mean percent reduction in lesions 56 [95% CI 54-58] versus 44 percent
[95% CI 41-46] after treatment for 10 to 12 weeks). In addition, treatment with gels containing
benzoyl peroxide and clindamycin resulted in more rapid improvement of both inflammatory and
1033
noninflammatory lesions than clindamycin alone (mean percentage reductions in lesions were 41
[95% CI 37-44] versus 21 percent [95% CI 17-26] and of 26 percent [95% CI 22-30] versus 10 percent
[95% CI 5-15], respectively, after two to four weeks of treatment).
Three fixed-dose topical benzoyl peroxide and antibiotic combination products are available in the
United States:
●Benzoyl peroxide 5% and clindamycin 1% gel
●Benzoyl peroxide 5% and erythromycin 3% gel
●Benzoyl peroxide 2.5% and clindamycin 1.2% gel
●Benzoyl peroxide 3.75% and clindamycin 1.2% gel
When oral antibiotic therapy is indicated, concomitant use of topical benzoyl peroxide is also
advised to decrease antibiotic resistance. For patients who may not tolerate continuous use of
benzoyl peroxide, pulse therapy of benzoyl peroxide or use between antibiotic courses has been
suggested [122].
AZELAIC ACID Azelaic acid is a naturally occurring dicarboxylic acid with

antimicrobial, comedolytic, and mild anti-inflammatory properties. Azelaic acid also has an inhibitory
effect on tyrosinase and can improve acne-induced postinflammatory hyperpigmentation. The
product is available in a 15% gel and 20% cream.
Azelaic acid 20% cream is effective for the treatment of both inflammatory and noninflammatory
acne, and has comparable efficacy with tretinoin 0.05% cream, benzoyl peroxide 5% gel, or topical
2% erythromycin for mild to moderate acne [123].
The 15% gel is FDA approved only for the treatment of rosacea, although it is approved for the
treatment of acne in many European countries. Two randomized controlled trials revealed that
azelaic acid gel is well tolerated and as effective as 5% benzoyl peroxide gel or 1% clindamycin gel in
the treatment of mild to moderate acne vulgaris [124].
SALICYLIC ACID Topical salicylic acid is an alternative comedolytic

agent that is useful for patients who cannot tolerate or cannot obtain a topical retinoid. In the United
States, salicylic acid is available without a prescription. Salicylic acid is discussed in greater detail
separately. (See "Light-based, adjunctive, and other therapies for acne vulgaris", section on 'Salicylic
acid'.)
1034
ORAL ANTIBIOTICS Multiple studies, including randomized trials,
have shown oral antibiotics effective for the management of inflammatory acne [86,125-132].
Utilization of these drugs is primarily indicated for patients with moderate to severe inflammatory
acne and forms of inflammatory acne that are resistant to topical treatment [7]. Oral antibiotics may
also be used for patients who have milder truncal acne, for whom the application of topical
antibiotics is difficult.
Oral antibiotics improve inflammatory acne by inhibiting the growth of C. acnes within the
pilosebaceous unit. The tetracycline antibiotics also have direct anti-inflammatory properties [133].
Systemic antibiotics produce more rapid clinical improvement than topical preparations, but may
induce side effects such as vaginal candidiasis or gastrointestinal distress.
Oral antibiotics should be prescribed for the shortest possible period of time to limit the emergence
of antibiotic resistance. Ideally, treatment is limited to three to four months, with simultaneous use of
a topical retinoid to facilitate discontinuation of the antibiotic [7]. No consensus exists regarding
whether oral antibiotics should be tapered or abruptly stopped [134]. Select patients who require
longer courses should be followed closely to ensure that antibiotic therapy is given for the shortest
duration necessary [7]. Oral antibiotics used in the treatment of acne include tetracycline,
doxycycline, minocycline, sarecycline, erythromycin, trimethoprim-sulfamethoxazole, clindamycin,
and azithromycin (table 1).
Antibiotic resistance — Antibiotic resistance is increasing in patients with

acne [135]. One report suggests that the incidence of C. acnes antibiotic resistance increased from
20 percent in 1978 to 62 percent in 1996 [136]. Factors that contribute to this increasing incidence
include the widespread use of oral antibiotics and the practice of rotating antibiotics. Resistance is
most commonly reported with erythromycin; resistance to minocycline is rare, but may be emerging
in the United States [137].
The rise of C. acnes antibiotic resistance is a concern for acne management; there is some evidence
that the presence of resistant organisms can reduce treatment efficacy [138]. There is also concern
that long-term antibiotic therapy affects other host bacterial flora, although the clinical impact of this
is unclear. In one cross-sectional study (n = 107), patients taking oral tetracyclines or topical
antibiotics for at least three months had a threefold increase in the prevalence of Streptococcus
pyogenes in the oropharynx compared with those who were not on antibiotic therapy (33 versus 10
percent) [139]. However, the number of patients reporting upper respiratory tract illness or
symptoms was not different in the two groups.
Other studies have found an increased rate of upper respiratory infections in acne patients treated
with oral antibiotic therapy. A more than threefold increase in pharyngitis was reported in a
prospective cohort study and a cross-sectional study, and a large retrospective study (n = 118,496)
found a twofold greater risk for upper respiratory infection among acne patients treated with either
topical or oral antibiotics [140,141]. In the prospective study, which consisted of 36 university
1035
students with acne who received oral antibiotic therapy and 543 students with or without acne who
were not treated with oral antibiotics, more students in the antibiotic therapy group reported visits to
a healthcare provider for pharyngitis (11 versus 3 percent; adjusted odds ratio [OR] 4.34; 95% CI
1.51-12.47). In contrast to the cross-sectional study described above, an effect of antibiotic use on
group A streptococcus colonization was not detected. Further prospective studies are necessary to
evaluate the effect of antibiotic therapy on upper respiratory tract infections.
The following practices may reduce the incidence of resistance:
●Only prescribe antibiotics when necessary. The duration of treatment should be limited (ideally
three to four months); an oral antibiotic should be discontinued when there is no additional clinical
improvement or clinical improvement is absent [122].
●If oral antibiotics are stopped and need to be restarted, prescribe the same antibiotic the second
time as long as it remains effective [122,134].
●Avoid use of antibiotics (topical or oral) as monotherapy or as maintenance therapy [7].
●Prescribe benzoyl peroxide at the start of antibiotic therapy [134]. Concomitant use of benzoyl
peroxide can decrease the incidence of antibiotic resistance. It may also be helpful to use benzoyl
peroxide for a minimum of five to seven days between antibiotic courses [122]. (See 'Topical
antimicrobials' above.)
●Prescribe a topical retinoid. A topical retinoid should be used at the start of treatment with an oral
antibiotic [122,142]. Combination therapy with a retinoid and oral antibiotic improved treatment
efficacy in several studies, including two randomized trials [143-147].
Topical retinoids are effective as long-term maintenance therapy [43-46] and can decrease
dependence on the extended use of antibiotics [9]. (See 'Maintenance therapy' below.)
In select cases, antibiotics may be continued indefinitely at the lowest effective dose in patients with
persistent acne, although this practice can lead to antibiotic resistance. Oral isotretinoin can be
another option for patients who are unable to discontinue oral antibiotics despite adherence to a
regimen for maintenance therapy [9,148]. (See 'Maintenance therapy' below.)
Tetracyclines — In the past, tetracycline was the preferred oral antibiotic due to its
low cost and studies showing high efficacy. However, the tetracycline derivatives doxycycline and
minocycline are now used more commonly. Sarecycline is a new tetracycline with a narrower
spectrum of antibiotic activity [149,150].
Choice of agents — Doxycycline and minocycline have replaced erythromycin and

tetracycline as the most frequently used oral antibiotics for acne therapy by dermatologists in the
United States, both due to better tolerability and the presence of higher rates of C. acnes resistance
1036
to erythromycin and tetracycline [114,151]. A shortage of tetracycline in North America in 2011 and
2012 has also contributed to the increased use of these agents. Unlike tetracycline, doxycycline and
minocycline can be taken with meals since absorption is not inhibited by food.
In the past, minocycline was widely considered the most effective tetracycline derivative for the
treatment of acne [114,152,153]. However, the evidence that supports the greater efficacy of
minocycline in clinical response has methodologic flaws, including lack of blinding in clinical studies
[154]. A systematic review of minocycline for the treatment of acne did not find sufficient evidence to
support the conclusion that minocycline is superior to other tetracyclines [154].
Some studies have suggested that minocycline induces more rapid improvement in inflammatory
acne than tetracycline [155-157]. However, the magnitude of clinical improvement with tetracycline
or minocycline at the end of the treatment period was equivalent for all studies.
Minocycline is not used as first-line therapy due to a lack of clear additional benefit compared with
tetracycline and doxycycline, as well as concerns about more severe toxicities than other
tetracyclines [158,159]. Some patients who have failed therapy with doxycycline or tetracycline may
respond to minocycline.
Sarecycline offers the advantage of a narrower spectrum of antibacterial activity than other
tetracyclines, which in theory may help to reduce deleterious effects of antibiotic therapy on the
microbiome. The drug demonstrated efficacy for moderate to severe acne vulgaris in two placebo-
controlled, phase 3, randomized trials (n = 968 and n = 1034) [150]. Rates of treatment success
(investigator assessment of clear or almost clear and at least a two-point improvement on a five-
point grading scale) at week 12 were 22 and 23 percent in the sarecycline groups compared with 11
and 15 percent in the placebo groups, respectively. The efficacy of sarecycline has not been
compared with other tetracyclines.
Precautions — Tetracycline, doxycycline, minocycline, and sarecycline should not be

administered to children under the age of nine or to pregnant women due to the potential for
discoloration of developing permanent teeth and reduced bone growth. The safety and efficacy of an
extended-release formulation of minocycline has only been confirmed in acne patients ≥12 years
old. Antibiotics in the tetracycline class can cause gastrointestinal distress, and rarely esophagitis,
esophageal ulceration, or idiopathic intracranial hypertension (pseudotumor cerebri).
Photosensitivity may also occur, with doxycycline as the most photosensitizing drug. Patients taking
doxycycline, tetracycline, or sarecycline must be cautioned regarding this potential side effect and
should be encouraged to engage in sun-protective behavior.
Minocycline is the least photosensitizing of the three drugs, but can cause vertigo, skin discoloration
(picture 5A-B), serum sickness, and a lupus-like syndrome [160-163].
Dosing — Tetracycline is initiated at a dose of 500 mg twice daily, although 250 mg twice daily
may also be effective.
1037
Absorption is inhibited by food, dairy products, antacids, and iron; it must be taken on an empty
stomach. Patients should be instructed to take tetracycline at least one hour prior to a meal or two
hours after eating. Because of these requirements, compliance to therapy may be difficult for some
patients.
Unlike tetracycline, doxycycline and minocycline can be taken with food and drink; doing so may
reduce the risk for gastrointestinal side effects. Typical doses of doxycycline for teenagers and
adults are 50 to 100 mg twice daily or 100 mg once daily [9,164-166]. An extended release form is
given as a loading dose of 100 mg every 12 hours for one day, then as 100 mg once daily.
Minocycline is usually prescribed as 50 mg taken one to three times daily. However, newer research
has provided additional dosing options for these drugs.
●Extended-release minocycline– Newer research has provided an additional dosing option for
minocycline. A once-daily, extended-release formulation of minocycline is prescribed as a weight-
based dose. The lowest effective dose with the most favorable side effect profile was determined to
be 1 mg/kg/day; higher doses did not offer additional benefit [167-169]. Extended-release
minocycline is available as 45, 90, and 135 mg tablets as a generic and in additional tablet doses as
a brand.
●Subantimicrobial dose doxycycline– Concern over the induction of antibiotic resistance with long-
term antibiotic use for acne has led to the investigation of subantimicrobial doses of doxycycline for
the treatment of acne vulgaris. Subantimicrobial doses of antibiotics are doses for which the anti-
inflammatory properties are maintained, but antibacterial action is absent. In this manner, the
potential for inducing antibacterial resistance is diminished. The tetracyclines, particularly
doxycycline, are often administered at subantimicrobial doses for treating acne. This lower dosage
may block inflammation in acne through multiple mechanisms, including the inhibition of matrix
metalloproteinases, regulation of inflammatory cytokines, inhibition of leukocyte chemotaxis and
activation, and antioxidation [170].
A multicenter, randomized trial revealed that doxycycline 20 mg twice daily was more effective than
placebo for the treatment of moderate acne vulgaris [125]. However, there are minimal data
comparing subantimicrobial doxycycline to higher doses of the drug. In one randomized trial (n =
100), patients with moderate acne treated with either 20 mg or 100 mg doxycycline twice daily
exhibited numerically similar reductions in inflammatory lesions [171]. Additional studies are
necessary prior to a recommendation that subantimicrobial dosing can replace traditional doses for
the treatment of acne vulgaris.
Sarecycline is given once daily and dosing is weight based (60 mg for patients weighing 33 to 54 kg,
100 mg for patients weighing 55 to 84 kg, 150 mg for patients weighing 85 to 136 kg patients).
Macrolides — Erythromycin may be administered for acne in doses of 500 mg twice

daily. However, it has less anti-inflammatory activity than the tetracyclines. In addition, C. acnes often
develops resistance to this drug, resulting in treatment failure [172]. Many patients experience
1038
intolerable gastrointestinal side effects. The use of erythromycin is now recommended only for
patients in whom tetracycline derivatives are contraindicated [86,125]. (See 'Tetracyclines' above.)
Azithromycin, another oral macrolide antibiotic, has shown efficacy for the treatment of acne [173-
175]. The optimum dosing remains to be determined. Concern regarding the use of azithromycin for
the routine treatment of acne is related to the rising incidence of antibiotic resistance to this drug.
Azithromycin is often used as a first-line agent for the treatment of respiratory infections and is also
prescribed as an alternative drug for the treatment of other gram positive cocci infections in patients
allergic to beta-lactam antibiotics. The risk of increasing the prevalence of antibiotic resistance
makes azithromycin a less favorable choice for routine acne therapy. (See "Azithromycin and
clarithromycin", section on 'Resistance' and "Resistance of Streptococcus pneumoniae to the
macrolides, azalides, lincosamides, and ketolides".)
Other antibiotics — Routine use of antibiotics other than tetracyclines and

macrolides is discouraged [7].
●Trimethoprim-sulfamethoxazole– Trimethoprim-sulfamethoxazole is effective in the treatment of

severe acne. However, its use is limited by the potential for bone marrow suppression and for the
development of severe immune-mediated drug eruptions such as toxic epidermal necrolysis. Use of
trimethoprim-sulfamethoxazole should be restricted to patients who cannot tolerate tetracyclines or
who have treatment-resistant acne [7]. (See "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Clindamycin– The use of oral clindamycin is limited because of the potential to induce
pseudomembranous colitis. Other antibiotics are generally preferred. (See "Clostridioides (formerly
Clostridium) difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section
on 'Pathophysiology'.)
●Cephalexin– While some clinicians use cephalexin to treat acne, the data to support its use are
sparse. A retrospective study of 93 patients treated with cephalexin (primarily 500 mg twice daily)
for a mean duration of nine months found that acne clearing or much improvement in acne occurred
in 4 and 45 percent of patients, respectively [176]. Of note, most patients received concomitant
therapy with other anti-acne agents.
Potential disadvantages of cephalosporin antibiotics include their hydrophilic nature, which prevents
penetration into the pilosebaceous unit, the site of C. acnes colonization, and the potential for the
promotion of methicillin resistant Staphylococcus aureus. In general, we favor tetracyclines over
cephalexin for the treatment of acne. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in
adults: Epidemiology", section on 'Antibiotic use'.)
HORMONAL THERAPY Further evaluation and hormonal

therapies should be considered for patients with evidence for hyperandrogenism. Women without
hyperandrogenism can also benefit from therapies that reduce androgen production or block
1039
androgen receptors. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris",
section on 'Additional tests' and "Hormonal therapy for women with acne vulgaris".)
ORAL ISOTRETINOIN Oral isotretinoin, a retinoid, is effective for

the treatment of severe, recalcitrant nodular acne [177]. In clinical practice, it is also used for milder
acne that is resistant to other treatments or associated with significant scarring. Oral isotretinoin is
used as monotherapy; a typical treatment course is 120 to 150 mg/kg, which usually translates to a
20-week course for most patients. The risk for adverse effects, including teratogenicity, precludes
the use of this drug as routine acne therapy. (See "Oral isotretinoin therapy for acne vulgaris".)
NONPRESCRIPTION THERAPY In addition to

benzoyl peroxide, other nonprescription agents including salicylic acid, sulfur, alpha hydroxy acid,
and tea tree oil have been used in the treatment of acne. (See "Light-based, adjunctive, and other
therapies for acne vulgaris", section on 'Other topical medications'.)
In July 2016, the US Food and Drug Administration approved adapalene 0.1% gel for over-the-
counter use. (See 'Topical retinoids' above.)
PROCEDURAL THERAPY Treatment of acne vulgaris with

lasers, visible light, chemical peels, and other procedures is discussed separately. (See "Light-based,
adjunctive, and other therapies for acne vulgaris", section on 'Light/laser therapies' and "Light-based,
adjunctive, and other therapies for acne vulgaris", section on 'Adjunctive therapies'.)
MAINTENANCE THERAPY In many patients, acne is a

disorder in which symptoms typically recur over years. Consequently, identifying a sustainable
treatment regimen is an important component of acne management. Concern regarding antibiotic
resistance provides an incentive to limit the use of antibiotics, though effective, as long-term therapy.
Topical retinoids are a compelling option for maintenance therapy for patients with acne vulgaris. In
addition to their ability to combat active acne through comedolytic and anti-inflammatory properties,
these drugs play a critical preventive role through the inhibition of the formation of the
microcomedone, the precursor lesion in acne vulgaris.
Several randomized controlled trials support the use of retinoids as maintenance therapy following
the cessation of antimicrobial agents [43-46,178]. Representative trials include:
●A 12-week randomized controlled trial involving 241 patients with moderate to moderately severe
acne evaluated the effect of maintenance therapy for patients who had at least moderate
improvement after treatment with adapalene 0.1% gel and clindamycin 1% solution or clindamycin
1040
solution alone [43]. Patients who continued therapy with adapalene 0.1% gel had a 41.6 percent
reduction in total lesion counts. Patients who stopped treatment exhibited a 92 percent increase in
total lesion counts.
●A 16-week randomized controlled trial evaluated 253 subjects with severe acne who achieved at
least moderate improvement after treatment with adapalene 0.1% gel and doxycycline 100 mg or
doxycycline 100 mg and a vehicle gel [45]. The percentage of patients sustaining 50 percent
improvement in lesion counts was 75 percent in the adapalene group versus 54 percent in the
vehicle group.
For some patients, monotherapy with a topical retinoid may not be sufficient to sustain clinical
improvement. In these cases, an antimicrobial agent containing benzoyl peroxide can be added to
the treatment regimen [122,179].
Additional studies will be useful for determining the best maintenance regimens.
THERAPY FOR
POSTINFLAMMATORY
HYPERPIGMENTATION Postinflammatory
hyperpigmentation can be a significant problem for patients with darker skin complexions and acne.
In many cases, patients are more distressed by the "dark spots" that take several months or more to
resolve than by active acne lesions that resolve more quickly (picture 6) [180]. (See
"Postinflammatory hyperpigmentation".)
Both topical retinoids and azelaic acid accelerate the resolution of postinflammatory
hyperpigmentation [181,182]. In one randomized trial, black patients who applied tretinoin 0.1%
cream exhibited significantly greater lightening of facial postinflammatory hyperpigmentation than
those treated with vehicle [181]. A regimen containing either of these agents will treat active acne
and improve postinflammatory hyperpigmentation.
Topical hydroquinone is a depigmenting agent that inhibits melanin production, and is considered
the "gold standard" for treatment of hyperpigmentation [180,182,183]. Hydroquinone is available as
2% over-the-counter formulations and in prescription products in a 3 or 4% concentration.
Exogenous ochronosis, a condition in which grayish discoloration of the skin occurs in sites of
application, is an uncommon consequence of topical hydroquinone usage [184]. Additional safety
concerns were raised when oral hydroquinone was reported to be tumorigenic in rodents [185].
Carcinogenic effects have not been reported in humans [184].
We suggest the use of a topical retinoid as a component of acne treatment regimens for patients
with acne-induced postinflammatory hyperpigmentation [186]. Azelaic acid is an alternative to a
topical retinoid in patients who cannot tolerate the latter. Topical hydroquinone can be applied twice
1041
daily to individual hyperpigmented lesions for greater improvement.
Additionally, patients may benefit from superficial chemical peels with glycolic acid or salicylic acid,
although care must be taken to avoid chemical peel-induced postinflammatory hyperpigmentation.
An overview of the management of postinflammatory hyperpigmentation is provided separately.

(See "Postinflammatory hyperpigmentation", section on 'Treatment'.)
THERAPY FOR SCARRING Once active acne is well

controlled, scars secondary to acne can be treated. Options for patients who desire treatment of
scars include minor surgical procedures, laser therapy, chemical peels, injectable soft tissue fillers,
and other interventions. The treatment of acne scars is discussed in detail separately. (See
"Management of acne scars".)
HOME SKIN CARE

RECOMMENDATIONS Patients frequently ask questions about
general skin care. The following are some suggestions that patients will find useful, based upon
clinical experience and clinical trials:
●Patients should apply a gentle synthetic detergent cleanser (ie, syndet) with their fingers, and rinse
with warm (not hot) water twice daily [9]. Synthetic detergent cleansers possess a pH of 5.5 to 7,
which is close to normal skin pH, while soap has a pH of 9 to 10. The lower pH of synthetic
detergents, such as Cetaphil, minimizes skin irritation and dryness [187,188]. In a small randomized
trial, patients with moderate acne (treated with a benzoyl peroxide/erythromycin combination gel
alone or combined with adapalene) were instructed to wash their faces with either a synthetic
detergent bar (Dove Sensitive Skin Bar) or soap [189]. After four weeks, the patients washing with
the synthetic detergent bar exhibited less skin peeling, dryness, and irritation than those using soap.
●Patients should not aggressively scrub the skin; gentle massage with the fingertips is sufficient for
cleansing. Repetitive mechanical trauma can aggravate inflammatory acne and promote the
development of new acne lesions [9].
●Several reports have suggested that antibacterial soaps such as triclosan, povidone-iodine, and
chlorhexidine can improve acne vulgaris [190-192]. However, data supporting their use are limited,
and these agents have not been proven superior to conventional therapy. We do not recommend
these soaps for the management of acne vulgaris.
●Water-based lotions, cosmetics, and hair products are less comedogenic than oil-based products.
Patients should be encouraged to seek out noncomedogenic skin care and cosmetic products.
●Patients should be advised not to pick their acne lesions, as this may exacerbate scarring.
1042
PREGNANCY AND ACNE THERAPY A
number of treatments for acne are contraindicated in pregnancy. In particular, oral isotretinoin and
topical tazarotene are classified as pregnancy category X drugs, and must never be given to
pregnant women or women who are attempting pregnancy.
In deciding whether to treat acne during pregnancy, as well as choosing a specific therapy, careful
consideration should be given to the grade of acne, the patient's risk tolerance, and the preferences
of the patient's obstetrical provider. If acne therapy is desired, reasonable options include oral or
topical erythromycin, topical clindamycin, and topical azelaic acid, which are pregnancy class B
drugs [193,194]. Benzoyl peroxide is categorized as pregnancy class C.
A description of the pregnancy category labels (table 5) and a list of pregnancy categories of acne
medications are provided (table 6).
EMERGING THERAPY Data from two phase 3 randomized

trials (n = 708 and n = 732) support efficacy of clascoterone 1% cream, an investigational topical
androgen receptor inhibitor, for acne vulgaris [195]. In the trials, female and male patients (ages nine
years and older) with acne vulgaris were randomly assigned to twice-daily application of either
clascoterone 1% cream or vehicle cream to the entire face for 12 weeks. At week 12, 18 percent
(point estimate 2.3, 95% CI 1.4-3.8) and 20 percent (point estimate 3.7, 95% CI 2.2-6.3) of patients in
the clascoterone groups achieved treatment success compared with only 9 and 7 percent of patients
in the vehicle groups. Treatment success was defined as at least a two-point reduction in the five-
point Investigator's Global Assessment score and a score of 0 (clear) or 1 (almost clear).
Efficacy of clascoterone may involve competitive inhibition of binding of dihydrotestosterone to the

androgen receptor. This may contribute to inhibition of transcription of androgen-responsive genes
that promote sebum production and activation of inflammatory pathways.


1043
SUMMARY AND
RECOMMENDATIONS
●Determining the most effective course of treatment for acne involves a comprehensive assessment
of the patient. Treatment of acne is aimed at counteracting follicular hyperproliferation, increased
sebum production, Cutibacterium (formerly Propionibacterium) acnes proliferation, and inflammation.
(See 'Pretreatment assessment' above and 'Treatment principles' above.)
●The choice of acne therapy should be individualized, depending on acne severity and type of
lesions, as well as tolerance and other factors (table 2). (See 'Pretreatment assessment' above and
'Treatment principles' above and 'Approach to treatment' above.)
●Medications that are effective for comedonal acne include topical retinoids, benzoyl peroxide,
azelaic acid, and salicylic acid. For patients with comedonal acne who desire treatment, we suggest
topical retinoids as first-line therapy (Grade 2A). (See 'Topical retinoids' above.)
●For patients with mild to moderate inflammatory acne with or without prominent comedonal
lesions, we suggest the use of a topical retinoid, topical antibiotic, and benzoyl peroxide (Grade 2A).
When benzoyl peroxide is used with a topical antibiotic, treatment is more effective than either agent
alone. To reduce the development of antibiotic resistance, we prescribe topical antibiotics with
benzoyl peroxide. (See 'Topical antimicrobials' above and 'Combination therapy' above.)
●For patients with moderate to severe inflammatory acne with or without prominent comedonal
lesions, we suggest the use of a topical retinoid, topical benzoyl peroxide, and an oral antibiotic,
rather than topical agents alone (Grade 2A). Oral antibiotics should be used for a limited course,
ideally up to three to four months. Concomitant topical benzoyl peroxide should be prescribed to
decrease the risk of antibiotic resistance. (See 'Oral antibiotics' above.)
●Patients with severe, recalcitrant, nodular acne are generally treated with oral isotretinoin. Oral
isotretinoin therapy is discussed separately. (See "Oral isotretinoin therapy for acne vulgaris".)
●Women with signs of hyperandrogenism should be evaluated for underlying endocrine disorders.
Hormonal therapy can be a useful addition to a therapeutic regimen for moderate to severe acne
vulgaris in women with or without hyperandrogenism. (See 'Hormonal therapy' above and "Hormonal
therapy for women with acne vulgaris".)
1044
●Acne may persist for years. In addition to their use in treatment, topical retinoids are also effective
for the prevention of acne lesions, and can reduce the use of long-term antibiotic therapy. In patients
with acne that has improved with therapy, we suggest long-term treatment with a topical retinoid for
maintenance, rather than discontinuing treatment (Grade 2A). For patients in whom improvement
cannot be sustained with topical retinoids alone, an antimicrobial agent with benzoyl peroxide can
be added. (See 'Maintenance therapy' above.)
●Acne-induced postinflammatory hyperpigmentation is a particular concern for patients with dark

skin pigmentation. For patients with acne-induced postinflammatory hyperpigmentation, we suggest
the use of a topical retinoid as a component of acne therapy (Grade 2B). The use of hydroquinone,
azelaic acid, or chemical peels can also be beneficial. (See 'Therapy for postinflammatory
hyperpigmentation' above.)
●Patients with acne should use gentle cleansers and should avoid irritating skin care products.
Patients should select "noncomedogenic" skin care products and cosmetics. (See 'Home skin care
recommendations' above.)
●Pregnant women should not be treated with topical retinoids. If treatment during pregnancy is
necessary, oral or topical erythromycin, topical clindamycin, or topical azelaic acid may be
considered after a review of the risks and benefits of therapy. (See 'Pregnancy and acne therapy'
above.)
1045
Oral isotretinoin therapy for acne vulgaris
uptodate.com/contents/oral-isotretinoin-therapy-for-acne-vulgaris/print
INTRODUCTION Oral isotretinoin (13-cis retinoic acid) is a retinoid most

often used for the treatment of acne vulgaris, particularly severe or recalcitrant disease. Isotretinoin
is teratogenic and associated with a number of other adverse effects that can limit its use. Thus, it
must be used with caution and should only be prescribed by clinicians who are completely familiar
with the medication.
The clinical use of oral isotretinoin for acne vulgaris will be reviewed here. Discussions of the clinical
manifestations, diagnosis, and approach to treatment for acne vulgaris as well as detailed drug
information on isotretinoin are provided separately.
●(See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)
●(See "Treatment of acne vulgaris".)
●(See "Hormonal therapy for women with acne vulgaris".)
●(See "Isotretinoin: Drug information".)
●(See "Isotretinoin: Pediatric drug information".)
1046
MECHANISM OF ACTION Oral isotretinoin counteracts
the pathogenic factors that contribute to the development of acne vulgaris [1,2]. Therapy leads to
shrinkage of sebaceous glands and a marked attenuation of sebum secretion. The decrease in
sebum results in the inhibition of the sebum-dependent bacterium Cutibacterium (formerly
Propionibacterium) acnes, which is a key promoter of inflammation in acne vulgaris. Oral isotretinoin
also inhibits comedogenesis by fostering keratinocyte differentiation and by normalizing
desquamation. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section
on 'Pathogenesis'.)
ADVERSE EFFECTS Isotretinoin is associated with a broad range

of mucocutaneous and extracutaneous adverse effects. Mucocutaneous side effects are most
common. Isotretinoin is also teratogenic.
Side effects of isotretinoin are usually manageable, permitting continuation of therapy. In a 2018
systematic review of 11 randomized trials, severe adverse effects requiring withdrawal from trials
occurred in only 12 of 372 patients taking isotretinoin (3 percent). The severe adverse effects
included elevated liver enzymes, cheilitis, xerosis, acne flare, photophobia, and Stevens-Johnson
syndrome [3].
The management of common side effects is reviewed below. (See 'Management of complications'
below.)
Mucocutaneous — The common mucocutaneous side effects of isotretinoin,

including cheilitis, dry skin and mucous membranes, epistaxis, desquamation, photosensitivity, and
pruritus, are predictable and dose dependent. In the systematic review, dermatologic side effects
represented nearly 65 percent of all reported side effects, with cheilitis and xerosis as the most
frequent [3].
Isotretinoin is also associated with risk for ocular abnormalities (eg, dryness, irritation,
conjunctivitis) related to dysfunction of meibomian glands within the conjunctiva and cutaneous
staphylococcal infections [3-6]. Paronychia, pyogenic granulomas, temporary diffuse alopecia, and
nail brittleness occasionally appear [7].
Transient worsening of acne may occur in the beginning of isotretinoin therapy. Rarely, isotretinoin
induces acne fulminans, a severe manifestation [8,9]. (See 'Severe acne' below and "Pathogenesis,
clinical manifestations, and diagnosis of acne vulgaris", section on 'Acne fulminans' and "Treatment
of acne vulgaris", section on 'Acne fulminans'.)
Teratogenicity — Isotretinoin causes both spontaneous abortions and severe life-

threatening congenital malformations [10]. Embryopathy associated with exposure in the first
trimester of pregnancy includes craniofacial, cardiac, thymic, and central nervous system
1047
malformations [11]. Fetal abnormalities have not been attributed to the use of isotretinoin in men [2].
(See "Birth defects: Causes", section on 'Drug exposure'.)
Among pregnant women exposed to isotretinoin, the risk of spontaneous abortion is approximately
20 percent; among pregnancies that progress, approximately 20 to 30 percent of neonates have
evidence of embryopathy [12]. Although data are limited, children who appear physically normal may
still have a higher rate of intellectual disability and impaired neuropsychologic function [12].
Psychiatric effects — Concerns have been raised about a possible association

of isotretinoin with depression and suicide. However, reviews, including a systematic review and
meta-analysis, have concluded that data on suicidal behavior and depression during treatment with
isotretinoin are inadequate to establish a causal relationship [13-17].
Some authors have proposed that psychologic distress over severe acne, rather than isotretinoin,
could be a contributing factor to suicide or depression in patients treated with the drug [18-20]. In a
population-based cohort study, risk for major depressive disorder was higher among patients with
acne than in the general population without acne [19]. The risk was unchanged after excluding
patients who received isotretinoin.
In sum, the relationship between isotretinoin and depression and suicide is uncertain. Patients
should be advised of a possible link and should be followed closely for the development of
depression or suicidal ideation [21]. (See "Suicidal ideation and behavior in adults" and "Suicidal
ideation and behavior in children and adolescents: Evaluation and management".)
Inflammatory bowel disease — Observational studies have found

conflicting results on the relationship between isotretinoin therapy and inflammatory bowel disease
(IBD). A 2012 meta-analysis of three case-control studies and two additional unpublished studies did
not find a statistically significant relationship between isotretinoin therapy and IBD (relative risk for
IBD 0.94, 95% CI 0.65-1.36) [22].
In addition, a subsequent 12-year cohort study of 46,922 patients treated with isotretinoin, 184,824
patients treated with topical acne medication, and 1,526,946 untreated controls (all between the
ages of 12 and 29) did not find a significant association between isotretinoin use and IBD on primary
analysis (rate ratio 1.14, 95% CI 0.92-1.41) [23]. Although an association between isotretinoin and
IBD was detected in a subgroup of patients aged 12 to 19 years (rate ratio 1.39, 95% CI 1.03-1.87), a
similar association was detected between the use of topical acne medications and ulcerative colitis
(rate ratio 1.19, 95% CI 1.00-1.42), suggesting that acne may contribute to risk for IBD.
More studies are necessary to determine whether isotretinoin therapy is a risk factor for IBD. Until
additional information is available, during discussions of the potential adverse effects of isotretinoin
with patients, it is reasonable to mention that although an increased risk for IBD has been reported, a
relationship between these disorders remains to be proven.
1048
Other side effects — Isotretinoin has been associated with a number of other
side effects [3]. Hypertriglyceridemia is common, occurring in up to 45 percent of patients taking
isotretinoin, and total cholesterol and low-density lipoprotein elevations occur in approximately 30
percent [24].
Other less common side effects include myalgias (particularly in patients who engage in vigorous
physical activity), visual changes (decreased night vision, corneal opacities), hepatotoxicity, bone
marrow suppression, idiopathic intracranial hypertension (pseudotumor cerebri), and bone changes
(hyperostosis and, rarely, premature epiphyseal closure) [25-29]. (See "Idiopathic intracranial
hypertension (pseudotumor cerebri): Epidemiology and pathogenesis", section on 'Medications'.)
For additional information on isotretinoin side effects, refer to the Lexicomp drug information
monograph included within UpToDate. (See "Isotretinoin: Drug information".)
CONTRAINDICATIONS AND
PRECAUTIONS
Contraindications — Isotretinoin should not be given to pregnant individuals or
individuals who may become pregnant during or within one month after therapy. Effective measures
to prevent pregnancy are indicated for females who are fertile. Also, individuals with a history of
hypersensitivity to isotretinoin or any of its components should not receive isotretinoin.
Drug interactions — Simultaneous treatment with medications that share the

side effect of idiopathic intracranial hypertension with isotretinoin, such as tetracyclines, should be
avoided. In addition, vitamin A supplementation may increase risk for adverse effects of isotretinoin
and should be avoided. A list of additional drug interactions is provided separately. (See
"Isotretinoin: Drug information".)
Specific interactions of isotretinoin with other medications may be determined using the Lexicomp
drug interactions tool (Lexi-Interact) included in UpToDate. This tool can also be accessed from the
UpToDate online search page or through the individual drug information topics (also referred to as
monographs) in the section on Drug interactions.
Children — The effectiveness and safety of isotretinoin has not been established in
children under 12 years of age.
Cutaneous procedures — Delaying cutaneous procedures until at least 6

to 12 months after the completion of oral isotretinoin therapy is commonly practiced due to concern
for increased risk for abnormal scarring and delayed wound healing; however, data to support this
1049
action are limited.
Based upon a systematic review of the literature, a multispecialty panel of experts found insufficient
evidence to recommend delaying manual dermabrasion, superficial chemical peels, cutaneous
surgery, laser hair removal, and fractional ablative and nonablative laser procedures for patients with
current or recent isotretinoin use [30]. The panel recommended avoidance of mechanical
dermabrasion and fully ablative laser procedures in patients with recent isotretinoin use based upon
limited evidence suggesting increased risk for scarring. Although prospective controlled trials are
necessary to confirm the level of risk associated with cutaneous procedures in this population, the
findings of the systematic review aid in counseling patients who may benefit from earlier
performance of procedures.
Alcohol use — Although alcohol consumption is not contraindicated during isotretinoin

therapy, we generally counsel patients to avoid excessive alcohol consumption. Similar to
isotretinoin, alcohol consumption may contribute to hypertriglyceridemia and hepatic transaminase
elevations. Moreover, excessive alcohol consumption may contribute to impaired judgment and
substandard use of pregnancy prevention methods and has negative effects on overall health. (See
"Overview of the risks and benefits of alcohol consumption".)
INITIATION OF THERAPY The initiation of isotretinoin

therapy involves careful patient counseling and a pretreatment clinical and laboratory assessment.
The goal is to support successful treatment and minimize risk for serious adverse effects. (See
'Patient counseling' below and 'Baseline clinical and laboratory evaluation' below and 'Dosing and
administration' below and 'Use of other acne medications' below.)
Patient counseling — In addition to a discussion of the risks and benefits of

treatment, patients who will begin isotretinoin therapy should be thoroughly informed of the
monitoring and pregnancy prevention measures that are required for isotretinoin therapy. Some
countries have implemented mandatory risk management programs designed to prevent fetal
exposure to isotretinoin, though positive effects of such programs on reducing fetal exposure are
unproven [31].
In the United States, prescribing and receipt of isotretinoin requires participation in the iPLEDGE
program. The iPLEDGE program provides detailed guidelines for pregnancy prevention counseling,
pregnancy screening, and contraceptive use during treatment. (See 'iPLEDGE program' below.)
In general, prescribing clinicians should be able to discuss contraceptive options and appropriate
use with patients of childbearing potential. Alternatively, these patients should be referred to a
provider who can provide this service. All patients who are at risk for pregnancy during treatment
should begin highly effective contraceptive measures one month prior to, during, and for one month
1050
after completion of isotretinoin therapy. In addition, to avoid isotretinoin exposure to other
individuals, all patients should agree to avoid sharing isotretinoin pills with others and should agree
to avoid blood donation during therapy.
A discussion of the ocular side effects of isotretinoin may be particularly important for patients in or
entering occupations with strict guidelines for vision, such as airline pilots. In the United States, the
Federal Aviation Administration has policies regarding isotretinoin therapy.
iPLEDGE program — In 2006, the US Food and Drug Administration (FDA)

established a computer-based Risk Evaluation and Mitigation Strategy (REMS) risk management
program with the goal of eliminating fetal exposure to isotretinoin (iPLEDGE). Prescribers,
pharmacies dispensing isotretinoin, wholesalers distributing isotretinoin, and all patients receiving
isotretinoin are required to comply with the registry requirements.
Access to the iPLEDGE program is available online. The iPLEDGE program requires the following
[32]:
●All patients of childbearing potential must select and commit to the use of two forms of birth
control for at least one month prior to starting isotretinoin therapy, during therapy, and for one month
after therapy. The forms of contraception that meet these requirements are specified by the iPLEDGE
program.
●All female patients who can become pregnant must have two negative urine or blood pregnancy
tests (with a sensitivity of at least 25 milli-international units/mL) before receiving the initial
prescription. The second pregnancy test must be conducted in a Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratory. For each month of therapy and one month after completing
therapy, female patients must return to their clinicians for evaluation, counseling, education, and a
pregnancy test conducted by a CLIA-certified laboratory.
●For female patients who can become pregnant, prescribing clinicians must, on a monthly basis,
document in the iPLEDGE system the results of the pregnancy test as well as report the two forms of
birth control being used by the patient. The clinician must also confirm that the patient has received
counseling and education. For all other patients, prescribers must document that the patient was
counseled on the iPLEDGE program requirements, which include knowledge of the birth defects that
may result from the use of isotretinoin by females of childbearing potential.
●As part of this system, clinicians must certify expertise in the diagnosis and treatment of acne, and
knowledge of the risk and severity of birth defects with isotretinoin.
Baseline clinical and laboratory evaluation — The

pretreatment clinical and laboratory evaluation serves to identify patients who are not candidates for
isotretinoin therapy (eg, pregnant individuals) and patients who may require closer monitoring during
therapy. Examples of patients for whom additional counseling or monitoring may be helpful include
1051
patients with prior contraceptive failure; a personal or family history of psychiatric disease,
hyperlipidemia, or inflammatory bowel disease; eye or vision problems (particularly dry eyes and
contact lens use); heavy alcohol use; or extreme physical activity [2].
Current medications should be reviewed to identify potential drug interactions. In particular,

treatment with other drugs that may cause pseudotumor cerebri, such as tetracyclines, should be
avoided. (See 'Drug interactions' above.)
Baseline laboratory testing is indicated to identify pregnant patients and patients at increased risk
for isotretinoin adverse effects. Standard pretreatment tests include [2,29,33]:
●Liver function tests
●Lipid panel (fasting serum triglyceride and cholesterol levels)
●Urine or serum pregnancy test in females of childbearing potential (note two tests are required
prior to the start of therapy for the iPLEDGE program)
Dosing and administration — Absorption of isotretinoin is improved

when taken with food (especially high-fat meals); thus, administration during meals is
recommended. A formulation of isotretinoin that uses lipid encapsulation technology to enclose
isotretinoin demonstrates increased bioavailability in the fasting state [34]. This formulation is dosed
twice daily and can be given without regard to meals.
Severe acne — Severe acne is considered acne with many inflammatory nodules that is
unresponsive to other therapies, including oral antibiotics (picture 1A-F). The treatment goal for
these patients is a cumulative dose of 120 to 150 mg/kg of isotretinoin [29]. Most patients achieve
this goal within 20 to 24 weeks.
Treatment is usually initiated at a dose of 0.5 mg/kg per day for the first month of therapy to
minimize risk for isotretinoin-induced acne flares and is subsequently increased to 1 mg/kg per day.
Dosing can be once daily or divided into two daily doses.
However, severe flares may occur at the start of isotretinoin therapy in patients with severe
inflammatory acne (eg, acne conglobata, acne fulminans). Starting doses lower than 0.5 mg/kg per
day are suggested for this population. In addition, systemic glucocorticoids may be given prior to the
start of isotretinoin or concurrently for the first two to four weeks. (See "Treatment of acne vulgaris",
section on 'Acne fulminans' and "Treatment of acne vulgaris", section on 'Acne conglobata'.)
There is some evidence that high cumulative doses (eg, ≥220 mg/kg) of isotretinoin may reduce the
risk of relapse in patients with severe acne vulgaris [35,36]. Additional studies are needed to confirm
this finding as well as the safety of high-dose isotretinoin therapy.
1052
Moderate acne — Moderate acne appropriate for isotretinoin therapy may be
considered acne without nodules that is treatment resistant, relapses rapidly after cessation of oral
antibiotic therapy, scars, or induces significant psychosocial distress (picture 2) [29]. Although
patients with moderate acne may be treated with a regimen identical to that used for severe acne, a
lower dose regimen (0.3 to 0.5 mg/kg per day for the duration of therapy) is an accepted alternative
[29]. The advantage of this lower dose is reduced risk for drug side effects [29]. Treatment is
continued until acne is resolved or for up to 24 weeks.
Benefit of this dose range for moderate acne is supported in the literature [37-39]. In a 24-week,
single-blind, randomized trial, 60 patients with moderate acne were treated with one of three
regimens of isotretinoin: 0.5 to 0.7 mg/kg per day (higher dose regimen), 0.25 to 0.4 mg/kg per day
(lower dose regimen), or 0.5 to 0.7 mg/kg daily for one week every four weeks (intermittent regimen)
[38]. All three treatment courses resulted in clinically significant improvement. The lower dose and
higher dose regimens were similarly effective and had equivalent rates of relapse after one year;
however, more adverse effects were reported in the higher dose group during treatment. A lesser
degree of improvement and a lower duration of effect were detected in the patients who received
intermittent therapy.
Use of other acne medications — Other acne medications are

typically discontinued at the start of isotretinoin therapy. Isotretinoin causes temporary xerosis,
cutaneous atrophy, and skin fragility, and topical acne medications may be poorly tolerated [2].
Isotretinoin should not be given with tetracyclines due to the risk of idiopathic intracranial
hypertension (pseudotumor cerebri) associated with both of these drugs.
DURING THERAPY Follow-up visits are typically held on a monthly

basis to assess response and side effects, address patient questions, and fulfill the counseling and
monitoring requirements of the iPLEDGE program.
Clinical assessment — Patient assessment should include a patient history

and skin examination to assess for response and adverse effects. We typically ask the patient about
the following:
●Perceived worsening/improvement of acne
●Dryness of skin or mucous membranes
●Nosebleeds
●Vision changes
●Headaches
1053
●Abdominal pain
●Muscle or bone pain
●Bowel symptoms
●Mood changes, symptoms of depression, or suicidality
We examine involved skin as well as any other areas of concern for the patient. In our experience,
signs of improvement in acne often become evident after the first one to two months of therapy, with
progressive improvement over subsequent months.
Laboratory monitoring — Monthly pregnancy tests are warranted in

individuals of childbearing potential.
Product information for isotretinoin also recommends checking fasting lipids weekly or biweekly
until the lipid response has been established; however, in otherwise healthy, asymptomatic, young
individuals without a personal or family history of diabetes or dyslipidemia, many practitioners,
including ourselves, perform these tests on a less frequent basis.
The findings of a systematic review and meta-analysis of studies reporting laboratory values during
isotretinoin therapy for acne support less frequent testing; although isotretinoin was associated with
statistically significant changes in the mean values of some laboratory tests (white blood cell count,
hepatic panel, lipid panel), the changes did not meet criteria for high risk, and the proportion of
patients with laboratory abnormalities was low [40].
The suggested approach to monitoring liver function tests and lipid panels after baseline testing is
as follows [41] (see 'Baseline clinical and laboratory evaluation' above):
●If baseline liver function and lipid panels are normal, liver function tests and a lipid panel should be
obtained after two months of therapy (after peak dose has been initiated).
●If the results of testing after two months of treatment are normal and the dose of isotretinoin is not
increased, then further monitoring is not required.
●If the results of testing after two months of treatment are abnormal, or if the patient has a known
lipid abnormality, then periodic monitoring should be continued.
●Development of new symptoms (eg, abdominal pain) or the initiation of new medications or
supplements may warrant retesting.
Monitoring of complete blood counts is not necessary in the absence of a known abnormality or risk
factor for leukopenia. Obtaining a creatine kinase level is not indicated in the absence of severe
muscular pain [2].
1054
Management of complications — Most of the adverse effects
associated with isotretinoin can be managed without discontinuing the drug.
Exacerbation of acne — Transient worsening of acne may occur during the first
month of treatment, particularly in patients with severe disease (see 'Severe acne' above). Significant
flares may require adjustments to therapeutic approach. For mild flares, no adjustment in treatment
is needed.
The approach to isotretinoin-induced acne fulminans is reviewed separately (picture 3 and algorithm
1). (See "Treatment of acne vulgaris", section on 'Acne fulminans'.)
Mucocutaneous — Dry skin and mucous membranes are common during treatment.
In particular, cheilitis can be significant and often requires the liberal use of topical emollients, such
as petroleum jelly or other lip moisturizers.
To minimize dry skin, patients are advised to wash with a gentle, nondetergent cleanser followed by
the application of emollients. A noncomedogenic emollient is recommended for acne-prone skin
areas. (See "Treatment of atopic dermatitis (eczema)", section on 'Emollients and moisturizers'.)
For patients with nasal crusting or dryness or with epistaxis, saline nasal spray and application of
petroleum jelly to the nostrils can be helpful. Artificial tears may help to reduce symptoms of eye
dryness. Patients who wear contact lenses may not be able to tolerate them during treatment and
may need to discontinue their use.
Sun-protective measures are indicated to minimize the effects of isotretinoin-induced

photosensitivity. Patients should use a facial moisturizer with a sun protection factor (SPF) of at
least 30 daily, and sun-protective clothing should be worn during sun exposure. Sunscreen should be
applied to exposed skin areas prior to sun exposure and reapplied every two to three hours. (See
"Selection of sunscreen and sun-protective measures".)
Myalgias — Although checking of creatine kinase (CK) levels is not indicated in the absence
of severe muscle pain, CK levels are elevated in approximately 15 to 50 percent of patients with
isotretinoin-induced myalgias [2]. Mild to moderate pain usually can be managed with anti-
inflammatory drugs. Isotretinoin should be discontinued if pain becomes severe or cannot be
improved with anti-inflammatory drugs [2].
Laboratory abnormalities — Hypertriglyceridemia, hepatic transaminase

elevations, and CK elevations are common laboratory abnormalities during isotretinoin treatment:
●Hypertriglyceridemia – Minor or moderate elevations in triglyceride levels (300 to 500 mg/dL) do

not necessitate alteration of the isotretinoin dose and can be managed with lifestyle modification
[42]. (See "Hypertriglyceridemia", section on 'Lifestyle modifications'.)
1055
Triglyceride levels between 500 and 800 mg/dL require additional intervention, such as reduction of
the dose of isotretinoin and/or the addition of a lipid-lowering agent [42]. (See "Hypertriglyceridemia",
section on 'Management'.)
Severe hypertriglyceridemia (eg, above 800 mg/dL) may warrant cessation of isotretinoin therapy
because of the risk of acute pancreatitis [42,43]. However, pancreatitis secondary to isotretinoin is
rare [44].
Although hypertriglyceridemia usually resolves with cessation of isotretinoin, patients may need
ongoing monitoring since one report suggests that they may be at increased risk for future
hyperlipidemia and metabolic syndrome [45]. In a cross-sectional study, 102 patients in whom the
serum triglyceride concentration increased at least 89 mg/dL (1 mmol/L) during isotretinoin therapy
(hyper-responders) were compared with 100 patients in whom the serum triglyceride concentration
changed ≤9 mg/dL (0.1 mmol/L, nonresponders). Four years after completion of isotretinoin therapy,
hyper-responders were significantly more likely to have hypertriglyceridemia (odds ratio [OR] 4.8,
95% CI 1.6-13.8), hypercholesterolemia (OR 9.1, 95% CI 1.9-43), truncal obesity (OR 11.0, 95% CI 2.0-
59), and hyperinsulinemia (OR 3.0, 95% CI 1.6-5.7).
●Hepatic transaminase elevations – Mild, transient elevations in hepatic transaminases occur early
in the course of therapy in approximately 15 to 20 percent of patients; levels typically normalize
within a few weeks [2]. Discontinuation of isotretinoin is recommended if hepatic transaminase
levels reach more than three times greater than normal values [2,33].
Pregnancy — If pregnancy occurs during treatment, isotretinoin should be stopped

immediately. The pregnant patient should be referred to an obstetrician-gynecologist with
experience in reproductive toxicity for management and counseling [46]. In the United States, the
iPLEDGE program requires reporting of pregnancies that occur during therapy.
Other — The management of other extracutaneous adverse effects of isotretinoin (eg,

psychiatric effects, severe eye symptoms), may warrant consultation with appropriate specialists to
determine the best course of action for individual patients. Patients with signs and symptoms
suggestive of pseudotumor cerebri (eg, headache with new-onset vision changes) require specialist
evaluation and should discontinue use of isotretinoin. (See "Idiopathic intracranial hypertension
(pseudotumor cerebri): Clinical features and diagnosis" and "Idiopathic intracranial hypertension
(pseudotumor cerebri): Prognosis and treatment".)
STOPPING THERAPY In patients treated for severe acne,

isotretinoin is usually discontinued after achievement of a total dose of 120 to 150 mg/kg. The drug
can be stopped abruptly; tapering is not necessary.
AFTER THERAPY
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Outcomes — Oral isotretinoin is the only acne medication that can permanently alter the
natural course of the disorder. The majority of patients experience long-term improvement in acne
severity after one course of treatment [47]. In addition, continued improvement may occur for
several months after cessation of therapy; thus, at least five months should elapse before
considering retreatment with isotretinoin.
Despite the high response rate after a single course of isotretinoin, only a minority of patients are
truly cured. In one series of 179 patients treated with isotretinoin, 39 percent were cured but 61
percent still required the use of topical therapy (16.9 percent), topical therapy plus an oral antibiotic
(25.3 percent), or another course of isotretinoin (18.8 percent) [48]. Following isotretinoin treatment,
acne is more likely to be responsive to conventional therapies [33]. Response rates after a second
course of isotretinoin are similar to those following the initial course of treatment [33].
The vast majority of relapses (96 percent) occur within the first three years of stopping therapy;
among patients treated for severe or refractory acne, the highest relapse rates occur in patients with
predominantly truncal acne or in those receiving a total cumulative dose of less than 120 mg/kg
[47]. Reported relapse rates for patients treated with 120 to 150 mg/kg of isotretinoin range between
20 and 60 percent [35]. In one study of 88 patients treated with isotretinoin for severe or refractory
acne and followed for up to 10 years, 82 percent of patients who received cumulative doses <120
mg/kg relapsed (defined as deterioration in acne sufficient to merit systemic antibiotic or
isotretinoin therapy), compared with only 20 percent of patients given >120 mg/kg [47]. Most
relapses (78 percent) occurred within the first 18 months after treatment.
For moderate acne, a 24-week, randomized trial (n = 60) suggests relatively low relapse rates in the
first year after treatment, even for patients receiving a cumulative dose less than 120 mg/kg [38].
Relapse rates after one year (defined as deterioration to moderate or more severe acne) were similar
for patients treated with 0.25 to 0.4 mg/kg per day and patients treated with 0.5 to 0.7 mg/kg per day
(18 versus 13 percent). The mean cumulative doses for these groups were 61 mg/kg and 90 mg/kg,
respectively.
Patients who receive isotretinoin as young teenagers (under age 16) may also have an increased risk
for relapse [49].
Follow-up — Females of childbearing potential require a final pregnancy test one month
after completion of isotretinoin. Additional routine follow-up is not necessary after isotretinoin
therapy. We counsel patients to return for reevaluation if acne recurs.

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SUMMARY AND
RECOMMENDATIONS
●Isotretinoin is a treatment for acne vulgaris that is thought to improve acne through reducing
sebum production, inhibiting the growth of Cutibacterium (formerly Propionibacterium) acnes, and
inhibiting comedogenesis. (See 'Mechanism of action' above.)
●Isotretinoin has multiple side effects, including teratogenicity, mucocutaneous disorders, myalgias,
visual changes, idiopathic intracranial hypertension, hepatotoxicity, and hyperlipidemia. (See
'Adverse effects' above.)
●Isotretinoin is teratogenic and should not be administered in pregnancy. In the United States, all
prescribing clinicians and patients are required to participate in the iPLEDGE program, an online
registry initiated by the US Food and Drug Administration (FDA) in an attempt to minimize the risk of
fetal exposure to isotretinoin. (See 'Teratogenicity' above and 'Patient counseling' above and
'iPLEDGE program' above.)
●For the treatment of severe acne, isotretinoin is typically started at a low dose (0.5 mg/kg per day)
during the first month of therapy and then increased to 1 mg/kg per day. A total dose of 120 to 150
mg/kg of isotretinoin is given over the course of treatment. The duration of treatment is often
between 20 and 24 weeks. (See 'Dosing and administration' above.)
●Patients with severe inflammatory acne (eg, acne conglobata, acne fulminans) may require a lower
initial dose and/or concomitant treatment with systemic glucocorticoids starting before or at the
initiation of oral isotretinoin therapy. (See 'Severe acne' above and "Treatment of acne vulgaris",
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section on 'Acne fulminans' and "Treatment of acne vulgaris", section on 'Acne conglobata'.)
●Other acne medications are typically discontinued during isotretinoin therapy. In particular, the use
of isotretinoin with tetracyclines should be avoided due to the risk of idiopathic intracranial
hypertension (pseudotumor cerebri). (See 'Drug interactions' above and 'Use of other acne
medications' above.)
●Most patients improve after isotretinoin therapy, although the majority of patients will continue to
require the use of other acne therapies. Continued improvement may occur for several months after
isotretinoin therapy; therefore, subsequent courses of isotretinoin should not be initiated until at
least five months after completion of the previous treatment period. (See 'Outcomes' above.)
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Hormonal therapy for women with acne vulgaris
uptodate.com/contents/hormonal-therapy-for-women-with-acne-vulgaris/print
INTRODUCTION Androgens play an important role in the pathogenesis of

acne vulgaris. Thus, hormonal interventions that reduce androgen activity can be effective
treatments. Postmenarchal women with moderate to severe acne are the primary candidates for
hormonal therapy. Oral contraceptives and spironolactone are commonly prescribed hormonal
therapies.
Hormonal therapy for women with acne vulgaris is discussed here. Nonhormonal acne therapy is
reviewed separately. (See "Treatment of acne vulgaris" and "Oral isotretinoin therapy for acne
vulgaris" and "Light-based, adjunctive, and other therapies for acne vulgaris".)
HORMONES IN ACNE Androgens and estrogens significantly

impact the pathogenesis of acne. Therefore, understanding the role of these hormones is important
for grasping the rationale for hormonal therapy. In general, androgens have stimulatory effects on
acne, whereas estrogens have inhibitory effects on acne.
Androgens — Androgens contribute to acne through the promotion of sebum

production by sebaceous glands in the skin [1]. The increase in sebum production contributes to the
accumulation of sebum and keratinous material in pilosebaceous follicles. This leads to partial
1060
obstruction of the follicle, resulting in the formation of comedones, the primary lesions of acne
(picture 1A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section
on 'Pathogenesis'.)
Sebum also provides a growth medium for Cutibacterium (formerly Propionibacterium) acnes, a
bacterium that resides in pilosebaceous follicles and contributes to the inflammatory response in
acne vulgaris (picture 2) [2]. The correlation between the normal rise in serum androgen levels and
sebum production in the prepubertal period and the typical age of onset of acne (also the
prepubertal period) supports an important role for androgens in acne. This importance of androgens
is also supported by the occurrence of acne as a clinical feature of hyperandrogenism. (See "Adrenal
hyperandrogenism", section on 'Clinical manifestations' and "Clinical manifestations of polycystic
ovary syndrome in adults", section on 'Hyperandrogenism'.)
The major sources of circulating androgens are the adrenal glands and gonads; however, androgens
are also produced in the sebaceous glands within the skin. Androgen production in the sebaceous
glands occurs as a result of a series of enzymatic processes that convert dehydroepiandrosterone
sulfate (DHEAS), an adrenal precursor hormone, to testosterone and dihydrotestosterone (DHT)
(table 1). DHT is a more potent androgen than testosterone, having 5 to 10 times more affinity for the
androgen receptor than testosterone [1]. The type 1 5-alpha reductase isoenzyme converts
testosterone to DHT in sebaceous glands.
Testosterone and DHT exert their effects by binding to androgen receptors on cell surfaces, which
results in translocation of these hormones into cell nuclei, where they initiate transcription of
androgen-responsive genes [1]. In the skin, androgen receptors are found in the basal layer of
sebaceous glands and on the keratinocytes in the outer root sheath of hair follicles [3,4]. In addition
to effects via action on sebaceous glands, androgens may also contribute to acne through the
promotion of follicular hyperkeratinization [5]. The specific genes that contribute to the development
of acne as a result of androgen receptor binding are unclear.
Although endogenous or exogenous factors that cause hyperandrogenism can induce or exacerbate
acne, most patients with acne have serum androgen levels that are within normal limits. Increased
sensitivity of sebaceous glands to androgens is a proposed mechanism for the development of acne
in these patients. The presence of normal serum androgen levels in most women is supported by a
small study of 18 women without endocrine disease that found that both women with acne and
women without acne had serum androgen levels within the normal range [6]. However, the authors
also noted that women with acne had significantly higher serum androgen levels than women
without acne despite having serum androgen levels within in the normal range. (See "Postadolescent
acne in women", section on 'Pathogenesis'.)
Patients with excessive levels of serum androgens secondary to disorders such as polycystic
ovarian syndrome, congenital adrenal hyperplasia, adrenal tumors, or androgen-secreting ovarian
tumors are more likely to develop acne. In a study of 52 women (ages 18 to 35 years) with mild acne
and their age-matched controls, polycystic ovary syndrome was significantly more common in the
patients with acne than in the control group (27 versus 8 percent) [7]. In general, women who present
1061
with acne and concomitant hirsutism or menstrual irregularity should have a gynecologic and
hormonal evaluation (picture 3). (See "Pathogenesis, clinical manifestations, and diagnosis of acne
vulgaris", section on 'Sebaceous glands and the role of androgens'.)
Estrogens — The inhibitory effect of estrogens on acne is thought to be related to

estrogen-mediated suppression of sebum production. However, the mechanism through which this
occurs in not completely understood. Proposed mechanisms include estrogen-mediated opposition
of androgens within the sebaceous gland, inhibition of gonadal androgen production through a
negative feedback loop on gonadotrophin release, increases in sex-hormone binding globulin (which
reduces the bioavailability of androgens), and effects on regulation of genes involved in sebaceous
gland growth or lipid production [1]. (See "Treatment of hirsutism", section on 'Mechanisms of action
in hyperandrogenism/hirsutism'.)
OVERVIEW OF HORMONAL
THERAPY The goal of hormonal therapy for acne is to minimize acne via the
reduction of androgen action on cutaneous pilosebaceous units (see 'Androgens' above). Treatment
with hormonal therapy involves the selection of the appropriate medication and an appropriate
candidate for treatment. The potential for adverse effects of hormonal therapies must also be
considered prior to treatment.
Agents — The primary hormonal therapies used to improve acne in women are oral
contraceptives and spironolactone.
●Oral contraceptives –Oral contraceptives containing estrogen and progestin may reduce androgen
action via a variety of mechanisms. The estrogen component in oral contraceptives is known to
inhibit ovarian androgen production and increase production of sex hormone binding globulin
(resulting in reduced serum-free androgen levels), and is hypothesized to have additional inhibitory
effects on androgen action within the sebaceous gland [1]. Most progestins in oral contraceptives
have androgenic properties, although this is counteracted by the antiandrogenic effects of the
estrogen component. Some progestins (eg, drospirenone, cyproterone acetate, chlormadinone
acetate, and dienogest) have antiandrogenic properties [8]. (See 'Estrogens' above and 'Oral
contraceptives' below and "Combined estrogen-progestin oral contraceptives: Patient selection,
counseling, and use", section on 'Hormone components'.)
●Spironolactone – Spironolactone is an androgen receptor blocker. The drug competitively inhibits

the binding of androgens to androgen receptors [8]. Additional antiandrogenic effects of
spironolactone may also include inhibition of enzymatic conversion of androstenedione to
testosterone, inhibition of 5-alpha reductase, and increased steroid-hormone binding globulin [1].
(See 'Spironolactone' below.)
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Additional therapies with antiandrogenic properties may improve acne, but are not typically used for
this indication due to specific indications or concern for adverse effects.
●Systemic glucocorticoids – Systemic glucocorticoid therapy is used to suppress adrenal androgen

production in patients with hyperandrogenism secondary to congenital adrenal hyperplasia [9].
Treatment with systemic glucocorticoids provides cortisol replacement, thereby reducing the
excessive secretion of corticotropin-releasing hormone and corticotropin (ACTH) that contributes to
excessive adrenal androgen production, acne, and other associated clinical manifestations (figure
1). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in
adults".)
●Flutamide – Flutamide is an androgen receptor blocker that is not typically used for the treatment
of acne because of the potential for flutamide-induced fatal hepatitis [10,11].
The role of 5-alpha reductase inhibitors, which inhibit conversion of testosterone to the more potent
androgen dihydrotestosterone (DHT), in the treatment of acne is unclear. An investigational type 1 5-
alpha reductase inhibitor was not better than placebo for the treatment of moderate to severe
inflammatory acne in a randomized trial in which 128 patients were randomly assigned to treatment
with placebo or the type 1 5-alpha reductase inhibitor with or without concomitant minocycline
therapy [12]. In addition, a randomized trial of 48 hyperandrogenic women with acne found that
results with finasteride (a type 2 5-alpha reductase inhibitor) were not better than flutamide or
cyproterone acetate/ethinyl estradiol therapy [13]. Thus, there are insufficient data to support 5-
alpha reductase inhibitor therapy.
Indications — Both women with acne related to hyperandrogenism and women with
acne and normal serum androgen levels can benefit from hormonal treatment [14]. (See "Treatment
of acne vulgaris", section on 'Oral antibiotics' and "Oral isotretinoin therapy for acne vulgaris".)
●Women without hyperandrogenism – Among women with normal androgen levels, hormonal
therapy is typically used for postmenarchal adolescent and adult females with moderate to severe
acne who are not trying to become pregnant and who cannot be effectively managed with topical
therapy. Clinical experience suggests that hormonal therapy may be particularly efficacious in adult
women who present with inflammatory acne involving the lower face and neck and premenstrual
acne flares (picture 4) [15,16].
Women with milder acne who choose oral contraceptives for the purpose of pregnancy prevention
can also experience the ancillary benefit of improvement in their acne. However, these patients often
can be managed successfully with topical therapy.
●Women with hyperandrogenism – Hormonal therapy is useful for the management of acne in
women with hyperandrogenism because treatment reduces the excessive hormonal stimulus for
acne in these patients [8,17]. (See "Treatment of hirsutism", section on 'Combined estrogen-progestin
oral contraceptives'.)
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Approach to therapy — Oral antibiotics, hormonal therapy, and oral
isotretinoin are the major systemic treatment options for women. Although both oral antibiotics and
oral contraceptives are well accepted as appropriate first-line systemic therapies for women with
moderate to severe acne, data comparing the efficacy of these treatments are limited. More studies
are necessary to confirm findings from a meta-analysis of randomized trials that suggest similar
efficacy of these treatments [18]. (See 'Comparison to oral antibiotic therapy' below and "Treatment
of acne vulgaris", section on 'Oral antibiotics'.)
Given the uncertainty regarding relative efficacy, the decision to proceed with an oral antibiotic or a
hormonal agent as the initial systemic drug is based upon consideration of patient-specific factors,
such as a history of prior failure to respond to an oral antibiotic or oral contraceptive, individual risk
factors for drug-related side effects, the presence of hyperandrogenism, and in the case of oral
contraceptives, the patient’s desire for simultaneous contraceptive benefit. In addition, as mentioned
above, clinical experience suggests that women with normal serum androgen levels who present
with acne involving the lower face and premenstrual acne flares may be more likely to respond to
hormonal agents. Hormonal therapy should be a first-line therapy for women with acne related to
hyperandrogenism.
Hormonal therapy is typically given as a component of a therapeutic regimen that combines the
hormonal agent with other acne therapies with the goal of optimizing the response to treatment. A
topical retinoid (a mainstay of acne therapy) should be used simultaneously. Concomitant topical or
oral antimicrobial treatment also may be given if needed (table 2A-B) [19]. (See "Treatment of acne
vulgaris".)
The mainstays of hormonal therapy for acne are oral contraceptives and spironolactone. Oral
contraceptive treatment has the most amount of data in support of efficacy and typically is our initial
choice for hormonal therapy [20]. Spironolactone is often given in conjunction with oral
contraceptive therapy because the drug may cause menstrual irregularities. Thus, in the clinical
setting, spironolactone is often initiated in an attempt to obtain a higher level of response in women
already receiving oral contraceptive therapy. Treatment with oral contraceptives and spironolactone
is contraindicated in pregnancy. Absolute and relative contraindications for oral contraceptive
treatment are reviewed in detail separately.
In general, the effects of hormonal therapies are not immediate. A minimum of three to six months
of therapy is required for evaluation of efficacy.
THERAPIES Data on the efficacy and adverse effects of oral contraceptives and
spironolactone, the hormonal treatments most frequently used for acne, are described below.
Oral contraceptives — Combined oral contraceptives containing both

estrogen and progestin are effective therapies for acne vulgaris in women. The estrogen component
of most combined oral contraceptives is ethinyl estradiol. The progestin component consists of one
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of multiple progestins, which are classified into generations. Although the earlier-generation
progestins have more cross-reactivity with the androgen receptors than later generations (and
therefore, more androgenic activity), oral contraceptives containing all generations of progestins can
be effective for acne. Some progestins have antiandrogenic properties. (See 'Combination oral
contraceptives with antiandrogenic progestins' below and "Combined estrogen-progestin oral
contraceptives: Patient selection, counseling, and use", section on 'Hormone components'.)
Efficacy — A systematic review of randomized trials found results that support the efficacy of
oral contraceptives over placebo [20]. However, efficacy differences amongst combined oral
contraceptives with varying progestins are less clear.
Combination oral contraceptives with antiandrogenic

progestins — Oral contraceptives with antiandrogenic progestins are a subclass of
combination oral contraceptives. These include agents that contain cyproterone acetate,
chlormadinone acetate, drospirenone, or dienogest plus an estrogen [21-23]. Oral contraceptives
containing cyproterone acetate or chlormadinone acetate are not available in the United States, but
are used in Europe [19]. Ethinyl estradiol 30 mcg/drospirenone 3 mg and ethinyl estradiol 20
mcg/drospirenone 3 mg are the two drospirenone-containing oral contraceptives that are prescribed
in the United States.
Examples of studies that support the efficacy of these agents include:
●A pooled analysis of two placebo-controlled randomized trials with a total of 893 females with
moderate facial acne found that patients treated with ethinyl estradiol 20 mcg/drospirenone 3 mg
for six cycles were more likely to attain clear or almost clear skin than patients treated with placebo
(odds ratio [OR] 3.41, 95% CI 2.15-5.43) and had greater mean reductions in acne lesion counts [24].
In one trial, total lesion counts were reduced 46.3 percent for the combination oral contraceptive
group and 30.6 percent for the placebo group [25]. Beneficial effects were observed by the third
cycle.
●An oral contraceptive containing ethinyl estradiol 30 mcg/dienogest 2 mg was superior to placebo
in a large randomized trial; total lesion counts were reduced by 55 versus 39 percent [23].
●A randomized trial (n = 40) in which a topical form of cyproterone acetate was compared with oral
ethinyl estradiol 35 mcg/cyproterone acetate 2 mg and placebo found that the oral agent was
superior to placebo for reduction of the acne severity grade and lesion counts [26].
Comparison to oral antibiotic therapy — Few studies have directly compared

the efficacy of oral contraceptive and oral antibiotic therapy [27,28], contributing to uncertainty
regarding the relative efficacy of the two treatments.
The results of the first meta-analysis to compare the efficacy of oral contraceptive therapy and oral
antibiotic therapy suggest similar efficacy for the treatment of acne [18]. The meta-analysis included
randomized trials that contained at least one investigational arm that consisted of oral antibiotic or
1065
oral contraceptive therapy and assessed efficacy for acne after three and/or six months of
treatment. Analysis of the data after six months of treatment revealed that mean percent reductions
in acne lesions after oral antibiotic treatment and oral contraceptive therapy were similar and
superior to placebo (53, 55, and 25 percent, respectively). However, antibiotic therapy appeared to
induce a more rapid response than oral contraceptive treatment. The mean percent reduction in
acne lesions was significantly greater for oral antibiotics than oral contraceptives at the three month
time point (48 versus 37 percent, respectively).
The findings of this study suggest similar efficacy of oral contraceptives and oral antibiotics and
support the status of oral contraceptives as effective therapies for acne. Limitations of the meta-
analysis included wide variation in treatment protocols and patient population (eg, trials of antibiotic
therapy included both men and women, while oral contraceptive trials were limited to women). The
performance of head-to-head trials would help to clarify the comparative efficacy of these
treatments.
Selection of an oral contraceptive — All low-dose combination oral

contraceptives are estrogen-dominant. Therefore, despite the inclusion of an androgenic progestin,
all combined oral contraceptives have an overall antiandrogenic effect [20,29,30]. (See "Combined
estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Hormone
components'.)
Although the results of a few randomized trials have suggested slightly greater benefit of ethinyl
estradiol 30 mcg/drospirenone 3 mg over ethinyl estradiol 35 mcg/norgestimate 0.180/0.125/0.250
mg [31], and for cyproterone acetate or chlormadinone acetate containing oral contraceptives over
levonorgestrel containing agents [32-34], additional high-quality trials are necessary to confirm these
results. Similarly, while newer third-generation progestins (norgestimate, desogestrel, and
gestodene) are considered to be less androgenic than their second-generation precursors (eg,
levonorgestrel, norethindrone), data are inadequate to conclude that third-generation agents offer
superior efficacy for acne [20].
Only three oral contraceptives have been approved by the US Food and Drug Administration (FDA)
for treatment of acne. These include ethinyl estradiol 20/30/35 mcg/norethindrone 1 mg (Estrostep),
ethinyl estradiol 35 mcg/norgestimate 180/215/250 mcg (Ortho Tri-Cyclen), and ethinyl estradiol 20
mcg/drospirenone 3 mg (Yaz).
Progestin-only contraceptives — Progestin-only contraceptives, including

low-dose oral pills that contain androgenic progestins (eg, norethindrone or desogestrel) and
injections of medroxyprogesterone, may exacerbate acne [19]. The development or exacerbation of
acne has been reported in connection with the levonorgestrel intrauterine device [35,36] and
etonogestrel implant [37]. Patients with acne may benefit from alternative contraceptive options.
(See "Contraceptive counseling and selection for women".)
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Side effects — The risks and benefits of taking oral contraceptives should be considered
and discussed with all patients prior to the initiation of therapy. Thromboembolism is a potential
serious adverse effect of oral contraceptive use [38,39], and treatment should be avoided in patients
with underlying thrombophilic disorders or a history of a venous thromboembolic event. There is
concern for increased risk for venous thromboembolism associated with the use of oral
contraceptives with third-generation progestins or antiandrogenic progestins compared with other
oral contraceptives.
Additional guidelines for the use of oral contraceptives are reviewed in detail separately. (See
"Combined estrogen-progestin contraception: Side effects and health concerns".)
Drospirenone has a potassium-sparing diuretic effect similar to the drug spironolactone. An

increased risk for hyperkalemia was not demonstrated in a cohort study of 22,429 patients given
ethinyl estradiol 30 mcg/drospirenone 3 mg and 44,858 given other oral contraceptives [19].
However, based on theoretical concerns for hyperkalemia in selected patients, treatment with ethinyl
estradiol 20 mcg/drospirenone 3 mg and ethinyl estradiol 30 mcg/drospirenone 3 mg is
contraindicated in patients with renal insufficiency, hepatic dysfunction, or adrenal insufficiency [40].
In addition, monitoring of serum potassium is recommended during the first cycle for patients taking
medications with potassium-retaining properties [40].
Antibiotics and contraceptive efficacy — In some cases, patients

may be treated with oral contraceptives and oral antibiotics simultaneously. There is no definitive
evidence that oral antibiotics, with the exception of rifampin, reduce oral contraceptive
effectiveness for pregnancy prevention [41]. The use of antibiotics other than rifampin does not
warrant an additional form of pregnancy protection. (See "Combined estrogen-progestin oral
contraceptives: Patient selection, counseling, and use", section on 'Drug interactions'.)
Spironolactone — Spironolactone has been used for many years to treat disorders
such as acne, hirsutism, and androgenic alopecia in women although it is not FDA approved for
these conditions. Spironolactone therapy may be considered for women whose moderate to severe
acne has not responded to conventional treatments and who prefer to avoid oral isotretinoin. Our
experience suggests that female patients whose acne flares cyclically around the time of menses
and whose acne is distributed in the lower face and jaw line may be good candidates for
spironolactone therapy.
Spironolactone is an oral antiandrogen that blocks androgen receptors and inhibits androgen
biosynthesis [1]. The drug decreases 17-beta-hydroxysteroid dehydrogenase, therefore halting the
conversion of androstenedione to testosterone [42]. Spironolactone may also inhibit 5-alpha-
reductase, thereby preventing the conversion of testosterone to dihydrotestosterone (DHT).
Additionally, spironolactone may increase steroid-hormone binding globulin [43]. Together these
mechanisms of action result in a 30 to 50 percent reduction in sebum excretion [44].
1067
Efficacy and administration — Although the authors of a 2009 systematic
review of randomized trials found insufficient evidence to confirm the efficacy of spironolactone for
women with acne [45], several studies (including two small randomized trials and case series) have
reported treatment benefit [46-50]. Additional studies are necessary to explore the role of
spironolactone in women with acne [8,51].
We typically utilize doses of 50 to 100 mg per day (given in a single dose or in two divided doses)
when treating women with acne [51]. Initiating treatment with total doses of 25 to 50 mg per day,
with subsequent dose escalation according to patient tolerance and response, will help to minimize
side effects [19].
Spironolactone has also been prescribed in doses of up to 200 mg per day for acne [46-48,52].
However, lower doses may still be effective and may reduce the risk for adverse effects [49,53,54]. A
retrospective analysis found that responses to 50 to 100 mg per day of spironolactone were similar
to previously reported responses to doses of 150 to 200 mg per day [53]. Additionally, in a series of
35 women with acne who were treated with 50 mg twice daily for 16 consecutive days per month for
three months, 24 out of 28 women who completed treatment had clinically significant improvement
[49]. Clinical experience also suggests that clinical improvement can occur with doses as low as 25
mg per day [1].
Side effects — Side effects of spironolactone include menstrual irregularities, breast

tenderness, minor gastrointestinal symptoms (anorexia, nausea, vomiting, and diarrhea), orthostatic
hypotension, and central nervous system symptoms (headaches, dizziness, and fatigue). Side
effects (excluding central nervous system symptoms) are less frequent at lower doses (≤100 mg per
day) [53]. Side effects such as menstrual irregularities and breast tenderness can be counteracted
by concomitant use of an oral contraceptive.
Spironolactone is a potassium-sparing diuretic, and hyperkalemia is a potentially serious adverse

effect when given at high doses or to patients with renal insufficiency or severe heart failure [55,56].
However, there does not appear to be a significant risk for hyperkalemia in young, healthy women
given spironolactone in doses typically used for acne [52,53,57,58]. The largest study of the risk for
spironolactone-induced hyperkalemia in acne patients is a retrospective analysis of women (ages 18
to 45 years) prescribed spironolactone for acne or an endocrine disorder with acne as a secondary
feature [58]. The rate of hyperkalemia in 1802 measurements from 974 women during treatment
with spironolactone was 0.72 percent, and the baseline rate of hyperkalemia in 4209 measurements
from 1165 women taking or not taking spironolactone was 0.76 percent. There were no serious
elevations of potassium in the group taking spironolactone; all the elevations were mild or moderate.
Of note, patients with heart failure or renal disease and patients receiving medications that affect the
renin-angiotensin-aldosterone system were excluded.
Given that the risk of hyperkalemia is low, we do not check serum potassium levels in healthy, young
women receiving spironolactone therapy for acne. However, the patient's comorbidities and
medication history must be considered. Periodic laboratory monitoring of serum potassium is
appropriate in women with multiple medical problems, cardiac disease, or renal disease, and women
1068
who are taking medications that may increase risk for hyperkalemia [1]. In these patients, potassium
levels can be checked at baseline, during therapy, and after dose increases [14]. (See 'Side effects'
above.)
Monitoring of serum potassium may also be beneficial for healthy women over the age of 45, and we
suggest periodic monitoring in this population. A study that compared the rate of incident
hyperkalemia during spironolactone therapy among 112 women aged 18 to 45 years and 12 women
aged 46 to 65 years through the analysis of data in a medical record data repository found incident
hyperkalemia in 0.01 and 17 percent of women, respectively [59]. Included women had assessments
of serum potassium at baseline (or within one year prior to the start of spironolactone) and within
one year after the start of spironolactone. Women with hypertension, renal failure, or diabetes
mellitus were excluded.
The oral contraceptive progestin drospirenone also possesses potassium-sparing diuretic

properties; 3 mg of drospirenone is equivalent to approximately 25 mg of spironolactone [57].
Although hyperkalemia was not demonstrated in one small prospective study of patients
concurrently taking oral contraceptives with drospirenone and 100 mg per day of spironolactone
[60], further larger studies are needed to fully elucidate the risk of hyperkalemia.
The development of tumors, including mammary tumors, in rats treated with spironolactone or a
related compound has been reported [61]. The relationship between spironolactone use and breast
cancer has been debated [62-65]. However, no definitive evidence linking human breast or other
estrogen-dependent tumors to the use of spironolactone exists.
Feminization of the male fetus may occur in patients who become pregnant while taking
spironolactone. Animal studies have demonstrated feminization of male offspring of rodents treated
with high doses of spironolactone [66]. While there are human case reports of feminization of the
male fetus, there are also reports of women taking oral spironolactone and delivering healthy male
offspring [67,68]. The co-administration of spironolactone with an oral contraceptive is advised
because of this potential serious fetal effect, along with the menstrual irregularities that may occur
during treatment [1].
There have been no documented cases of breast carcinomas and case controls have not shown an
overall increase risk for breast carcinoma [69].


1069
SUMMARY AND
RECOMMENDATIONS
●Androgens play a key role in the development of acne vulgaris through the induction of sebum
production. Thus, antiandrogenic therapies can be useful for the management of female patients
with moderate to severe acne. (See 'Hormones in acne' above.)
●Androgen levels are normal in the majority of women with acne. Women with signs of
hyperandrogenism should be evaluated for underlying disorders such as polycystic ovarian
syndrome, congenital adrenal hyperplasia, or adrenal or ovarian tumors. Women without
hyperandrogenism whose acne has been unresponsive to other therapies can benefit from treatment
with hormonal therapies. (See 'Overview of hormonal therapy' above.)
●Hormonal therapy should be prescribed as part of an acne treatment regimen containing topical
retinoids with or without antimicrobial agents. Oral contraceptives and spironolactone are the most
common hormonal agents utilized for the treatment of acne. A minimum of three to six months of
therapy is required in order to evaluate treatment efficacy. (See 'Overview of hormonal therapy'
above.)
●In women with moderate to severe acne who have had an inadequate response to topical therapy
and oral antibiotics and who do not desire pregnancy, we suggest the use of combination oral
contraceptives (Grade 2A). Women with milder acne who choose oral contraceptives for pregnancy
prevention can experience the collateral benefit of improvement in their acne. Although newer third-
generation progestins have lower androgenicity than first- or second-generation progestins, all low-
dose combination oral contraceptives can be used for the treatment of acne. (See 'Oral
contraceptives' above.)
●Oral contraceptive therapy is generally well tolerated, but is associated with a variety of adverse
effects, including increased risk for venous thromboembolic disease. Adverse effects and
contraindications to treatment should be considered carefully prior to treatment. (See "Combined
1070
estrogen-progestin contraception: Side effects and health concerns".)
●Contraceptives containing androgenic progestins only can exacerbate acne and cannot be used for
treatment of this condition. (See 'Progestin-only contraceptives' above.)
●Spironolactone is the most common androgen receptor blocker used for the treatment of acne in
the United States. In adult women with moderate to severe acne that is unresponsive to topical
treatment, oral antibiotics, and oral contraceptives, we suggest treatment with spironolactone (Grade
2B). Topical retinoids should be continued; in women who have had no response to antimicrobials,
they can be discontinued. A reasonable alternative to spironolactone would be to proceed to therapy
with oral isotretinoin. (See 'Spironolactone' above and "Oral isotretinoin therapy for acne vulgaris".)
●Spironolactone can cause fetal harm and menstrual irregularity, and is usually given with an oral
contraceptive. (See 'Spironolactone' above.)
1071
Light-based, adjunctive, and other therapies for acne vulgaris
uptodate.com/contents/light-based-adjunctive-and-other-therapies-for-acne-vulgaris/print
INTRODUCTION Acne vulgaris is a common condition, and there is

significant demand for effective acne therapies. Many over-the-counter products are marketed. In
addition, a number of procedural therapies are utilized for the treatment of acne vulgaris with
variable effectiveness.
The use of over-the-counter and light-based therapies as well as several adjunctive therapies (office-
based chemical peels, microdermabrasion, comedo extraction, intralesional glucocorticoids, and
heat therapy) will be reviewed here. Conventional therapies, hormonal therapy, and isotretinoin
therapy for acne vulgaris are discussed separately. (See "Treatment of acne vulgaris" and "Hormonal
therapy for women with acne vulgaris" and "Oral isotretinoin therapy for acne vulgaris".)
OTHER TOPICAL MEDICATIONS For many

people with acne, treatment begins with nonprescription regimens. Numerous products are
available, and nonprescription treatments are effective for some individuals. Some of the most
common ingredients found in nonprescription acne products include salicylic acid, benzoyl peroxide,
sulfur, and alpha hydroxy acids. Tea tree oil has also been used for treatment of acne. In July 2016,
the US Food and Drug Administration (FDA) approved adapalene 0.1% gel for over-the-counter use,
making it the first topical retinoid approved for distribution directly to consumers. (See "Treatment of
acne vulgaris", section on 'Topical retinoids'.)
Patients with mild to moderate acne who do not respond to nonprescription products after three
months of treatment should be clinically evaluated. Patients with more severe acne should be
evaluated earlier, to consider the use of the most effective treatment regimens to prevent or
minimize scarring.
Topical nonprescription acne therapies are generally well tolerated. However, rare but serious and
potentially life-threatening hypersensitivity reactions to nonprescription topical acne products
containing salicylic acid or benzoyl peroxide have been reported [1]. Whether these active
ingredients or inactive ingredients are responsible for the reactions is unclear. Symptoms may occur
within minutes to one day or longer after product use and may include severe skin reactions, throat
tightness, difficulty breathing, feeling faint, or swelling of the eyes, face, lips, or tongue. The US FDA
recommends limiting application of these products to one or two small affected areas during the
initial three days of use to test for hypersensitivity [1].
1072
Salicylic acid — Salicylic acid (0.5 to 2%) is a beta hydroxy acid available in a number
of nonprescription gels, lotions, solutions, cleansers, pads, and masks. It is a desquamating agent,
and its lipophilic properties enable it to penetrate the pilosebaceous follicle, producing a comedolytic
effect [2]. Topical salicylic acid also possesses mild anti-inflammatory properties. Salicylic acid is
usually applied once daily and subsequently increased to two or three times per day if needed [3].
The frequency of application can be reduced to once daily or every other day if the patient develops
skin dryness or peeling [3].
In three placebo-controlled studies, salicylic acid was an effective treatment for acne [4]. It is a
treatment option for patients who cannot tolerate topical retinoids or benzoyl peroxide [5,6]. Salicylic
acid can also be used in combination with benzoyl peroxide, as the mechanisms of action of these
drugs complement each other in the treatment of acne. (See "Treatment of acne vulgaris", section on
'Benzoyl peroxide'.)
Higher concentrations of salicylic acid may be used in the office to perform superficial chemical
peels. (See 'Office-based superficial chemical peels' below.)
Benzoyl peroxide — Benzoyl peroxide is a commonly used antimicrobial acne

treatment that also possesses comedolytic properties. The drug is an effective treatment for
inflammatory and comedonal acne. It is available in both nonprescription and prescription
formulations. (See "Treatment of acne vulgaris", section on 'Benzoyl peroxide'.)
The combination of benzoyl peroxide and salicylic acid may be useful for patients who desire a
nonprescription regimen [2,7].
Sulfur — Topical sulfur has been used for the treatment of acne for many years, although
there are few data supporting its efficacy [8]. The mechanism of action remains unknown. It is
thought that sulfur interacts with cysteine in keratinocytes, resulting in the production of hydrogen
sulfide, which has a keratolytic effect [9]. Sulfur also inhibits the proliferation of Cutibacterium
(formerly Propionibacterium) acnes [8]. Older formulations of sulfur were sometimes offensive to
patients due to an unpleasant, rotten egg-like odor. This odor is minimized in newer formulations.
Sulfur is often combined with salicylic acid in nonprescription products. In addition, sulfur has been
studied in combination with benzoyl peroxide. In a case series of 113 patients with acne, a
combination of 2.5 to 5% sulfur and 10% benzoyl peroxide was efficacious for the majority of
patients [10].
Prescription products that combine sulfur with sulfacetamide, an ingredient with antibacterial
properties, are available and have been effective in open-label studies [11,12]. (See "Treatment of
acne vulgaris", section on 'Sulfacetamide'.)
1073
Alpha hydroxy acids — The most commonly used alpha hydroxy acids are
glycolic acid and lactic acid. Alpha hydroxy acids are weak organic acids that cause desquamation
and diminish corneocyte cohesion, thereby normalizing follicular keratinization [13]. These agents
may also promote dispersing of basal layer melanin, which can help to improve postinflammatory
hyperpigmentation.
Alpha hydroxy acids in low concentrations and buffered alpha hydroxy acids in higher
concentrations are available as over the counter washes, lotions, creams, and at-home peel systems.
High concentrations with more free acid are used in the office to perform superficial chemical peels.
(See 'Office-based superficial chemical peels' below.)
Only low-quality evidence is available regarding the use of low concentrations of alpha hydroxy
acids for the treatment of acne. Alpha hydroxy acids may be most effective as components of a
treatment regimen containing other acne medications [14]. Glycolic acid is generally considered to
be less effective than topical tretinoin, when used as monotherapy. However, a synergistic effect has
been observed when the two medications are combined [13].
Alpha hydroxy acids also diminish the signs of aging skin, and are marketed for use in antiaging skin
care regimens.
Tea tree oil — Tea tree oil is a product derived from the Australian Melaleuca alternifolia
tree that possesses antimicrobial and anti-inflammatory properties. Two randomized controlled
trials have investigated this agent for the management of acne vulgaris. In a 45-day trial of 60
patients with mild to moderate acne vulgaris, patients treated with 5% tea tree oil exhibited a 44
percent reduction in total lesion counts, compared with a 12 percent reduction in the placebo group
[15]. In another trial comparing treatment with 5% tea tree oil or 5% benzoyl peroxide (n = 124),
patients in both groups showed a significant reduction in inflammatory and noninflammatory acne
lesions, but a slower onset of action occurred with tea tree oil therapy [16].
LIGHT/LASER THERAPIES Clinician-administered light

sources are used for the treatment of acne, though well-designed clinical trials supporting the
benefit of these treatments are limited, and there is uncertainty about the efficacy of these
interventions [17]. Examples of light-based therapies include [18]:
●Broad-spectrum continuous-wave visible light sources (blue light, red light)
●Intense pulsed light
●Laser sources including the potassium titanyl phosphate (KTP) laser, pulsed dye laser (PDL), and
infrared lasers
●Photodynamic therapy
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●Photopneumatic technology
Photodynamic therapy involves the application of a photosensitizing agent such as aminolevulinic

acid (ALA) or methyl aminolevulinic acid (MAL) prior to exposure to blue or red light, lasers, pulsed
light sources, or nonpulsed broad spectrum light. It is hypothesized that once applied to the skin,
ALA and MAL are preferentially taken up by the pilosebaceous unit and augment the response to
light therapy [19]. Additional topical photosensitizers that have been less extensively studied in
photodynamic therapy for acne include indocyanine green and indole-3-acetic acid [20,21].
Photopneumatic technology is a newer therapeutic modality. It has been less extensively studied for
the treatment of acne than other light treatments. Photopneumatic devices combine gentle negative
pressure with broadband pulsed light (400 to 1200 nm). The suction pressure helps to open follicular
ostia through the evacuation of sebum and brings pilosebaceous units closer to the treatment tip.
The broadband light exerts antibacterial and anti-inflammatory effects [22-24].
Mechanism of action — The mechanisms of action for light-based

therapies in the treatment of acne are not completely understood. Proposed theories regarding the
mechanisms through which these modalities work include the following:
●Blue and red light therapy for acne are thought to work via the absorption of light by porphyrins
produced by C. acnes [25,26]. The porphyrins absorb light wavelengths between 400 and 700 nm,
and absorb most effectively at wavelengths around 410 nm, which is within the absorption spectrum
of blue light. As a result of light exposure, the porphyrins become activated, leading to the
production of free oxygen radicals and bacterial death. Red light activates porphyrins less intensely
than blue light, but penetrates more deeply into the skin.
●Infrared lasers (1320 nm, 1450 nm), radiofrequency devices, and photodynamic therapy are
thought to inflict thermal damage to sebaceous glands and decrease sebum production.
Photodynamic therapy also reduces obstruction of follicles, hyperkeratosis, and inflammation within
acne lesions [27].
●Intense pulsed light (400 to 1200 nm), pulsed dye lasers (585 to 595 nm), and KTP lasers (532 nm)
may function through inhibition of C. acnes and/or damage to the sebaceous glands [28].
Efficacy — The efficacy of light-based therapies for the treatment of acne vulgaris remains
under investigation. High-quality data to support a recommendation for routine use of light-based
therapies are lacking [17].
Although many articles on the use of photodynamic therapy in acne have been published, as with
other light-based interventions, the efficacy of this intervention remains unclear. There is a lack of
consensus regarding the optimal treatment protocol: the best photosensitizer, the best
photosensitizer delivery method, the ideal contact time, the preferred light source and light dose, and
1075
the optimal treatment interval remain to be determined [29]. Photodynamic therapy is also
associated with side effects that are unacceptable for some patients (eg, erythema, crusting, pain,
and postinflammatory dyspigmentation) [19,30].
Only a few studies have compared light-based treatments with traditional acne therapies [17]. As an
example, a small randomized controlled trial found blue-red light more effective than 5% benzoyl
peroxide for treatment of inflammatory lesions, with a 17.6 percent difference in mean percentage
improvement [31]. No difference in treatment efficacy was noted in small randomized controlled
trials of blue light therapy versus clindamycin 1% solution (n = 34) [32], intense pulsed light plus
benzoyl peroxide versus benzoyl peroxide alone (n = 30) [33], or pulsed-dye laser treatment plus
topical clindamycin/benzoyl peroxide versus topical clindamycin/benzoyl peroxide alone [34]. In
another small randomized trial, improvement in inflammatory lesions with photodynamic therapy
was found to be less than that with adapalene 0.1% gel [35].
Additional randomized controlled trials and comparative treatment studies are necessary to clarify
the role for laser and other light-based therapies in the treatment of acne. Continued research may
also be useful for identifying new light-based therapies that will be useful for acne. An in vitro study
found that laser wavelengths of 1720 nm were able to selectively target sebaceous glands without
damaging adjacent skin structures [36]. If laser treatments at this wavelength are determined to be
safe and effective, this may present a future treatment option for acne.
Emerging therapy — The findings of two small randomized trials suggest that
topical application of light-absorbing gold microparticles followed by exposure to an 800 nm diode
laser may improve inflammatory acne [37]. The treatment causes selective photothermolysis of
sebaceous glands.
Home-use devices — The use of home-use, handheld devices for acne,

particularly those using light-emitting diode, is gaining popularity. Although there have been small
studies published supporting its efficacy and safety, high-quality, peer-reviewed data are lacking [38].
ADJUNCTIVE THERAPIES
Office-based superficial chemical peels — Superficial
chemical peels are most appropriate for patients with primarily comedonal acne, and work to
quicken the process of comedone resolution [39]. Of note, multiple treatments are required, results
are temporary, and improvement may be mild [3]. Glycolic acid (an alpha hydroxy acid) and salicylic
acid (a beta hydroxy acid) are the most common agents utilized. Resorcinol, lactic acid,
trichloroacetic acid, and pyruvic acid may also be used.
High-quality, placebo-controlled efficacy trials are lacking. A randomized trial and several case series
have supported the efficacy of glycolic acid and salicylic acid chemical peels [40-43]. The split-face
randomized trial (n = 20) compared the treatment of facial acne with glycolic acid peels versus
1076
salicylic acid peels [40]. After 12 weeks, the treatments were similarly effective for the reduction of
acne lesions. However, at two months post treatment, only the salicylic acid-treated areas
maintained a significant decrease in the number of acne lesions.
Patients on oral retinoids should not be treated with chemical peels due to the potential for
significant irritation. It is also recommended that patients on topical retinoids discontinue treatment
for several days prior to treatment with chemical peels. Patients with skin phototypes IV to VI (table
1) are at increased risk of postinflammatory hypo- or hyperpigmentation, and care must be taken to
minimize this risk.
Microdermabrasion — Microdermabrasion is a noninvasive procedure in

which abrasive crystals (eg, aluminum oxide) are propelled onto the skin within a controlled vacuum
suction system, leading to exfoliation of the stratum corneum. Microdermabrasion was reported to
show benefit in a nonrandomized pilot study (n = 24) comparing severity of acne in photographs
before and after treatment [44]. Patients continued to adjust acne medications throughout the study
period, and the severity assessment was not quantitative. Thus, the effectiveness of
microdermabrasion has been called into question [45].
Microdermabrasion may have benefit as a pretreatment for photodynamic therapy to decrease

incubation time of the topical photosensitizer [39,46].
Comedo extraction — Mechanical removal of comedones can be a useful

adjunct to topical therapy in patients with resistant comedones [3]. Pretreatment with tretinoin
cream for four to six weeks often facilitates the procedure [47].
To perform the extraction, gently excise the roof or enlarge the opening of the comedo with an 18-
gauge needle, sterile lancet, or no. 11 blade. Gently but firmly apply pressure with a comedo
extractor to the skin to remove the keratin plug or milial cyst through the opening of the extractor.
Lidocaine/prilocaine cream (EMLA) may be applied under an occlusive dressing for 1.5 to 2 hours
prior to the procedure for anesthesia. Scarring is a potential risk.
Intralesional glucocorticoids — Intralesional glucocorticoids are a

treatment option for nodular acne lesions that might otherwise take weeks to resolve. Treated
lesions typically flatten in 48 to 72 hours, improving appearance and discomfort [48]. Triamcinolone
acetonide, in concentrations of 1.25 to 2.5 mg/mL, is typically injected using a 30-gauge needle.
There is no high-quality evidence demonstrating the efficacy of such injections, but extensive clinical
experience supports their use. Lower concentrations of triamcinolone may be as effective as higher
concentrations and may reduce the risk of adverse effects; in one small randomized trial, lesions
treated with 0.63, 1.25, or 2.5 mg/mL of triamcinolone acetonide exhibited similar improvement
scores [48].
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Patients should be cautioned regarding potential side effects including cutaneous atrophy,
hypopigmentation, and telangiectasias. (See "Intralesional corticosteroid injection".)
Heat — The US Food and Drug Administration approved a home device (ThermaClear) that
provides a pulse of heat for acne treatment. An unpublished five-day trial of the device compared
heat treatment on one side of the face with no treatment on the other side [49]. A blinded analysis of
photographs found that a greater percentage of treated lesions (44 versus 11 percent of untreated
lesions) completely cleared. Other available devices include Zeno and the Radiancy Clear Touch Lite
Acne Clearance System [50]. The latter uses a combination of heat and pulsed light.
Because of the lack of published studies supporting their efficacy and safety, heat sources are not
recommended as first-line treatments for acne.
Diet — The relationship between diet and acne is controversial, but several studies published in
the last decade suggest that dietary modifications may affect acne severity. The data on diet and
acne are reviewed elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of acne
vulgaris", section on 'Diet'.)
Additional study is needed prior to a recommendation for dietary changes in the treatment of acne
[3].


1078
SUMMARY AND
RECOMMENDATIONS
●Numerous nonprescription products are available for the treatment of acne. Common ingredients
in nonprescription products include salicylic acid, benzoyl peroxide, sulfur, and alpha hydroxy acids.
●For patients with mild to moderate acne who do not want to initiate prescription medications, we
suggest a trial of benzoyl peroxide and/or salicylic acid (Grade 2B). For patients with inflammatory
lesions, benzoyl peroxide is preferred due to the drug's antimicrobial properties. Combination
therapy with both drugs may lead to additional benefit. Patients with mild to moderate acne who do
not respond to nonprescription products after three months of treatment should be clinically
evaluated. Patients with more severe acne should be evaluated earlier, to consider use of more
effective treatments to prevent or minimize irreversible scarring. (See 'Other topical medications'
above and "Treatment of acne vulgaris".)
●The role of laser and other light-based therapies in the treatment of acne is not clearly defined. We
suggest that light-based therapies should not be used as first-line treatment for acne vulgaris (Grade
2B). These therapies may be utilized as an adjunct to medical acne therapy or as an option for
patients who decline medical therapy although further studies are necessary to clarify their role.
(See 'Light/laser therapies' above.)
●In patients with primarily comedonal acne who desire an accelerated treatment response, we
suggest superficial chemical peels (Grade 2B). However, peels should be avoided in patients taking
oral isotretinoin and should be used with caution in patients with dark skin pigmentation. (See
'Office-based superficial chemical peels' above.)
●Until further evidence is available, we suggest not using microdermabrasion for the treatment of
acne (Grade 2C). However, this procedure may be useful as a pretreatment for photodynamic
therapy. (See 'Microdermabrasion' above.)
●We suggest intralesional glucocorticoids for selected nodular inflammatory acne lesions in order to
accelerate their resolution (Grade 2C). Patients should be warned of the potential side effects of
cutaneous atrophy, hypopigmentation, and telangiectasias prior to treatment. (See 'Intralesional
glucocorticoids' above.)
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Perioral (periorificial) dermatitis - UpToDate
uptodate.com/contents/perioral-periorificial-dermatitis/print
INTRODUCTION Perioral dermatitis (POD), also known as periorificial

dermatitis, is a skin disorder that typically presents with multiple small, inflammatory papules
around the mouth, nose, or eyes (picture 1A-L). Although the name "perioral dermatitis" suggests a
primarily eczematous condition, POD most often resembles an acneiform or rosacea-like eruption
with or without associated features of a mild eczematous dermatitis.
The pathogenesis of POD is poorly understood; both intrinsic factors and extrinsic factors, such as
irritants and topical corticosteroids, may contribute to this disorder. Topical anti-inflammatory
agents and topical or systemic antibiotics constitute the major pharmacologic treatment options
(algorithm 1).
1080
The clinical features, diagnosis, and management of POD will be discussed here. The differential
diagnosis of disorders that present with inflammation of facial skin is reviewed separately. (See
"Approach to the patient with facial erythema".)
TERMINOLOGY POD was first described in 1957 under the moniker "light
sensitive seborrheid" [1]. Since then, an association with light exposure has largely been discounted
[2,3]. In 1964, "perioral dermatitis" was introduced as the preferred term to refer to this disease [4].
Some authors have advocated for utilization of the term "periorificial dermatitis," a name that reflects
the various potential sites of POD [5,6]. (See 'Clinical manifestations' below.)
EPIDEMIOLOGY POD occurs worldwide and in individuals of all racial and

ethnic backgrounds. Although women between the ages of 16 and 45 constitute the vast majority of
patients affected by POD, POD may also occur in older individuals, men, and children [7,8].
Childhood POD often occurs in young children. A retrospective study of 222 children with POD seen
at an academic dermatology department found an average age of presentation of 6.6 years [9]. POD
may develop in infants as young as three months of age [9]. Girls may be slightly more likely to
develop POD than boys. In a retrospective study, 46 of 79 children and adolescents with POD (58
percent) were female [5].
ETIOLOGY AND PATHOGENESIS The

pathways that lead to the development of POD are not well understood. Deficiencies in skin barrier
function and features of atopy have been detected at increased frequency in patients with POD
[10,11]. Although it is conceivable that these factors could augment the risk for persistent cutaneous
inflammation after exposures to external irritants [10-12], a definitive role for skin barrier dysfunction
and atopic diatheses in POD has not been established.
Topical corticosteroid use is frequently reported in association with POD, with the classic history
being a papular and slightly scaly facial eruption that initially improves with topical corticosteroid
use, but recurs or worsens with continued use or attempts to discontinue corticosteroid therapy
[2,5,13,14]. Whether topical corticosteroids are capable of inducing POD during treatment of
unrelated facial dermatoses or whether they may simply exacerbate preexisting POD remains
uncertain. Reports vary widely on the proportion of patients who recount a history of topical
corticosteroid therapy [2,5,11,15,16].
Despite the uncertainty in the specific role of corticosteroids in POD, there appears to be a
connection between POD and topical corticosteroid use, particularly with potent formulations. There
is an impression that fluorinated topical corticosteroids are particularly likely to contribute to POD,
which may be related to their high potencies, rather than a specific effect of fluorination [2,17,18].
Further support for a contributory role of corticosteroids arises from reports of POD that developed
after the administration of oral [19,20] or inhaled corticosteroids [21,22].
1081
The reason for an association between POD and corticosteroids remains unclear. Some authors
have suggested that corticosteroid-induced damage to the epidermal barrier may be a contributing
factor [7].
In addition to topical corticosteroids, several other factors have been proposed as potential
contributors to POD, including fluoridated toothpaste, skin moisturizers and cosmetic products,
fusobacteria, Candida albicans, hormonal fluctuations in women, and oral contraceptive therapy
[2,3,13,23-28]. Whether these factors truly contribute to the development of POD is uncertain [2,15].
Classic perioral dermatitis — POD typically manifests as multiple 1 to
2 mm, clustered, erythematous papules, papulovesicles, or papulopustules with or without mild
scale (picture 1A-L). In some patients, features consistent with a mild eczematous dermatitis also
are present. Occasionally, the eczematous component is prominent.
The inflammatory papules and scaling of POD occur most frequently in the perioral region, but a
narrow zone around the vermilion border of the lip is usually spared [3]. Less often, the perinasal and
periorbital areas are sites of significant involvement (picture 1K-L). In a retrospective study of 79
children and adolescents with POD, perioral, perinasal, or periocular lesions were present in 70, 43,
and 25 percent of patients, respectively [5]. Lesions in these classic locations may also be
accompanied by lesions in other areas, such as the cheeks, chin, forehead, and neck [5].
POD may be asymptomatic or may be accompanied by mild to moderate stinging or burning

sensations in the affected areas [7]. The skin lesions usually resolve without scarring.
Granulomatous periorificial
dermatitis — Granulomatous periorificial dermatitis represents a clinical variant of POD
that typically occurs in prepubescent children [29-32]. The term Afro-Caribbean childhood eruption
has also been used to describe this condition in black children. Children typically develop numerous
small, flesh-colored, red-brown, or yellow-brown, inflammatory papules in perioral, perinasal, or
periocular areas (picture 2). Papulopustules and papulovesicles are typically absent, and,
occasionally, sites other than the face are affected [33,34].
Disease course — POD is generally considered a benign and self-limited disorder.

In some patients, POD resolves within a few months without pharmacologic therapy, while in others,
the disorder may persist for several years [35].
Topical corticosteroid use may contribute to the chronicity of POD. Although improvement may be
noted early in the course of corticosteroid treatment, continued use may perpetuate or exacerbate
the disorder [2,5]. (See 'Elimination of corticosteroids and irritants (zero therapy)' below.)
1082
DIAGNOSIS The diagnosis of POD can usually be made via assessment of the
patient history and recognition of the classic clinical features. The presence of multiple small,
inflammatory papules, papulovesicles, or papulopustules clustered on the perioral, perinasal, or
periocular skin suggests this diagnosis (picture 1A-L). The following additional findings also support
a diagnosis of POD:
●Sparing of the skin immediately adjacent to the vermilion border of the lip.
●Coexisting features of eczematous dermatitis.
●Burning or stinging sensations.
●Recent use of topical, nasal, or inhaled corticosteroids.
●History of disease flares after topical corticosteroid withdrawal.
●Absence of comedones (comedones are a manifestation of acne vulgaris).
Skin biopsies are rarely necessary, but a small punch biopsy (eg, 3 mm punch) can be used to
differentiate POD from other disorders when the diagnosis is uncertain. The histopathologic findings
of POD are nonspecific and vary with the type of lesion biopsied: Scaling, eczematous-appearing
areas show parakeratosis, epidermal spongiosis, and mild acanthosis, and biopsies of papules
typically exhibit perifollicular and perivascular lymphocytic infiltrates. Biopsies taken from lesions of
granulomatous periorificial dermatitis demonstrate epithelioid granulomas that resemble those
found in granulomatous rosacea [36-38]. (See "Approach to the patient with facial erythema", section
on 'Biopsy' and "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Granulomatous
rosacea'.)
Serologic studies are not useful for confirming a diagnosis of POD.
DIFFERENTIAL DIAGNOSIS Multiple other skin

disorders may present with inflammatory eruptions around the mouth, nose, or eyes. Examples
●Acne vulgaris – Acne vulgaris is a common disorder that manifests as comedones and
inflammatory papules or pustules (picture 3A-B). Although the detection of comedones on the skin
supports a diagnosis of acne vulgaris, acne vulgaris and POD may coexist. Unlike acne vulgaris,
scarring is uncommon in POD. (See "Pathogenesis, clinical manifestations, and diagnosis of acne
vulgaris", section on 'Clinical manifestations'.)
●Rosacea – Papulopustular rosacea presents with inflammatory papules and pustules that are
primarily distributed on the central face (picture 4). Centrofacial erythema and telangiectasias may
also be present. A predilection for the cheeks rather than periorificial sites suggests a diagnosis of
1083
papulopustular rosacea. In the absence of other findings consistent with rosacea, lesions of
granulomatous rosacea may be impossible to distinguish from granulomatous periorificial
dermatitis. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
●Seborrheic dermatitis –Seborrheic dermatitis is a common inflammatory condition that frequently

presents with erythema and scale involving the perinasal skin (picture 5). Scaling macules and
patches are typically present. In contrast to POD, small papules are not a typical feature of
seborrheic dermatitis, and a perioral distribution is unusual in seborrheic dermatitis. The detection
of seborrheic dermatitis in other commonly affected sites, such as the scalp, eyebrows, nasolabial
folds, and chest, can be useful for diagnosis. (See "Seborrheic dermatitis in adolescents and
adults".)
●Allergic contact dermatitis – Allergic contact dermatitis is a manifestation of a type IV

hypersensitivity reaction to agents that come in contact with the skin. Patients may present with
inflammatory papules, vesicles, weeping, or crusting (picture 6). The distribution of lesions is
dependent upon the specific sites of contact with the inciting agent. Unlike POD, intense pruritus is
usually present, scale is often prominent, and lesions fail to improve with antibiotic therapy. (See
"Clinical features and diagnosis of allergic contact dermatitis".)
●Irritant contact dermatitis – The clinical findings of irritant contact dermatitis vary based upon the
nature of the external insult and site of involvement. Papules, vesicles, scale, erythema, or edema
may be seen. Unlike allergic contact dermatitis, but similar to POD, a burning sensation, rather than
pruritus, is often the predominating symptom. The patient history is of value for identifying this
diagnosis. As an example, irritant dermatitis related to chronic lip-licking behavior can resemble POD
(picture 7). (See "Irritant contact dermatitis in adults".)
●Impetigo – Impetigo is a common staphylococcal or streptococcal skin infection that most

frequently occurs in children. The perinasal skin is a common site for involvement. Erosions,
vesicles, and yellow crusts may be present (picture 8). Scaling and acne-like papules are
uncommon. Gram stains and bacterial cultures can be used to confirm this diagnosis. (See
"Impetigo".)
●Dermatophyte infections – Tinea corporis and tinea barbae may present with inflammatory
papules or pustules on the face (picture 9). Unlike POD, dermatophyte infections almost always have
an asymmetrical distribution. A potassium hydroxide preparation (KOH) is useful for diagnosis. (See
"Dermatophyte (tinea) infections" and "Office-based dermatologic diagnostic procedures", section on
'Potassium hydroxide preparation'.)
Less common causes of facial lesions that may exhibit features suggestive of POD include Demodex
folliculitis (which can demonstrate numerous Demodex mites on KOH preparation), lupus miliaris
disseminatus faciei (which may represent a variant of rosacea) (picture 10), cutaneous sarcoidosis
(picture 11), gram-negative folliculitis, eosinophilic folliculitis with or without associated HIV
infection, and cutaneous syringomas. (See "Infectious folliculitis" and "HIV-associated eosinophilic
folliculitis".)
1084
MANAGEMENT The management of POD generally involves the
discontinuation of topical corticosteroids, avoidance of topical products that may promote or
exacerbate POD, and pharmacologic therapy (algorithm 1). Although POD may improve within a few
months with the first two interventions, distress over the appearance of POD and the disease's
unpredictable course cause most patients to desire intervention to reduce the duration of
symptoms. Limited data suggest that some pharmacologic therapies are useful; disease severity
influences the selection of treatment. (See 'Disease course' above and 'Elimination of corticosteroids
and irritants (zero therapy)' below and 'Mild disease' below and 'Moderate to severe disease' below.)
All patients — Elimination of corticosteroids and skin irritants is considered an

important therapeutic measure for all patients with POD.
Elimination of corticosteroids and irritants (zero

therapy) — The discontinuation of topical corticosteroids and avoidance of skin care
products and cosmetics that may irritate or occlude the skin is also referred to as "zero therapy."
This approach is supported by the observation that many vehicle- or placebo-treated patients in
randomized trials have improved within two to three months without active therapy [12,39,40].
Although the cessation of topical corticosteroid use is accepted as an important component of

management, patients typically become distressed when disease flares occur following cessation.
Some clinicians attempt to reduce the likelihood of a rebound flare by either transitioning patients
utilizing high- or medium-potency topical corticosteroids to low-potency agents (eg, hydrocortisone
1%) or slowly tapering the frequency of corticosteroid application prior to treatment cessation
[3,6,8,16]. The benefit of these techniques is unproven.
An effort to minimize potential skin irritants and allergens typically involves [8,24]:
●Gentle skin cleansing practices (gently cleansing the skin with a fragrance-free, nonsoap cleanser
promptly followed by complete and gentle rinsing of the cleanser from the skin)
●Limiting the use of topical products (eg, cosmetics, sunscreens, emollients) on the face to the
occasional "only as needed" application of a bland, nonocclusive moisturizing lotion
Once stable remission is attained, skin care products may be slowly restarted (eg, one product per
week). The patient should pay close attention to the skin's response to each product. Products that
seem to induce recurrences should be promptly discontinued.
Mild disease — Mild POD may be considered the presence of lesions that involve a
relatively small area of facial skin and do not cause the patient significant emotional distress
(picture 1A-B, 1D, 1F). In an attempt to accelerate clinical improvement in children and adults with
mild disease, we usually prescribe topical medication in addition to zero therapy.
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Initial therapy — We prefer topical therapy rather than systemic therapy for the initial
treatment of mild POD due to the relatively low risk for drug-induced systemic adverse effects. We
favor topical pimecrolimus, a calcineurin inhibitor, as this agent has the most evidence in support of
its efficacy [12,39,41,42]. However, the expense of this drug is a limiting factor. Topical erythromycin
and topical metronidazole are less expensive options for therapy.
Pimecrolimus
●Administration – Pimecrolimus 1% cream is applied to the affected area twice daily. Signs of
improvement typically occur within the first month of therapy. (See 'Moderate to severe disease'
below.)
Treatment with pimecrolimus is usually well tolerated. Although the US Food and Drug
Administration has placed a boxed warning on topical calcineurin inhibitors due to concerns about
an association between these agents and malignancies, the risk for such events appears to be
minimal [43]. (See "Treatment of atopic dermatitis (eczema)", section on 'Long-term safety
concerns'.)
●Efficacy – In a multicenter randomized trial in which 124 adults were treated for up to four weeks
with twice-daily applications of pimecrolimus 1% cream or a vehicle cream, pimecrolimus therapy
was associated with more rapid improvement [12]. After eight days, greater than 50 percent
reductions in disease severity scores occurred in 24 of 60 patients in the pimecrolimus group (40
percent) and only 7 of 64 patients in the vehicle group (11 percent). In addition, the median time to
response was 14 versus 28 days. Patients with a history of topical corticosteroid use appeared to
respond best to pimecrolimus. However, the benefit of pimecrolimus dissipated over time; by day 29,
disease severity scores were similar in both groups.
The efficacy of pimecrolimus for POD was also supported by a smaller randomized trial in which 40
adults were treated with either pimecrolimus 1% cream or vehicle cream applied twice daily [39].
Throughout the four weeks of treatment, the reduction in disease severity was greater in patients
treated with pimecrolimus, and after the first week of treatment, at least a 50 percent reduction in the
disease severity score was present in 50 versus 15 percent of patients. As in the larger trial, the
duration of treatment benefit was limited. Four weeks after the end of treatment, the response rates
were similar in both groups. No randomized trials of pimecrolimus therapy have been performed in
children.
In the randomized trials, adverse effects were mild and primarily limited to the sites of treatment,
and post-treatment disease flares did not appear to occur after the cessation of pimecrolimus
[12,39].
Topical erythromycin
●Administration – We typically prescribe twice-daily application of erythromycin 2% gel.
Improvement is usually evident within four to eight weeks.
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●Efficacy – The efficacy of topical erythromycin for POD is supported by an 80-day randomized trial
and documentation of clinical experience [40,44]. In the randomized trial, 99 patients who were
treated with either a topical erythromycin emulsion containing 1% erythromycin base (treatment
regimen unspecified), oral tetracycline (500 mg twice daily for 10 days and 250 mg twice daily for 10
days), or a placebo pill returned for the assessment of the response to therapy [40]. Both drugs were
superior to placebo, and statistically significant differences between the response to topical
erythromycin and oral tetracycline were not detected. (See 'Oral tetracyclines' below.)
Topical metronidazole
●Administration – We typically prescribe metronidazole lotion, gel, or cream (0.75% or 1%) once
daily and continue treatment for at least eight weeks. Improvement is often noted within this period,
but longer periods of treatment may be required for complete clearing [5,16].
●Efficacy – Metronidazole 1% cream was compared with oral tetracycline (250 mg twice daily) in an
eight-week randomized trial of 108 patients [35]. Patients in both groups improved, but the response
of papular lesions was slower with metronidazole therapy (see 'Oral tetracyclines' below). Additional
data on topical metronidazole come from small case series and case reports that document efficacy
in children [15,45].
Course and follow-up — Patients who demonstrate progressive improvement

with topical therapy may discontinue treatment upon resolution. We typically advise these patients
to continue gentle skin care practices and to engage in cautious reintroduction of skin care
products. (See 'Elimination of corticosteroids and irritants (zero therapy)' above.)
Patients who do not demonstrate progressive improvement within four to eight weeks with topical
pimecrolimus, erythromycin, or metronidazole may proceed to the oral therapies used for more
severe disease (algorithm 1). (See 'Moderate to severe disease' below.)
Moderate to severe disease — Moderate to severe POD may be

considered POD with numerous papules, large areas of confluent involvement, or bothersome
symptoms or significantly emotionally distressing POD (picture 1E-G, 1I-J). This category may also
include milder disease that has failed to resolve with topical therapy.
Adolescents and adults — Oral tetracyclines are the most common agents
used for systemic treatment of POD and are the preferred therapies for adolescents or adults with
moderate to severe POD. Oral erythromycin is an alternative for patients who cannot tolerate
tetracyclines. (See 'Children' below.)
Oral tetracyclines — Although oral tetracyclines (eg, tetracycline, doxycycline,

minocycline) are accepted as effective treatments for POD [2,46-49], the mechanism through which
these agents improve POD is unknown. Anti-inflammatory effects may account for their efficacy.
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●Administration – A typical course of oral tetracyclines for POD is approximately eight weeks.
Typical doses for adolescent and adult patients with POD are:
•Tetracycline (250 to 500 mg twice daily)
•Doxycycline (50 to 100 mg twice daily or 100 mg once daily)
•Minocycline (50 to 100 mg twice daily or 100 mg once daily)
Treatment with tetracyclines is generally well tolerated. Gastrointestinal distress is a common

adverse effect. Other potential side effects include photosensitivity and skin dyspigmentation.
●Efficacy –Two randomized trials support the use of tetracycline in POD:
•Tetracycline (500 mg twice daily for 10 days followed by 250 mg twice daily for 10 days) was
compared with a topical erythromycin emulsion (treatment regimen unspecified) and a placebo pill
in an 80-day unblinded randomized trial in which 99 out of 120 patients returned for follow-up
evaluation [40]. Papule counts were significantly lower in the tetracycline group than in the placebo
group between days 20 to 40, suggesting tetracycline therapy increased the rate of improvement. At
day 40, more than 80 percent of patients in the placebo group had more than 10 papules remaining,
compared with none of the patients treated with tetracycline. The trial did not find significant
differences in the efficacy of oral tetracycline and topical erythromycin. (See 'Topical erythromycin'
above.)
•An eight-week multicenter randomized trial of 108 adult patients with moderate POD compared oral
tetracycline (250 mg twice daily) with twice-daily applications of metronidazole 1% cream [35].
Although both agents were associated with reduced lesion counts, patients treated with tetracycline
improved more quickly. Significantly greater reductions in lesion counts were present in patients
treated with tetracycline at four weeks (96 versus 67 percent) and eight weeks (100 versus 92
percent). Improvement in skin erythema was similar in the two groups.
A third randomized trial failed to find a difference in efficacy between oral tetracycline and no
therapy [50]. However, the quality of this trial was poor, and the results were inconsistent with the
findings of other studies [46].
No randomized trials have evaluated the efficacy of doxycycline and minocycline, and their wide use
is primarily based upon the evidence from the studies of tetracycline and a few case reports [19,51].
Alternative therapy — Treatment with a macrolide, similar to the approach in young

children, is an option for adolescents and adults who cannot tolerate tetracyclines (algorithm 1). We
generally treat adults with erythromycin base (333 mg three times per day or 500 mg twice daily).
Administration with food may help to decrease associated gastrointestinal discomfort. (See
'Children' below.)
1088
Children — In children, topical therapy is often tried prior to systemic therapy because of
ease of administration and concern for side effects. If systemic therapy is necessary, the age of the
child impacts drug selection (algorithm 1).
Although older children may be treated with tetracyclines, oral erythromycin is the preferred
systemic agent for young children and other patients who cannot tolerate tetracyclines.
Tetracyclines are contraindicated in children under eight years of age because of adverse effects on
permanent teeth and bone. Although durations of tetracycline treatment under 22 days are generally
considered safe in young children, longer courses are generally used for POD. (See "Tetracyclines",
section on 'Young children' and 'Oral tetracyclines' above.)
The optimal dose of erythromycin for POD has not been established. We generally treat children over
four years of age with 40 mg/kg per day divided into three doses up to a maximum dose of 1000 mg
per day. Administration with food may help to decrease associated gastrointestinal discomfort.
Oral erythromycin has not been evaluated in randomized trials, but, based upon case reports and
case series, the drug may be effective [5,33,52-55]. Gastrointestinal distress is an adverse effect that
may limit use of erythromycin in some patients. Administration with food may help to decrease
associated gastrointestinal discomfort. Oral azithromycin may be an alternative; azithromycin
appeared effective for POD in a case series [9].
Course and follow-up — Treatment with oral antibiotics is generally continued for
eight weeks. For patients who respond within this period, the antibiotic can be discontinued at the
end of this course of treatment. We typically advise these patients to continue gentle skin care
practices and to engage in cautious reintroduction of skin care products. (See 'Elimination of
corticosteroids and irritants (zero therapy)' above.)
The best approach to patients who fail treatment with oral tetracyclines or oral erythromycin is
unclear. In general, if improvement has not occurred within eight weeks, reevaluation to confirm the
diagnosis and review of patient adherence to management recommendations is prudent. If POD
remains the most likely diagnosis and there has been appropriate adherence to treatment, trials of
less commonly used therapies are reasonable. In our experience, we have found topical ivermectin
or topical sulfur-sulfacetamide sodium helpful. (See 'Other therapies' below.)
Other therapies — Limited data suggest that other therapies may be effective for
POD.
Clinical use of ivermectin for POD is increasing. However, no randomized trials have evaluated use
of topical or oral ivermectin for POD. In a retrospective study that included four children treated with
compounded topical 1% ivermectin (applied once daily for three months), all achieved complete or
almost complete clearance of POD [56]. Treatment was well tolerated; one child experienced
1089
transient, mild desquamation. In the same study, all of three children treated with a single dose of
oral ivermectin (200 to 250 micrograms/kg) achieved complete or almost complete clearance of
disease. Oral ivermectin also was well tolerated. Two children had transient, mild desquamation.
Additional local therapies reported to be of benefit in small uncontrolled or case report studies
include azelaic acid 20% cream [57,58], topical clindamycin with or without hydrocortisone 1% lotion
[52,59], topical tetracycline [60], adapalene 0.1% gel [61], and topical sulfacetamide-sulfur combined
with oral tetracycline [62]. Efficacy of oral isotretinoin for refractory granulomatous periorificial
dermatitis has been described in case reports [63,64], and oral metronidazole appeared to resolve
granulomatous periorificial dermatitis in a child [65]. Marked improvement of POD linked to
fusobacteria after treatment with oral beta-lactam antibiotics has been reported in three children
[66]. In addition, we have anecdotally noted good responses of POD to topical precipitated sulfur in
patients with contraindications to standard treatments.
Tacrolimus ointment, another topical calcineurin inhibitor, has been associated with improvement in
granulomatous periorificial dermatitis in a few patients [7,32,51]. However, the development of
rosacea-like eruptions has also been associated with treatment with this agent [67]. Efficacy data
are too limited to recommend routine use of topical tacrolimus therapy.
Photodynamic therapy may be another option for the treatment of POD. This intervention was more
effective than clindamycin gel in a split-face study of 21 patients [59]. However, seven patients
dropped out of the study due to skin irritation related to photodynamic therapy, and three patients
developed treatment-related postinflammatory hyperpigmentation.
Further study is necessary to determine the efficacy of all of these agents.
PROGNOSIS Prognostic data on POD are limited. In a retrospective study of

222 children with POD, of the 131 children who presented for follow-up visits, 94 (72 percent) had
complete resolution of symptoms, and the average time to resolution of POD was 3.8 months [9].
Children in the study received topical and/or oral therapy.
The risk for disease recurrence after resolution has not been established. In our experience,
recurrences are common and can occur a few years after successful treatment.
SUMMARY AND
RECOMMENDATIONS
●Perioral dermatitis (POD), also known as periorificial dermatitis, is an inflammatory condition of
facial skin that primarily affects young women. Less frequently, the disorder occurs in older
individuals, men, and children. (See 'Epidemiology' above.)
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●Although a variety of intrinsic and extrinsic factors have been proposed as contributors to POD, the
pathogenesis of this disorder is not well understood. The factor most frequently reported in
association with the occurrence or persistence of POD is topical corticosteroid use. (See 'Etiology
and pathogenesis' above.)
●Patients with POD typically present with small, inflammatory papules, papulovesicles, or
papulopustules and scaling surrounding the mouth, nose, or eyes (picture 1A-L). In patients with
perioral lesions, the skin adjacent to the lip border is typically spared. (See 'Clinical manifestations'
above.)
●Chronic granulomatous periorificial dermatitis is a variant of POD that is typically seen in

prepubertal children (picture 2). Histopathologic examination of lesional skin reveals a
granulomatous infiltrate in these patients. (See 'Clinical manifestations' above.)
●The clinical history and physical examination is usually sufficient for the diagnosis of POD. The
histopathologic findings of POD are nonspecific, and skin biopsies are rarely necessary. (See
'Diagnosis' above.)
●The treatment of POD involves the discontinuation of topical corticosteroids and the avoidance of
skin irritants. Although patients may eventually improve without additional interventions,
pharmacologic therapy is often instituted in an attempt to accelerate lesion resolution (algorithm 1).
(See 'Management' above.)
●For adults and children with mild POD who desire an attempt to accelerate improvement, we
suggest treatment with topical pimecrolimus (Grade 2A). Topical erythromycin and topical
metronidazole are additional, less expensive options for therapy. (See 'Mild disease' above.)
●For adolescents and adults with moderate to severe POD or with milder disease refractory to
topical agents who desire an attempt to accelerate improvement, we suggest treatment with oral
tetracycline (Grade 2B). Doxycycline and minocycline may also be used for treatment. The response
to oral antibiotic therapy is often slow; a typical course of treatment is eight weeks. (See 'Moderate
to severe disease' above.)
●For children under the age of eight with moderate to severe POD or who fail treatment with topical
agents, we suggest treatment with oral erythromycin (Grade 2C). Oral azithromycin is an alternative.
Young children should not be treated with oral tetracyclines due to the potential for adverse effects
on tooth and bone development. (See 'Children' above.)
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Rosacea: Pathogenesis, clinical features, and diagnosis
uptodate.com/contents/rosacea-pathogenesis-clinical-features-and-diagnosis/print
INTRODUCTION Rosacea is a common, chronic disorder that can present

with a variety of cutaneous or ocular manifestations. Skin involvement primarily affects the central
face, with findings such as persistent centrofacial redness, papules, pustules, flushing,
telangiectasia, and phymatous skin changes (eg, rhinophyma). Ocular involvement may also occur,
manifesting with lid margin telangiectases, conjunctival injection, ocular irritation, or other signs and
symptoms.
The pathogenesis, clinical manifestations, and diagnosis of rosacea will be reviewed here. The
treatment of rosacea is discussed separately. (See "Management of rosacea".)
EPIDEMIOLOGY Rosacea is a common disorder that is most frequently

observed in individuals with lightly pigmented skin (skin phototypes I and II (table 1)). People of
Celtic and Northern European origin appear to have the greatest risk for this disorder [1,2]. The
prevalence of rosacea is difficult to assess due to its variable clinical manifestations and the wide
variety of skin disorders that exhibit similar clinical features (see 'Differential diagnosis' below).
Estimates of the prevalence of rosacea in fair-skinned populations range from 1 to 10 percent [1,3,4].
1092
Rosacea occurs in people with greater skin pigmentation but is less frequently diagnosed in such
populations (picture 1A-B) [5-10]. It is unknown whether factors such as masking of facial redness
by abundant skin pigment, protective effects of melanin against ultraviolet radiation (an
exacerbating factor for rosacea), or genetic differences in susceptibility to rosacea contribute to the
lower rate of diagnosis in people with dark skin.
Adults over the age of 30 are the primary age group affected by rosacea, and the disorder occurs
more frequently in women than in men [1,11]. Patients with phymatous skin changes are an
exception; the vast majority of affected patients are adult males (picture 2). Rosacea occasionally
occurs in adolescents. In this population, rosacea is often mistaken for acne vulgaris. Rarely,
rosacea occurs in children. Children may exhibit all subtypes except phymatous changes, and
symptoms may persist into adulthood [12-14].
Analyses of data from the Nurses' Health Study II suggest that obesity, a past smoking history, and
increased alcohol consumption may be risk factors for rosacea in women [15-17].
PATHOGENESIS The pathways that lead to the development of rosacea

are not well understood [18,19]. Proposed contributing factors include abnormalities in innate
immunity, inflammatory reactions to cutaneous microorganisms, ultraviolet damage, and vascular
dysfunction.
Immune dysfunction — The innate immune system plays a key role in the
cutaneous immune response to microorganisms and to insults, such as ultraviolet radiation and
physical or chemical trauma [20]. Dysfunction of the innate immune system may contribute to the
development of chronic inflammation and vascular abnormalities in rosacea.
The process through which aberrations of the innate immune system may contribute to rosacea may
involve the production of abnormal cathelicidin peptides that have vasoactive and inflammatory
properties [20]. Increased levels of abnormal cathelicidin and kallikrein 5 (a processing enzyme for
cathelicidin that is also known as stratum corneum tryptic enzyme) have been detected in skin from
patients with rosacea [21].
The subsequent discovery that toll-like receptor 2, a component of the innate immune system that
interacts with environmental stimuli, can stimulate release of kallikrein 5 from epidermal
keratinocytes offers a potential explanation for a link between environmental insults and
cathelicidin-mediated abnormalities in rosacea [22]. Moreover, a study in which the injection of
mouse skin with cathelicidin peptides from patients with rosacea led to inflammation and vascular
dilatation provides additional evidence to implicate cathelicidin as a pathogenic factor [21].
Microorganisms — Stimulation of inflammatory reactions by microbes in or on

the skin has been proposed as an inciting factor for cutaneous inflammation in rosacea.
1093
Demodex — Demodex folliculorum is a saprophytic mite that resides in sebaceous follicles.
Although Demodex mites can be found on normal skin in almost all adults, increased density of
Demodex mites in patients with rosacea has been reported in multiple studies [23-26]. In a meta-
analysis of case-control studies, a statistically significant association between Demodex infestation
and rosacea was detected, with the degree of infestation being more important than the rate of
infestation [23]. The role of Demodex mites as an inciting factor for rosacea remains uncertain.
Bacillus olenorium — The knowledge that papulopustular rosacea improves with

antibiotic therapy led to an in vitro study investigating Bacillus oleronius, a bacterium that was
isolated from a single Demodex mite, as a potential cause of inflammation in rosacea [27]. The study
found that antigens from B. oleronius stimulated proliferation of peripheral blood mononuclear cells
from 16 out of 22 patients with rosacea (73 percent) versus only 5 out of 17 patients without
rosacea (29 percent). Additional studies are necessary to determine whether B. oleronius is a
common colonizer of Demodex mites and whether the organism is involved in the pathogenesis of
rosacea.
Helicobacter pylori — A role for gastrointestinal Helicobacter pylori infection in

rosacea is controversial. Data conflict on whether the prevalence of H. pylori infection is increased in
patients with rosacea and reports of improvement in rosacea following antibiotic therapy for H. pylori
infection may be attributable to anti-inflammatory effects of the antibiotics used for treatment [28]. A
meta-analysis of 14 observational studies did not find a significant association between H. pylori
infection and rosacea (odds ratio 1.68, 95% CI 1.00-2.84) nor an effect of H. pylori eradication therapy
on rosacea symptomatic improvement (relative risk 1.28, 95% CI 0.98-1.67) [29].
Other — Staphylococcus epidermidis [30,31], Chlamydia pneumoniae [32], and small intestine
bacteria [33] have been linked to rosacea in a few studies. Additional investigation is necessary to
determine whether any of these organisms have a significant impact on the development of rosacea.
Ultraviolet radiation — Sun exposure is often cited as an exacerbating factor

for rosacea, based upon the distribution of lesions on chronically sun-exposed skin, the detection of
signs of solar elastosis on skin biopsy specimens, and the preferential appearance of the disorder in
fair-skinned individuals.
Several theories on the mechanisms through which sun exposure could promote rosacea have been
proposed. Ultraviolet B radiation has been shown to induce cutaneous angiogenesis in mice and can
stimulate the secretion of vascular endothelial growth factor (VEGF)-2 and fibroblast growth factor
(FGF)-2 from keratinocytes [34-36]. Ultraviolet radiation may also stimulate production of damaging
reactive oxygen species and may incite activation of the innate immune system [20].
However, study data confirming an association between all phenotypes of rosacea and ultraviolet
radiation are lacking [37]. Fewer than one-third of patients with rosacea report exacerbations of
symptoms with sunlight [37], and a retrospective study in Korea of 168 patients with rosacea found
1094
that although high daily sun exposure correlated with increased severity of erythematotelangiectatic
disease, it did not appear to have a significant effect on papulopustular, phymatous, or ocular
rosacea [8]. In addition, a study of 1000 adults in Ireland found no difference in the prevalence of
papulopustular rosacea in subjects with high sun exposure versus those with lower sun exposure
[4]. Further studies are necessary to explore the impact of ultraviolet radiation on rosacea.
As noted above, extremes of temperature can be an exacerbating factor for rosacea. Thus, aside
from ultraviolet light, infrared radiation (radiant heat) from sun exposure could contribute to
exacerbations of rosacea.
Vascular hyperreactivity — Frequent and prolonged flushing is a

common feature in rosacea, and triggers of flushing (eg, spicy foods, alcohol, and extremes of
temperature) have been anecdotally associated with worsening disease (see 'Exacerbating factors'
below). In addition, increased blood flow has been detected in the skin of some patients [10,38].
These observations suggest a role for vascular hyperreactivity in the pathogenesis of this disorder
[20]. Dysregulation of thermal mechanisms has also been proposed as a contributing factor to
flushing in rosacea [37].
The pathways that may lead to neurovascular dysregulation in rosacea are not well understood. One
theory proposes that activation of transient receptor potential vanilloid 1 and transient receptor
potential ankyrin 1 (receptors found on primary sensory neuron endings as well as keratinocytes) by
triggers of rosacea (eg, extremes of temperature, spices, etc) may stimulate the release of
vasoactive peptides that exacerbate rosacea [39].
Data conflict on whether rosacea is more common among people with migraines (another disorder
proposed to involve vascular dysregulation) [40-44]. A large, population-based, case-control study
found a slight increase in risk among women but did not identify a statistically significant
association between migraines and rosacea in men [40].
Genetics — Individuals with a family history of rosacea may be more likely to develop the
disorder [11]. One proposed risk factor is a polymorphism of the VEGF gene (+405C/G) [45]. Further
studies are necessary to explore the impact of family history and genetic background on risk for
rosacea.
CLASSIFICATION In 2002, the National Rosacea Society assembled an

expert committee to develop a standard classification system for rosacea. The committee
established four distinct subtypes of rosacea: erythematotelangiectatic, papulopustular, phymatous,
and ocular rosacea [46]. Since then, increasing knowledge of the pathophysiology of rosacea has
favored a view of rosacea as a consistent multivariate disease process with multiple clinical
manifestations rather than distinct subtypes of disease [47,48].
1095
Following recommendations from the Global Rosacea Consensus (ROSCO) Panel supporting use of
phenotype-based, rather than a subtype-based, approach to the diagnosis and classification of
rosacea, the National Rosacea Society expert committee released an update supporting a similar
approach [47,49]. The phenotype-based approach describes the individual clinical features of
rosacea and divides them into diagnostic, major, and secondary (or minor) features/phenotypes.
(See 'Clinical features' below and 'Diagnosis' below.)
CLINICAL FEATURES The various phenotypes of rosacea are

listed below. Recognition of these features is essential for diagnosis (see 'Diagnosis' below):
●Centrofacial erythema – Patients with rosacea may exhibit chronic redness of the nose and medial
cheeks (picture 3A-B). Involvement of other sites, such as the ears, lateral face, neck, scalp, and
chest, occasionally occurs [37].
●Phymatous changes – Phymatous rosacea exhibits tissue hypertrophy manifesting as thickened

skin with irregular contours (picture 2). Involvement most commonly occurs on the nose
(rhinophyma) but may also be seen in other sites, such as the chin (gnathophyma), forehead
(glabellophyma), and cheeks. Patients who develop this subtype of rosacea often have prominent
sebaceous hyperplasia and very oily skin. The vast majority of patients with phymatous rosacea are
adult men.
●Papules and pustules – Rosacea can manifest with papules and pustules primarily localized to the
central face (picture 1A-D). Lesions may be mistaken for inflammatory acne vulgaris. Unlike acne
vulgaris, comedones do not occur in rosacea, and inflammation may extend outward well beyond
the follicular unit to form plaques. As an example, in occasional patients the whole nose may be
tender, swollen, and red.
●Flushing – This can be wet (accompanied by sweating) or dry and may be associated with subtle,
transient, facial swelling. Examples of triggers for flushing are provided. (See 'Exacerbating factors'
below.)
●Telangiectasia – Telangiectasias are visible, enlarged, cutaneous blood vessels (picture 4). In
rosacea, telangiectasias are predominantly located on the central face, especially on the cheeks.
●Ocular features – Ocular involvement occurs in more than 50 percent of patients with rosacea [50].
Ocular rosacea may precede (20 percent), follow (50 percent), or occur concurrently with cutaneous
disease [46]. Both children and adults may be affected [12,51]. Manifestations that strongly suggest
rosacea include lid margin telangiectases, interpalpebral conjunctival injection, spade-shaped
infiltrates on the cornea, scleritis, and sclerokeratitis (picture 5) [47]. Patients may also experience
symptoms of burning, stinging, light sensitivity, and foreign body sensation and may develop
chalazia, conjunctivitis, crusting on eyelashes, lid margin irregularity, and evaporative tear
dysfunction [47].
1096
●Burning or stinging – Stinging or burning sensations in affected areas are common in patients with
rosacea. Skin care products may irritate the skin and aggravate symptoms.
●Edema – During or after an exacerbation of facial redness, facial edema can occur and may persist
for days.
●Dry appearance of skin – A dry quality to the skin, manifesting as roughness and scaling, is often
present.
EXACERBATING FACTORS Multiple factors have been

anecdotally associated with exacerbations of cutaneous signs and symptoms of rosacea, including:
●Exposure to extremes of temperature
●Sun exposure
●Hot beverages
●Spicy foods
●Alcohol
●Exercise
●Irritation from topical products
●Psychologic feelings, especially anger, rage, and embarrassment
●Certain drugs, such as nicotinic acid and vasodilators
●Skin barrier disruption
In particular, an analysis of data reported by over 82,000 women in the Nurses' Health II Study found
a slight increase in risk for a history of clinician-diagnosed rosacea among women with alcohol
intake compared with women who denied use of alcohol [15]. In the past, phymatous skin changes
in rosacea were perceived by the lay public to be a consequence of heavy alcohol consumption.
However, definitive evidence in support of an association between alcohol and increased risk for
phymatous skin changes is lacking [37].
Although consumption of hot beverages has been considered an exacerbating factor for rosacea,
consumption of coffee may not increase risk for rosacea. Caffeine has vasoconstrictive and
immunosuppressive properties that could theoretically inhibit rosacea. An analysis of data from a
cohort of over 80,000 women in the Nurses' Health Study II supports the theory that consumption of
caffeinated coffee does not increase risk for rosacea [52]. The study found 4945 incident cases of
rosacea and detected an inverse relationship between increased caffeine intake and risk of incident
rosacea (hazard ratio [HR] for highest quintile of caffeine intake versus the lowest quintile of 0.76,
1097
95% CI 0.69-0.84). Moreover, women who consumed at least four servings of caffeinated coffee per
day had a lower risk of rosacea than those who consumed less than one serving per month (HR
0.77, 95% CI 0.69-0.87). There was not a relationship between intake of decaffeinated coffee and
rosacea, suggesting an effect of caffeine rather than other components of coffee. There was not a
significant relationship between increased caffeine intake from tea or soda and risk for rosacea,
which the authors postulated to be related to low consumption of caffeine from these sources.
ASSOCIATED DISEASES Rosacea may be associated with

increased risk for other diseases [53-55]. Examples of reported associations include:
●A Danish nationwide cohort study that included over 49,475 patients with rosacea and over 4.3
million general population controls found modest associations between rosacea and several
gastrointestinal diseases, including celiac disease (adjusted hazard ratio [aHR] 1.46, 95% CI 1.11-
1.93), Crohn disease (aHR 1.45, 95% CI 1.19-1.77), ulcerative colitis (aHR 1.19, 95% CI 1.02-1.39), and
irritable bowel syndrome (aHR 1.34, 95% CI 1.19-1.50) [56].
●An analysis of diagnostic data from 33,553 patients with rosacea and age- and sex-matched
controls in the National Health Insurance Research Database in Taiwan found modest increases in
risk for dyslipidemia (odds ratio [OR] 1.41, 95% CI 1.36-1.46), coronary artery disease (OR 1.35, 95%
CI 1.29-1.41), and hypertension (OR 1.17, 95% CI 1.12-1.21) among patients with rosacea [57].
●A review of data from 75,088 Caucasian women included in the Nurses' Health Study II found
increased risk for thyroid cancer (OR 1.59, 95% CI 1.07-2.36) and basal cell carcinoma (OR 1.50, 95%
CI 1.35-1.67) in women with a history of rosacea [58].
●A Danish nationwide cohort study including all citizens older than 18 years, followed up from 1997
to 2011, found an increased risk for glioma in patients with rosacea (incidence rate ratio [IRR] 1.36,
95% CI 1.18-1.58) [59]. In a case-control study including nearly 7000 patients with rosacea and
34,000 matched controls from the same Danish cohort, patients with rosacea had an increased risk
of autoimmune diseases, including type 1 diabetes mellitus, celiac disease, multiple sclerosis, and
rheumatoid arthritis [60].
●A slight increase in risk for any type of dementia or Alzheimer disease was detected among
patients with rosacea in a Danish nationwide cohort that included over 82,439 patients with rosacea
and over 5.5 million controls followed from 1997 to 2012 (aHR 1.07, 95% CI 1.01-1.14 and 1.25, 95%
CI 1.14-1.37, respectively) [61].
●A case-control study of 65 patients with rosacea and matched controls found that patients with
rosacea were more likely to report allergies, respiratory diseases, gastroesophageal reflux disease,
other gastrointestinal diseases, hypertension, metabolic diseases, urogenital diseases, and female
hormone imbalances [62].
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The reasons for the observed associations between rosacea and other diseases are unclear; a
shared role for systemic inflammation is postulated for the association between rosacea and
cardiovascular disease. Further study is necessary to confirm these associations and to determine
whether patients with rosacea require increased screening for systemic diseases.
DIAGNOSIS Clinical assessment of the patient is usually sufficient for the

diagnosis of rosacea. The diagnosis can be made based upon an assessment for diagnostic, major,
and minor phenotypes. At least one diagnostic phenotype or two major phenotypes are required for
diagnosis:
●Diagnostic phenotypes
•Fixed centrofacial erythema in a characteristic pattern that may periodically intensify
•Phymatous changes
●Major phenotypes
•Papules and pustules
•Flushing
•Telangiectasia
•Ocular manifestations (eg, lid margin telangiectases, interpalpebral conjunctival injection, spade-
shaped infiltrates in the cornea, scleritis, sclerokeratitis)
●Secondary phenotypes
•Burning or stinging
•Edema
•Dry appearance
The cutaneous histopathologic findings in rosacea are nonspecific, and skin biopsies are rarely
indicated. When the diagnosis is uncertain, biopsies may be performed to rule out other disorders or
to provide support for a diagnosis of granulomatous rosacea. No serologic studies are useful for
diagnosis.
Histopathology — Specimens from erythematous facial skin exhibiting

centrofacial erythema and telangiectasias usually show dilation of superficial blood vessels and a
low-grade perivascular, lymphohistiocytic, inflammatory infiltrate with occasional plasma cells. Solar
elastosis is often present.
1099
Histopathologic examination of papular lesions usually reveals prominent perivascular and
perifollicular inflammatory infiltrates in the superficial and mid-dermis composed of lymphocytes,
neutrophils, and plasma cells. Superficial accumulations of neutrophils are present in pustules. In
contrast to acne vulgaris, inflammation often is more perivascular and extends well beyond the
follicle [63]. Demodex mites are often detected in follicular orifices.
The histopathologic findings in skin exhibiting phymatous changes include sebaceous gland
hyperplasia, follicular plugging, telangiectasias, pronounced dermal thickening and fibrosis, and
large amounts of dermal mucin. Increased numbers of Factor XIIIa positive cells may be present in
the dermis [64,65].
Referral to ophthalmology — Patients who have ocular symptoms or

who are found to have visible signs suggestive of ocular involvement should be referred to
ophthalmology for further evaluation.
DIFFERENTIAL DIAGNOSIS A variety of skin

conditions may present with clinical features that resemble rosacea.
Centrofacial erythema — Not all patients with red faces have rosacea.
(See "Approach to the patient with facial erythema".)
The following conditions share features with centrofacial erythema of rosacea:
●Ruddy complexion – Some fair-skinned patients, particularly those of Celtic origin, may have a
naturally ruddy complexion to the skin. In contrast to the ruddy complexion, redness in rosacea
primarily involves the central face.
●Sun-damaged skin – Telangiectasia may occur as a manifestation of sun-damaged skin.

Dyspigmentation and skin wrinkling are often also present. In contrast to rosacea, which primarily
affects the central face, sun damage is often most evident on the lateral face and neck. The
presence of other characteristics of rosacea, such as persistent facial erythema and frequent
flushing, also support a diagnosis of rosacea.
●Seborrheic dermatitis –Macular erythema and scale involving the perinasal area is a common
finding in seborrheic dermatitis (picture 6). A greasy quality to the scale and involvement of other
sites, such as the scalp, retroauricular skin, and brow, suggest this diagnosis. (See "Seborrheic
dermatitis in adolescents and adults".)
●Acute cutaneous lupus erythematosus – The centrofacial redness in rosacea may be confused
with malar erythema of systemic lupus erythematosus, particularly in patients who lack
papulopustular lesions (picture 7A-B). In acute cutaneous lupus erythematosus, the color of the skin
has a violaceous quality and may show a more abrupt cutoff, especially at its most lateral margins
(resembling a butterfly wing).
1100
Serologic testing for antinuclear antibodies in all patients with centrofacial erythema is not
indicated. Patients should be clinically assessed for signs or symptoms of systemic lupus
erythematosus; the need for laboratory work-up should be based upon the presence of
mucocutaneous or systemic findings suggestive of this disorder. Skin biopsies of acute cutaneous
lupus erythematosus usually (but not always) demonstrate interface dermatitis characterized by
necrotic keratinocytes, intraepidermal lymphocytes, basal vacuolar degeneration, colloid bodies, and
melanin incontinence. Although biopsies of rosacea may exhibit occasional intraepidermal
lymphocytes and pyknotic keratinocytes, true interface dermatitis does not occur in rosacea [66].
Differences in the likelihood of other pathologic findings have also been reported [66]. (See
"Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus'.)
●Dermatomyositis – Dermatomyositis is an idiopathic inflammatory disorder that can affect skin

and muscle tissue. Violaceous erythema involving the periorbital skin and central face can occur.
The dusky, violaceous color of the facial eruption differs from the bright erythema that is typically
seen in rosacea (picture 8). Examination for muscle weakness and other cutaneous signs of
dermatomyositis is useful for diagnosis. Like acute cutaneous lupus erythematosus, skin biopsies
reveal features of an interface dermatitis. (See "Clinical manifestations of dermatomyositis and
polymyositis in adults", section on 'Skin findings'.)
●Other flushing disorders – In addition to rosacea, facial flushing may occur in a wide variety of
disorders. Examples include medication reactions, menopausal hot flashes, neurologic disorders,
carcinoid syndrome, mastocytosis, pheochromocytoma, medullary thyroid carcinoma, and serotonin
syndrome. The possibility of such disorders should be considered in patients who present with
flushing. (See "Approach to flushing in adults".)
Papules and pustules — The following papular and pustular disorders

share features with rosacea:
●Acne vulgaris – Acne vulgaris is the most common skin disorder in the differential diagnosis of
papulopustular rosacea. Individual inflammatory lesions of the two disorders may appear clinically
identical. A key distinguishing feature between acne vulgaris and rosacea is the absence of
comedones in rosacea (picture 9). A prominent centrofacial distribution also suggests a diagnosis
of rosacea. Acne vulgaris and rosacea coexist in some patients. (See "Pathogenesis, clinical
manifestations, and diagnosis of acne vulgaris".)
●Topical corticosteroid-induced acneiform eruptions – Topical corticosteroid use can result in the
appearance of monomorphic inflammatory papules on facial skin. The patient history is valuable for
diagnosis. Topical corticosteroids can also cause redness and burning skin sensations as a
consequence of overuse. (See "Topical corticosteroids: Use and adverse effects", section on
'Cutaneous'.)
●Perioral dermatitis – Perioral dermatitis presents with numerous small papules with fine scale in
the perioral area (picture 10A-B). Sparing of the skin adjacent to the vermillion border of the lip is
characteristic. Lesions may also occur in periorbital and perinasal distributions. In patients who
1101
have erroneously attempted to treat the eruption with topical corticosteroids, acneiform eruptions
may also be present.
●Keratosis pilaris rubra faceii – Persistent, rough, 1 to 2 mm follicularly-based papules on the face
can occur as a manifestation of keratosis pilaris in children, adolescents, and young adults (picture
11). The condition presents with a rough, red, symmetrical, triangular patch of skin on each cheek
that lacks papules or pustules. Typical keratosis pilaris also may be present on the backs of the
arms and fronts of the thighs (picture 12A-B).
●Demodicosis (Demodex folliculitis) –Demodicosis can present with numerous inflammatory

papules on the face and is difficult to distinguish from papulopustular rosacea on clinical
examination [67]. Potassium hydroxide (KOH) preparation, skin surface sampling with cyanoacrylate
adhesive (superglue) [25], or skin punch biopsy may demonstrate numerous Demodex mites.
However, Demodex mites are also commonly detected in rosacea and in normal skin. Therefore,
finding Demodex mites in a skin surface sample or skin biopsy specimen does not necessarily
indicate demodicosis.
Immunocompromised patients are at increased risk for this disorder. Multiple therapies have been
reported to be effective for demodicosis in individual patients. Examples include topical permethrin,
topical crotamiton, oral ivermectin, and topical or oral metronidazole [67-71]. (See "Office-based
GRANULOMATOUS ROSACEA The relationship

of granulomatous rosacea to other presentations of rosacea has been debated, but in 2002, a
committee of experts recognized this disorder as a possible variant of rosacea [46]. Granulomatous
rosacea presents with yellow-brown or pink, persistent papules that are usually distributed on the
cheeks and periorbital or perioral skin; background facial erythema and flushing are often absent. A
granulomatous infiltrate is characteristically present on biopsy [37]. Granulomatous rosacea is
characterized by the presence of epithelioid granulomas adjacent to hair follicles. Caseation is
present in approximately 10 percent of cases [72].
The features of granulomatous rosacea overlap with other disorders described in the literature that
present with numerous, small, monomorphic facial papules and granulomatous infiltrates on biopsy.
In adults, lupus miliaris disseminatus faciei, which presents with multiple red-brown 2 to 5 mm
papules on the face and caseating granulomas on biopsy, has been reported [73-75]. Rarely, B cell
lymphomas and chronic lymphocytic leukemia present with facial cutaneous lesions that resemble
granulomatous rosacea or phymatous skin changes of rosacea [76].
In addition, granulomatous facial dermatoses identified as childhood granulomatous periorificial

dermatitis [77-79] and facial Afro-Caribbean childhood eruption [80,81] have been described in
children. The status of these disorders as independent entities or forms of rosacea is unclear.
1102
PYODERMA FACIALE (ROSACEA
FULMINANS) The relationship of pyoderma faciale (also known as rosacea
fulminans or rosacea conglobata) to rosacea also is uncertain [46]. Patients present with intensely
inflammatory, purulent facial plaques and nodules with draining sinuses on a background of
erythema (picture 13) [82,83]. A history of rosacea may or may not be present. Young women are
most commonly affected.

provided separately. (See "Society guideline links: Rosacea".)
SUMMARY AND
RECOMMENDATIONS
●Rosacea is a common skin disorder that may occur in adults of all ethnic backgrounds but is most
commonly diagnosed in individuals with fair skin. Rarely, rosacea occurs in children. (See
●The pathogenesis of rosacea is poorly understood. Factors such as abnormalities in the innate
immune system, inflammatory reactions to cutaneous microorganisms, ultraviolet radiation
exposure, and vascular hyperreactivity have been identified as potential contributing factors. (See
●Persistent centrofacial redness, phymatous skin changes, papules, pustules, flushing,

telangiectases, burning or stinging sensations, cutaneous edema, and dryness are potential
cutaneous manifestations of rosacea. Ocular abnormalities may also occur. (See 'Clinical features'
above.)
●In most patients, clinical assessment is sufficient for diagnosing rosacea and excluding other
disorders that may resemble rosacea. Skin biopsies are rarely indicated but can be useful in cases in
which another disorder with specific histopathologic findings is suspected or for supporting a
diagnosis of granulomatous rosacea. (See 'Diagnosis' above and 'Differential diagnosis' above.)
●Ocular involvement may present independently or in association with cutaneous manifestations of

rosacea. Patients may exhibit features such as lid margin telangiectases, conjunctival injection, and
ocular irritation. Patients with signs or symptoms of ocular rosacea should be referred to an
ophthalmologist for further evaluation. (See 'Referral to ophthalmology' above.)
1103
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Management of rosacea - UpToDate
uptodate.com/contents/management-of-rosacea/print
INTRODUCTION Rosacea is a chronic and relapsing inflammatory skin

disorder that primarily involves the central face. Common clinical features include facial erythema,
telangiectasias, and inflammatory papules or pustules. Many patients seek therapy due to concern
over the effect of rosacea on physical appearance. As there is no cure for rosacea, treatment is
focused on symptom suppression.
The management of rosacea will be discussed here. The pathogenesis and clinical features of
rosacea are reviewed separately. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
PATIENT ASSESSMENT Rosacea can manifest with a wide

variety of cutaneous features. Examples include persistent centrofacial redness, phymatous skin
changes (eg, rhinophyma), papules, pustules, flushing, telangiectases, burning or stinging
sensations, edema, and skin dryness (picture 1A-E). Ocular involvement may also occur, manifesting
with lid margin telangiectases, conjunctival injection, ocular irritation, or other signs and symptoms.
(See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)
The classification of rosacea has evolved from a division into distinct subtypes
(erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular
rosacea) to a phenotype-based approach that views the various features of rosacea as
1105
manifestations of a continuous multivariate disease process. The approach to treatment is guided
by the clinical features present in an individual patient. Given the common presence of multiple
features, combination therapy may be necessary to achieve satisfactory control of disease [1,2].
(See 'Facial redness, flushing, skin sensitivity, and skin dryness' below and 'Papules and pustules'
below and 'Ocular manifestations' below and 'Phymatous skin changes' below and "Rosacea:
Pathogenesis, clinical features, and diagnosis", section on 'Classification'.)
GENERAL MEASURES Nonpharmacologic interventions may

be useful for the management of the cutaneous manifestations of rosacea. These include avoidance
of triggers of flushing, gentle skin care, sun-protection, and the use of cosmetic products.
Avoidance of flushing — Easy flushing is a common feature of rosacea.

Flushing is a prominent and troubling symptom for some patients, and some authors have proposed
that flushing may contribute to worsening of other features of rosacea, such as inflammatory
papules, erythema, and skin sensitivity [3-5].
Potential triggers for flushing include [4,6-8]:
●Extremes of temperature
●Sunlight
●Spicy foods
●Alcohol
●Exercise
●Acute psychological stressors
●Medications
●Menopausal hot flashes
Individual patients may also have unique triggers for flushing, and the degree of flushing in response
to the above stimuli is variable. Thus, asking patients to keep a diary of flushing episodes and
potential associated factors can be useful for identifying and avoiding pertinent triggers. In addition,
practical measures to reduce flushing after encounters with stimuli, such as applying cool
compresses and transferring to cool environments, may be helpful.
A variety of pharmacologic agents, including clonidine, beta-blockers, antidepressants, gabapentin,

and topical oxymetazoline have been used in attempts to reduce flushing [9-16]. However, data are
limited on their efficacy in rosacea and no single therapy appears to be consistently effective.
Moreover, the potential for drug-related adverse effects must be considered. (See "Approach to
flushing in adults", section on 'Treatment'.)
1106
Laser, intense pulsed light, and photodynamic therapy also have been used for patients with
rosacea-related flushing, but data are limited on treatment effects [17-20].
Skin care — Patients with rosacea, particularly those with centrofacial erythema and
telangiectases, can experience heightened sensitivity of facial skin characterized by difficulty
tolerating topical cosmetics, skin care products, and topical medications [21]. In addition, rough, dry,
or scaly facial skin is a common feature.
It is unclear whether subjective skin sensitivity and dryness result from abnormalities in skin barrier
function that precede the development of rosacea, or whether they occur as a consequence of the
inflammatory process [22]. Regardless, gentle skin care practices may help to reduce symptoms.
Appropriate measures include:
●Frequent skin moisturization – Emollients help to repair and maintain cutaneous barrier function
and may be useful in rosacea [23,24]. In a 15-day, split-face study of 20 patients with rosacea
(manifesting as erythema, flushing, sensitive and dry skin, stinging, burning, and/or skin discomfort)
treated with metronidazole 0.75% gel, concomitant application of a moisturizing cream twice daily
was associated with a significant reduction in experimentally-induced symptoms of skin sensitivity
[24]. Relatively greater reductions in scores of skin dryness, roughness, and discomfort were also
detected.
●Gentle skin cleansing – Despite their sensitive skin, patients should cleanse their faces at least
once daily. Patients should be instructed to cleanse their skin gently with lukewarm water, to wash
with their fingers, and to avoid harsh mechanical scrubbing [21,25]. Non-soap cleansers with
synthetic detergents (eg, beauty bars, mild cleansing bars, many liquid facial cleansers) are usually
better tolerated than traditional soaps. The latter are alkaline, which may raise the pH of the skin to
abnormal levels and impair skin barrier function [26]. In contrast, synthetic detergent cleansers
typically have a pH that more closely approximates the normal pH of the skin (skin pH = 4.0 to 6.5).
●Avoidance of irritating topical products – Patients should avoid topical products that may irritate
the skin, such as toners, astringents, and chemical exfoliating agents (eg, alpha hydroxy acids)
[25,26]. Manual exfoliation with rough sponges or cloths also should be avoided. Skin care products
in the form of foams, powders, or creams are generally better tolerated than alcohol-based gels and
thin lotions [25]. In addition, cosmetics should be easy to remove to avoid the need for harsh
cleansing [25].
Sun protection — The role of sun exposure in the pathogenesis of rosacea is

uncertain. Flares of facial redness and flushing may be stimulated by exposure to radiant heat from
the sun, and ultraviolet radiation may induce cutaneous changes that promote rosacea. (See
"Rosacea: Pathogenesis, clinical features, and diagnosis", section on 'Ultraviolet radiation'.)
We routinely recommend daily application of a broad-spectrum sunscreen with a sun protection

factor (SPF) of at least 30, and educate patients on mid-day sun avoidance and the use of sun-
protective clothing. Sunscreens in the form of creams, lotions, or preparations that contain barrier
1107
protective silicones (eg, dimethicone or cyclomethicone) are preferred over those in an alcohol-
based vehicle, which may be more likely to cause irritation [27,28].
Cosmetic camouflage — For female patients who are bothered by facial

erythema or telangiectasias, green-tinted foundation can help to camouflage these features. A flesh-
colored facial foundation should be applied on top of the green-tinted foundation to achieve a color
that matches the patient's complexion [29]. For men, light application of a green-tinted cosmetic
facial powder can be useful for camouflaging facial redness.
FACIAL REDNESS, FLUSHING, SKIN

SENSITIVITY, AND SKIN DRYNESS
Approach to treatment — Nonpharmacologic measures may assist with
reducing facial redness, flushing, skin sensitivity, and skin dryness, and are sufficient for the
management of some patients with mild symptoms. When satisfactory improvement cannot be
attained with these interventions, treatment with lasers, intense pulsed light, or pharmacologic
agents is an option. The treatment of flushing is challenging; the management of this feature is
discussed in greater detail elsewhere. (See 'Avoidance of flushing' above and "Approach to flushing
in adults", section on 'Treatment'.)
First-line interventions — Behavioral changes can be beneficial. We educate all

patients on the avoidance of triggers of flushing, proper use of sun protection, and gentle skin care
[3,27]. (See 'General measures' above.)
Second-line interventions — Patients who fail to improve adequately with

behavioral interventions and who desire additional treatment may benefit from medical intervention.
Options include light-based modalities and pharmacologic agents.
Laser and intense pulsed light — Laser and light-based therapies, which have
been used extensively for the treatment of a variety of vascular lesions, have also been used for the
vascular features of rosacea, especially telangiectasias. During treatment, light energy is absorbed
by hemoglobin in cutaneous vessels, leading to vessel heating and coagulation. (See "Laser and
light therapy for cutaneous vascular lesions", section on 'Principles'.)
Vascular lesions are commonly treated with lasers that emit green or yellow light (eg, pulsed dye or
potassium titanyl phosphate [KTP] lasers) due to the relatively high absorption of light in these
ranges by hemoglobin (figure 1 and table 1). Intense pulsed light devices, which are also frequently
used for this indication, are lower energy light sources that emit noncoherent light in a broad range
of wavelengths. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Vascular
lasers'.)
1108
Improvement in both facial erythema and telangiectasias can occur after treatment with pulsed dye
lasers, KTP lasers, or intense pulsed light [17,30-43]. Most data on the efficacy of these modalities
are derived from uncontrolled studies. One split-face randomized trial compared treatment with a
pulsed dye laser with nonpurpuragenic settings to intense pulsed light and no treatment in 29
patients with rosacea. The two therapies were similarly beneficial for facial erythema and
telangiectasias [43]. (See "Laser and light therapy for cutaneous vascular lesions", section on
'Telangiectasias and the red face'.)
Near infrared lasers can be used to treat large, deep telangiectasias, but are associated with
increased risk for adverse effects (table 1). Improvement in other clinical features, such as flushing,
skin sensitivity, and skin texture have also been reported in patients treated with laser or intense
pulsed light therapy [17,19,44].
Light-based modalities do not cure rosacea, and periodic treatments to maintain improvement are
often required. Potential adverse effects of laser and intense pulsed light therapy include skin
dyspigmentation, blistering, ulceration, and scarring.
Pharmacologic therapy — The pharmacologic agent with the strongest evidence for
efficacy for persistent facial erythema in rosacea is topical brimonidine [45]. Data from studies in
patients with papulopustular rosacea suggest that medications primarily used for papulopustular
disease (eg, topical antimicrobials, azelaic acid, and oral antibiotics) may also have benefit for the
reduction of rosacea-associated facial erythema [46-54]. However, no high-quality randomized trials
have evaluated the efficacy of these therapies in patients without papules and pustules. In our
experience, satisfactory improvement in persistent facial erythema with medications used for
papulopustular disease is uncommon. Telangiectasias are particularly unlikely to improve with
medications, and are best managed with light-based treatments. (See 'Laser and intense pulsed light'
above.)
Topical brimonidine — Brimonidine tartrate, a vasoconstrictive alpha-2 adrenergic receptor

agonist used in the treatment of open angle glaucoma, has emerged as a treatment for rosacea-
associated facial erythema [45]. The efficacy of this agent when applied topically is supported by the
results of phase II and phase III randomized trials [55,56]. In 2013, the US Food and Drug
Administration (FDA) approved brimonidine 0.33% gel for the treatment of persistent (nontransient)
facial erythema of rosacea based upon the findings of two 29-day placebo-controlled randomized
trials conducted in a total of 553 adults with moderate to severe persistent facial erythema of
rosacea [57]. At the end of the study, at least two-grade reductions in both clinician and patient
assessment scales were achieved three hours after application by 31 and 25 percent of patients
treated with brimonidine 0.33% gel versus only 11 and 9 percent of patients treated with vehicle. The
efficacy of topical brimonidine has not been directly compared with laser or intense pulsed light
therapy.
Topical brimonidine 0.33% gel appears to be well tolerated [57,58]. An open-label study in which
women applied a 0.5% formulation of brimonidine tartrate gel supports the potential for continued
safety and efficacy of topical brimonidine over one year of treatment [59]. The most common
1109
adverse effects are erythema, flushing, skin burning sensation, and contact dermatitis. The
occurrence of severe, transient rebound erythema several hours after application has been reported
[60,61]. An occurrence of persistent erythema in skin adjacent to the site of long-term brimonidine
application also has been reported [62]. The true incidence of worsening erythema is not known but
has been estimated to be up to 20 percent [63]. Patients should be counseled about these side
effects prior to therapy.
Because of concern for risk for potentiation of vascular insufficiency and hypotension during
treatment with alpha-2 adrenergic agonists, cautious use is recommended in patients with
depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension,
thromboangiitis obliterans, scleroderma, Sjögren syndrome, and severe cardiovascular disease.
Caution is also recommended for patients who are receiving treatment with anti-hypertensives,
cardiac glycosides, central nervous system depressants, and monoamine oxidase inhibitors.
Ingestion of brimonidine may result in serious adverse effects and should be avoided.
The effect of brimonidine on papulopustular lesions of rosacea has not been specifically studied.
Topical brimonidine has not appeared to aggravate papulopustular lesions of rosacea in randomized
trials evaluating its efficacy for facial erythema [55,56]. Our experience suggests that brimonidine is
not effective for the treatment of papulopustular lesions.
Topical oxymetazoline — Oxymetazoline, an alpha-adrenergic receptor agonist used for the

treatment of nasal congestion, may have modest efficacy for facial erythema in rosacea [45]. The
2017 FDA approval of oxymetazoline 1% cream for reducing persistent facial erythema associated
with rosacea in adults was based upon two randomized trials in which a total of 885 adults with
rosacea applied either oxymetazoline or vehicle once daily for 29 days [64,65]. More patients in the
oxymetazoline groups achieved the primary efficacy endpoint (at least a two-grade reduction in
erythema from baseline on both a 5-point clinician erythema assessment scale and a 5-point patient
self-assessment scale at 3, 6, 9, and 12 hours after application) than in the vehicle groups. On day 29
in the first trial, 12 and 6 percent of patients receiving oxymetazoline and vehicle, respectively,
achieved this endpoint three hours after application. In the second trial, this was achieved at the
same time point by 14 and 7 percent of patients in the oxymetazoline and vehicle groups,
respectively. Potential side effects of oxymetazoline include application site dermatitis, worsening of
inflammatory rosacea lesions, pain, pruritus, and erythema. A 52-week, open-label study (REVEAL
study) of 440 patients treated with oxymetazoline for moderate to severe facial erythema of rosacea
supports long-term efficacy and tolerability [66].
Other interventions — Additional studies are required to determine the value of

topical retinoids [67,68], licochalcone A (an ingredient derived from the licorice plant) [69], oral
isotretinoin [27], oral apremilast [70], and dual-frequency ultrasound [71] in the treatment of facial
redness and skin sensitivity in rosacea. The role of topical calcineurin inhibitors (tacrolimus and
pimecrolimus) in this presentation of rosacea is uncertain. Improvement with topical tacrolimus has
been reported in small numbers of patients [72,73].
1110
PAPULES AND PUSTULES Rosacea can present with
inflammatory papules and/or pustules primarily distributed on the central face. Patients often also
exhibit persistent facial erythema, frequent flushing, and telangiectasias.
Approach to treatment — Most patients with mild to moderate disease

(picture 2A-B) can be managed with topical therapies such as metronidazole, azelaic acid, topical
ivermectin, or sulfacetamide-sulfur. Systemic agents are typically used in patients who fail to
respond satisfactorily to topical agents or who present with numerous inflammatory lesions (picture
1D). Tetracycline-class antibiotics are first-line systemic agents for papules and pustules of rosacea;
for patients who fail to respond to tetracyclines or who cannot tolerate these drugs, treatment with
other oral antibiotics is an option. Laser therapy, intense pulsed light, and photodynamic therapy
have also been used, but the efficacy of these therapies remains uncertain.
Mild to moderate disease — Topical metronidazole, azelaic acid, and topical

ivermectin are considered first-line therapies in mild to moderate disease (picture 2A-B) due to
evidence from randomized trials in support of their efficacy and the relative safety of these
medications. A systematic review found high-quality evidence to support the efficacy of these drugs
[74]. Other agents, such as sulfacetamide-sulfur, also may be beneficial.
Topical metronidazole — The mechanism through which metronidazole improves

rosacea is unknown, but may involve antimicrobial, anti-inflammatory, or antioxidant properties [75].
Topical metronidazole is most effective for the treatment of inflammatory papules and pustules, but
may also contribute to improvement in facial erythema.
A systematic review of randomized trials performed primarily in patients with papulopustular

features of rosacea found moderate certainty evidence in support of the use of topical
metronidazole [45]. Metronidazole was superior to placebo (relative risk [RR] 1.98; 95% CI 1.29-3.02).
Topical metronidazole is available as a 0.75% cream or gel, a 1% cream or gel, and a 0.75% lotion.
Unlike 1% formulations, which are labeled for once-daily application, drug labels for 0.75%
formulations recommend twice daily use. However, the product concentration, frequency of
application, and vehicle (cream, gel, or lotion) may not significantly affect treatment efficacy:
●In a 12-week single-blind randomized trial that compared once-daily application of 0.75% cream
with once-daily application of 1% cream in 72 patients with papulopustular presentations, no
significant difference in the percent reduction in median inflammatory lesion counts (62 versus 60
percent) or erythema scores (26 versus 30 percent) was detected [76].
●Data from a meta-analysis of randomized placebo-controlled trials were insufficient to draw

definitive conclusions on the relative efficacy of once versus twice daily dosing [77].
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●Randomized trials comparing metronidazole 0.75% cream versus 0.75% gel and 0.75% gel versus
0.75% lotion have found similar treatment efficacy [74,77].
The data above suggest that once daily application of 0.75% metronidazole may be sufficient, but
additional studies are necessary. The drug vehicle should be selected based upon patient preference
and tolerability.
Improvement in inflammatory lesions may occur after as few as two to four weeks of therapy, but
full results are typically observed after eight to nine weeks of treatment [78-81]. Relapses often
occur when metronidazole is discontinued; thus, long-term therapy is usually needed [82].
Topical metronidazole is generally well tolerated; the most common adverse effects are local
irritation, dryness, and stinging sensations [80].
Topical azelaic acid — Azelaic acid is a naturally occurring dicarboxylic acid with anti-
inflammatory and antioxidative properties. Similar to metronidazole, azelaic acid improves papular
and pustular lesions, and may also reduce erythema. The mechanism of action for azelaic acid in
rosacea is not well understood. Reductions in messenger RNA for cathelicidin and kallikrein 5,
potential contributors to the development of rosacea, have been detected following treatment with
topical azelaic acid in patients with rosacea [83]. Azelaic acid-induced modulation of the
inflammatory response via activation of peroxisome proliferator-activated receptor-gamma is an
additional potential mechanism of action [84]. (See "Rosacea: Pathogenesis, clinical features, and
diagnosis", section on 'Immune dysfunction'.)
Azelaic acid is available as a 20% cream or lotion, or as a 15% foam or gel [85]. The cream, foam and
gel formulations are available in the United States.
The utility of azelaic acid for rosacea is supported by a systematic review of randomized trials
performed primarily in patients with papulopustular rosacea that found high certainty evidence to
support this therapy. Azelaic acid was a more effective treatment than placebo (RR 1.40, 95% CI
1.28-1.53) [45]. Examples of trials demonstrating efficacy of this agent include:
●Two 12-week vehicle-controlled randomized trials with a total of 664 patients with papules,
pustules, persistent erythema, and telangiectasia found significantly greater mean reductions in
inflammatory lesions in patients treated with twice-daily applications of azelaic acid 15% gel than in
the vehicle group (58 versus 40 percent and 51 versus 39 percent, respectively) [47]. Patients in the
active treatment group were also more likely to exhibit improvement in erythema (44 versus 29
percent and 46 versus 28 percent, respectively). Facial telangiectasias did not respond to therapy.
●A three-month vehicle-controlled randomized trial in 116 patients with papules, pustules, persistent
erythema, and telangiectasia found that twice-daily application of azelaic acid 20% cream led to
superior mean percent reductions in inflammatory lesion counts (73 versus 50 percent) and
erythema severity scores (48 versus 38 percent) [86].
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Initial improvement from azelaic acid may be noted within the first few weeks of use. Better results
are typically observed after 12 to 15 weeks of therapy [81].
Although package inserts for azelaic acid recommend twice daily application, a randomized trial in
72 patients treated with the 15% gel failed to identify a difference in efficacy between once daily and
twice daily dosing, suggesting that once daily application may be sufficient for improvement [87].
Rates of adverse effects and treatment tolerability were similar in the two groups.
The most frequent side effect of azelaic acid is skin discomfort after application [86,88,89]. In two
randomized trials in which a total of 333 patients were treated with azelaic acid 15% gel, 38 percent
of patients reported burning, itching, or stinging sensations [47]. Symptoms were transient and mild
to moderate in the majority of patients, and less than 1 percent of all patients had severe, persistent
sensory symptoms.
Azelaic acid versus metronidazole — Azelaic acid appears to be at least equally as

effective as metronidazole for the treatment of papules and pustules in rosacea, and some trials
have demonstrated superior efficacy [45]:
●The largest randomized trial (n = 251) comparing azelaic acid with metronidazole in patients with
papules, pustules, persistent erythema, and telangiectasia found that twice-daily application of
azelaic acid 15% gel for up to 15 weeks was superior to twice-daily application metronidazole 0.75%
gel [81]. Azelaic acid was associated with significantly greater mean reductions in inflammatory
lesion counts (73 versus 56 percent with metronidazole) and a higher rate of improvement in
erythema (56 versus 42 percent of patients).
●A 15-week investigator-blinded randomized trial in 160 patients that compared twice-daily

applications of azelaic acid 15% gel with once-daily applications of metronidazole 1% gel found
similar improvements in inflammatory lesion counts and erythema [90].
●A 15-week split-face randomized trial (n = 40) in which twice daily application of azelaic acid 20%
cream was compared with twice daily application of metronidazole 0.75% cream found similar
improvements with the two preparations in inflammatory lesions, erythema, and skin dryness, and
no difference in burning sensations related to rosacea [48]. Stinging sensations associated with
drug application were more frequent in patients treated with azelaic acid.
●A randomized trial (n = 24) comparing azelaic acid 20% cream, metronidazole 0.75% cream, and
permethrin 5% cream found that azelaic acid was superior to the other therapies for the treatment of
inflammatory lesions [91]. The three agents had similar benefit for erythema.
Topical ivermectin — Ivermectin is an agent with both anti-inflammatory and

antiparasitic properties. The drug is commercially available for the treatment of inflammatory
lesions of rosacea as a 1% cream. Ivermectin 1% cream is applied once daily. A pea-sized amount is
applied to each affected area of the face (eg, forehead, chin, nose, each cheek) and spread into a thin
layer [92].
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Use of topical ivermectin 1% cream for papular and pustular lesions of rosacea is supported by two
high-quality, vehicle-controlled, randomized trials that demonstrated efficacy in adults with moderate
to severe rosacea (defined in the study as 15 to 70 inflammatory papules or pustules) [45,93]. In the
first trial, 173 of 451 patients (38 percent) treated with ivermectin were clear or almost clear of
inflammatory lesions after 12 weeks. In contrast, this endpoint was achieved by only 27 of 232
patients (12 percent) in the vehicle group. The results of the second trial were similar; after 12
weeks, 184 of 459 patients (40 percent) treated with ivermectin versus 43 of 229 patients (19
percent) given vehicle were clear or almost clear of inflammatory lesions.
Treatment with ivermectin cream is well tolerated. A long-term safety study found use of topical
ivermectin 1% cream safe and effective for up to 52 weeks [94].
The efficacy of topical ivermectin may be related to anti-Demodex and anti-inflammatory activity. Of
note, patients in the randomized trials were not evaluated for Demodex infestation prior to therapy.
Ivermectin versus metronidazole — A 16-week randomized trial that compared once-

daily use of ivermectin 1% cream with twice-daily use of metronidazole 0.75% cream in 962 adults
with moderate to severe rosacea presenting with papules, pustules, and erythema found that topical
ivermectin was more effective for reducing inflammatory lesions [95]. Moreover, a 36-week
extension phase of this study revealed longer remissions after treatment with topical ivermectin
than after treatment with topical metronidazole (115 versus 85 days) [96].
Choice of treatment — Based upon these observations, topical ivermectin,

metronidazole, and azelaic acid are reasonable choices for first-line topical therapy for papules and
pustules in rosacea. The lower cost of metronidazole 0.75% gel (the least expensive formulation of
metronidazole) compared with azelaic acid and ivermectin favors the initial use of metronidazole.
We also favor metronidazole or ivermectin in patients who present with significant facial sensitivity,
due to the fairly frequent occurrence of irritation early in the course of therapy with azelaic acid
[86,88,89,94]. (See 'Topical azelaic acid' above.)
Alternative topical agents — Less well-studied topical agents used for the
management of rosacea include topical sulfacetamide-sulfur, benzoyl peroxide, erythromycin,
clindamycin, topical retinoids, and permethrin. We generally utilize these agents in patients who
cannot tolerate or obtain metronidazole, ivermectin, or azelaic acid or who fail to respond to those
therapies but prefer to avoid oral agents.
Sulfacetamide-sulfur — Sulfacetamide-sulfur is available in a variety of formulations,

including topical suspensions, lotions, cleansers, creams, foams, and cleansing pads. The most
common concentration is sulfacetamide 10% with sulfur 5%. Other drug concentrations and
formulations with added sunscreen or cosmetically-beneficial green coloring are also available (see
'Cosmetic camouflage' above). The mechanism of action of sulfacetamide-sulfur in rosacea is
unknown.
1114
In comparison to metronidazole and azelaic acid, data on the efficacy of sulfacetamide-sulfur are
limited. A vehicle-controlled randomized trial in 103 patients and an open-label study in 59 patients
reported benefit of this agent for inflammatory lesions and erythema [97,98]. Additional studies are
necessary to confirm the results of a 12-week randomized trial of 152 patients that found that a
sulfacetamide 10%-sulfur 5% cream containing sunscreen was superior to metronidazole 0.75%
cream for the reduction of pustular, but not papular, lesions [99].
Side effects of sulfacetamide-sulfur include local irritation and allergic reactions [27,97]. Use of
sulfacetamide-sulfur should be avoided in patients with sulfonamide ("sulfa") allergies [27]. Of note,
some patients find the odor of sulfacetamide-sulfur agents unfavorable.
Other therapies
●Other topical antimicrobials –In a 12-week randomized trial of 53 patients with rosacea with
persistent erythema, telangiectases, papules, and pustules, a gel containing a combination of
benzoyl peroxide 5% and clindamycin 1% was superior to vehicle for the reduction of papulopustules
(mean percent reduction 71 versus 19 percent), erythema, and flushing/blushing [50]. Monotherapy
with clindamycin or erythromycin may also be beneficial; clindamycin lotion was as effective as
tetracycline in one randomized trial of 43 patients in whom papules and pustules were a major
manifestation of their disease [49], and erythromycin solution was associated with improvement in
papulopustules and erythema in an open-label study of 15 patients [100].
The efficacy of minocycline foam, a novel drug, for rosacea is under investigation. The findings of a
12-week phase 2 trial suggest benefit for papular and pustular manifestations of rosacea [101].
●Topical retinoids – Topical retinoids, which are known to have anti-inflammatory and extracellular
matrix repair properties, have been studied for the treatment of papules and pustules in rosacea with
variable results. In a 12-week randomized trial that compared adapalene 0.1% gel with metronidazole
0.75% gel in 55 patients with papulopustular rosacea, adapalene was associated with significantly
greater reductions in inflammatory lesions [102]. Unlike metronidazole, adapalene did not induce
significant improvement in erythema. Although improvement in papulopustular lesions was
observed after topical tretinoin therapy in a small randomized trial (n = 22) that compared treatment
with tretinoin 0.025% cream to oral isotretinoin [67], a subsequent randomized trial (n = 79) that
compared once-daily application of a gel containing tretinoin 0.025% and clindamycin 1.2% to
placebo failed to find a statistically significant difference in effect on papulopustular lesions
between the two groups [103]. Additional studies are necessary to confirm the effects of topical
retinoids on papulopustular lesions of rosacea. Skin irritation is a potential adverse effect of topical
retinoids.
●Permethrin– Although a causal relationship between Demodex mites and rosacea is uncertain,
topical permethrin, an antiparasitic agent, may have benefit for the treatment of rosacea. In a
randomized trial of 63 patients with papulopustular rosacea that compared treatment with
permethrin, metronidazole gel, and placebo, improvement with permethrin was equivalent to
metronidazole and superior to placebo [104]. The validity of these results may be questionable due
1115
to the close clinical resemblance of Demodex folliculitis to rosacea. The safety of long-term
permethrin use also is unknown. (See "Rosacea: Pathogenesis, clinical features, and diagnosis",
section on 'Demodex'.).
Topical calcineurin inhibitors do not appear to be beneficial for papulopustular rosacea. Small
placebo controlled randomized trials failed to find statistically superior efficacy for pimecrolimus 1%
cream [105,106], and tacrolimus 0.1% ointment was not effective for papulopustular lesions in a
small uncontrolled study [73]. In addition, the development of rosacea-like cutaneous eruptions has
been reported in patients treated with topical tacrolimus for other indications [107].
Moderate to severe disease — Patients who present with numerous

inflammatory papules or pustules (picture 1D), or those with milder disease that fails to respond to
one or more topical therapies may benefit from oral antibiotic therapy. Of the oral antibiotics,
tetracyclines are the best-studied agents.
Oral tetracyclines — Tetracycline, doxycycline, and minocycline have been used for many
years for the management of rosacea. These agents are most useful for improving inflammatory
papules and pustules, and may also reduce erythema [51,53].
Since no definitive microbial cause of rosacea has been identified, the efficacy of oral antibiotics in
rosacea is often attributed to their anti-inflammatory properties [108]. Tetracyclines may decrease
levels of proinflammatory cathelicidins (components of the innate immune system) through
inhibition of serine proteases, may reduce levels of proinflammatory cytokines, and may have
matrix-protecting capabilities [108,109]. (See "Rosacea: Pathogenesis, clinical features, and
diagnosis", section on 'Immune dysfunction'.)
Efficacy and administration — Traditional, antimicrobial doses for tetracycline are 250 mg
to 1000 mg per day and 100 to 200 mg per day for doxycycline and minocycline [110,111]. Few
placebo-controlled randomized trials have evaluated the efficacy of these doses in rosacea. In two
early, small trials, tetracycline (250 mg twice daily for four to eight weeks or 750 mg per day for one
week followed by 250 mg to 500 mg per day for five weeks) was associated with improvement in
inflammatory lesions [51,112]. In addition, randomized trials comparing doxycycline with other oral
antibiotics found that a 100 mg per day dose of doxycycline effectively improves papulopustular
rosacea [54,113]. (See 'Alternative oral antibiotics' below.)
Due to concern for the development of antibiotic resistance, interest has grown in the use of
subantimicrobial doses of antibiotics, which retain anti-inflammatory properties but lack
antibacterial effects. Support for the efficacy of subantimicrobial doses of doxycycline (20 mg taken
twice daily or a combination pill containing 30 mg of immediate release doxycycline and 10 mg of
delayed release doxycycline taken once daily) come from both randomized trials [114,115] and an
open label study of almost 1200 patients [53]. In two 16-week placebo-controlled randomized trials
performed in 537 patients with 10 to 40 inflammatory lesions, doxycycline was associated with
significantly greater reductions in inflammatory lesion counts [114]. In addition, one of the two trials
and the open-label study found improvement in erythema [53].
1116
Few randomized trials have compared subantimicrobial dose doxycycline with higher doses of oral
tetracyclines. One randomized trial with 91 patients compared subantimicrobial dose doxycycline
(40 mg once daily) with doxycycline 100 mg per day [116]. Both doses were similarly effective for the
treatment of inflammatory lesions, but the lower dose was associated with a reduced rate of
gastrointestinal side effects (5 versus 26 percent). In addition, a 16-week trial that compared
doxycycline (40 mg once daily) with minocycline (100 mg once daily) found similar reductions in
lesion counts in both groups [117].
We typically initiate treatment with doxycycline 100 mg twice daily, minocycline 100 mg twice daily,
or tetracycline 500 mg twice daily and continue treatment for 4 to 12 weeks in an attempt to quickly
decrease inflammation. Initiating treatment with subantimicrobial dose doxycycline is another
reasonable option. We generally favor doxycycline over minocycline for initial treatment because of
minocycline's broader side effect profile.
After satisfactory improvement is attained with the initial course of therapy, we transition patients to
a topical agent, most often metronidazole or azelaic acid (see 'Topical metronidazole' above and
'Topical azelaic acid' above). Continuing oral therapy at the lowest effective dose is another option in
patients who fail to maintain improvement or who are unable to tolerate topical therapy [3].
Subantimicrobial dose doxycycline is our preferred choice for long-term oral therapy.
Patients who respond well to topical maintenance therapy may have occasional "break-through"
flares of papulopustular lesions spaced by several months or more. For such patients, we have
found the administration of an abbreviated course of an oral antibiotic (eg, tetracycline 500 mg twice
daily for 10 days) useful for quieting the acute flares, circumventing the need for long-term oral
therapy. These patients are continued on topical maintenance therapy during and after oral
treatment.
Adverse effects of oral tetracyclines include gastrointestinal distress and photosensitivity.

Minocycline is the least photosensitizing of these agents, but it may cause vertigo, a lupus-like
syndrome, and skin discoloration. Tetracyclines should not be given to children under the age of
nine due to a risk for permanent tooth discoloration and reduced bone growth.
Combined with topical agents — Adding an oral antibiotic to topical therapy may improve
treatment results. Two randomized trials that compared treatment with topical metronidazole alone
to topical metronidazole plus subantimicrobial dose doxycycline found superior improvement in
inflammatory lesions with combination therapy [115,118]. Additional trials are necessary to
determine whether combination therapy has advantages over monotherapy with an oral antibiotic.
Alternative oral antibiotics — Other oral antibiotics are less frequently used for the
treatment of rosacea, but may also be effective. These include macrolides (clarithromycin,
azithromycin, and erythromycin) and oral metronidazole [27,52,54,113].
An eight-week randomized trial comparing clarithromycin (250 mg twice daily for four weeks
followed by 250 mg daily for four weeks) with doxycycline (100 mg twice daily for four weeks
followed by 100 mg once daily for four weeks) found significantly greater improvement in objective
1117
measures of inflammatory lesions, erythema, and telangiectasias in patients treated with
clarithromycin at early study time points, but differences among the two groups dissipated by week
eight [54]. A separate 12-week trial that compared azithromycin (500 mg three times per week
followed by a taper) with doxycycline 100 mg daily found that the drugs were similarly effective
[113].
Oral metronidazole is commonly used for the treatment of rosacea in Europe. In a randomized trial
of 40 patients that compared treatment with metronidazole (200 mg twice daily) to oxytetracycline
(250 mg twice daily), the agents appeared to be similarly effective [119]. Alcohol should be avoided
during treatment with metronidazole due to the possibility of the induction of a disulfiram-like
reaction.
Refractory disease
Oral isotretinoin — Patients who fail to respond to topical therapies and oral antibiotics
may improve with oral isotretinoin [67,120-122]. Oral isotretinoin is not used as first-line therapy due
to the drug's many adverse effects, including teratogenicity. In the United States, oral isotretinoin can
only be prescribed through the iPLEDGE program, an internet-based risk management program. (See
"Oral isotretinoin therapy for acne vulgaris", section on 'Teratogenicity' and "Oral isotretinoin therapy
for acne vulgaris", section on 'Adverse effects'.)
Although improvement in inflammatory lesions and facial erythema has been reported in several
randomized trials and observational studies [67,120-122], high quality data on the efficacy of
isotretinoin for rosacea are scarce, and the ideal regimen for treatment has not been established.
Doses of 0.5 to 1 mg/kg per day have been utilized in some patients, but lower doses may be
effective and better-tolerated.
The authors of a 12-week dose-comparison randomized trial reported a 90 percent reduction of

inflammatory lesions in patients treated with 0.3 mg/kg per day [122]. Additionally, compared with
patients who were treated with 0.5 mg/kg/day, these patients had a lower incidence of drug-related
facial dermatitis.
In another randomized trial, 156 patients with papulopustular rosacea that had failed to respond to
three or more previous treatments were treated with low-dose isotretinoin (0.25 mg/kg) or placebo
daily for four months [123]. The primary endpoint was a reduction in the lesion number of at least 90
percent. At the end of the study, more patients in the isotretinoin group than those in the placebo
group reached the primary endpoint (57 versus 10 percent, absolute difference 47 percent, 95% CI 34
to 60 percent; number needed to treat 2). Adverse effects, including cheilitis, dry skin, and abdominal
pain, were more common in the isotretinoin group than in the placebo group (69 versus 44 percent).
Patients were followed for 4 months after isotretinoin completion. Rosacea relapsed in 53 percent of
patients who responded to isotretinoin after a median time of 15 weeks.
1118
We typically treat patients with around 0.2 mg/kg per day (usually a total of 10 to 20 mg per day)
until the inflammatory component is consistently well controlled for one to two months. In our
experience, this usually occurs after five to six months of therapy.
The longevity of treatment effect varies; in a series of 20 patients with severe rosacea treated with
isotretinoin doses of 0.5 to 1 mg/kg per day for three to six months, remissions lasting at least one
year were reported in 17 patients [124]. Of note, five out of six patients initially treated with 1 mg/kg
per day required dose reductions due to adverse effects. The remission period may be shorter in
patients treated with low-doses [123].
After completion of a successful course of isotretinoin, we routinely initiate maintenance therapy

with topical metronidazole, azelaic acid, or other standard therapies for pustular rosacea in an
attempt to increase the likelihood of sustained remission. However, the efficacy of this approach has
not been studied.
Laser and intense pulsed light — Treatment with light-based therapies

has yielded variable results in patients with papules and pustules. Although the results of two
uncontrolled studies utilizing intense pulsed light or pulsed dye laser suggest that some
improvement in inflammatory papules is possible [125,126], other studies have found conflicting
results [35,127,128], and there is insufficient evidence to conclude that improvement is long-lasting.
Photodynamic therapy, which involves the application of a photosensitizing agent (aminolevulinic

acid or methyl aminolevulinic acid) to skin and exposure of the treatment site to a light source, has
also yielded mixed results. Improvement in inflammatory lesions lasting three months or longer was
reported in a small retrospective study and two out of four patients in a case series [129,130];
however, in another case series, disease severity returned to baseline in three out of four patients
within 12 weeks after treatment [127].
Maintenance therapy — Because rosacea is a chronic disorder and

treatments are not curative, continued therapy is typically necessary to maintain treatment
response. Most commonly, long-term topical therapy is administered. Subantimicrobial doses of
doxycycline are also an option. (See 'Oral tetracyclines' above.)
Investigational therapy
Topical minocycline — Two phase 3 randomized trials (FX2016-11 and FX2016-12)
support efficacy of minocycline 1.5% foam for papulopustular manifestations of rosacea [131]. In
the identical 12-week trials (n = 751 and n = 771), adults with moderate to severe papulopustular
rosacea were randomly assigned in a 2:1 ratio to either once-daily application of minocycline 1.5%
foam or vehicle to the entire face. Minocycline foam was more effective than vehicle for reducing the
number of inflammatory lesions (FX2016-11: -17.57 versus -15.65; FX2016-12: -18.54 versus -14.88).
In addition, patients in the minocycline groups were more likely to achieve treatment success
1119
(Investigator Global Assessment [IGA] score of 0 or 1 and at least a two-grade improvement from
baseline on the five-point IGA scale) than patients in the vehicle group (FX2016-11: 52 versus 43
percent; FX2016-12: 49 versus 39 percent). Treatment with minocycline foam was generally well
tolerated; the most common noncutaneous and cutaneous treatment-emergent adverse effects were
viral upper respiratory infection and pruritus, respectively. There were no serious treatment-related,
treatment-emergent adverse effects. Long-term side effects beyond 12 weeks are unknown.
The efficacy and safety of minocycline 4% foam, a commercially available formulation of topical
minocycline, in patients with rosacea is unclear.
OCULAR MANIFESTATIONS Ocular involvement

may occur in the presence or absence of cutaneous manifestations. Examples of features of ocular
rosacea include foreign body sensations, blepharitis, lid margin telangiectasia, tear abnormalities,
meibomian gland inflammation, frequent chalazion, conjunctivitis, and rarely, corneal ulcers and
vascularization [132]. Patients who present with signs or symptoms of ocular involvement should be
referred to an ophthalmologist for further evaluation. (See "Rosacea: Pathogenesis, clinical features,
and diagnosis", section on 'Clinical features'.)
Lid scrubs and warm compresses may help improve meibomian gland function [133], and topical
antibiotics such as topical erythromycin and metronidazole may quell mild lid inflammation
[132,134,135]. For those with moderate to severe ocular rosacea, short courses of oral tetracycline-
class antibiotics, macrolide antibiotics, or metronidazole are often needed [134,136,137]. Topical
cyclosporine may also minimize inflammation [138].
PHYMATOUS SKIN CHANGES Tissue

hypertrophy, dilated follicles, and irregular nodular overgrowths are characteristic features of the
phymatous skin changes of rosacea. These changes most commonly affect the nose (rhinophyma),
but may also affect other areas such as the chin, cheeks, and ears (picture 1E) [7,139]. Features of
other subtypes of rosacea may also be present. (See "Rosacea: Pathogenesis, clinical features, and
diagnosis", section on 'Clinical features'.)
Early disease — The best approach to the treatment of early phymatous skin
changes is unknown. Improvements in phymatous changes have been reported in patients treated
with 0.3 to 1 mg/kg per day of isotretinoin administered for periods of 12 to 28 weeks [122,140]. The
duration of benefit is uncertain.
Advanced disease — Laser ablation and surgical techniques can be used to

debulk and recontour tissue distorted by phymatous changes. Ablative carbon dioxide lasers [141]
and infrared diode lasers [142,143] have been used for this purpose. Surgical debulking can be
performed through dermabrasion, scalpel excision, electrosurgery, or cryosurgery [144,145].
1120
The potential side effects of laser and surgical interventions include hypopigmentation, scarring, and
pain. The risk for pigmentary changes rises with increasing skin pigmentation.
SPECIAL CASES
Granulomatous rosacea — Granulomatous rosacea may be a variant of
rosacea. It presents with uniform red-brown or yellow-brown papules on the face. Other
manifestations of rosacea may or may not be present [146-148]. (See "Rosacea: Pathogenesis,
clinical features, and diagnosis", section on 'Granulomatous rosacea'.)
Efficacy data on treatment for granulomatous rosacea are limited to case reports. Treatments are
similar to those used for papulopustular rosacea. However, lesions may be slower to respond or
less-likely to respond to therapy [149,150], and oral antibiotic therapy is often required [150,151].
Successful treatment with oral isotretinoin, oral dapsone, topical pimecrolimus, and intense pulsed
light has also been documented [152-156].
Pediatric rosacea — Infrequently, rosacea develops in children. All features,

except for phymatous changes, may occur. (See "Rosacea: Pathogenesis, clinical features, and
diagnosis", section on 'Epidemiology'.)
As with adults, nonpharmacologic measures aimed at reducing symptoms are recommended. Mild
to moderate papulopustular disease is usually managed with topical agents, such as metronidazole,
azelaic acid, sulfacetamide-sulfur, and erythromycin (see 'Mild to moderate disease' above). Oral
antibiotics may be necessary for patients with more severe papulopustular eruptions. Because
tetracyclines are contraindicated in children under the age of nine, oral erythromycin (30 to 50
mg/kg/day), azithromycin, or clarithromycin may be substituted as a first-line oral agent [149,157].
Oral metronidazole (20 to 30 mg/kg per day) has also been used in the treatment of children [158].
As in adults, after oral antibiotics produce a remission, treatment with a topical agent may be used to
maintain clearance.
Ocular manifestations of rosacea are managed similarly as in adults, with the exclusion of
tetracycline antibiotic therapy in children under the age of nine. Systemic antibiotics may be required
for several months to achieve complete remission [159]. Granulomatous rosacea in the pediatric
population may respond to topical or oral antibiotics [149,158]. Several months of treatment may be
required for improvement.
Pyoderma faciale — Pyoderma faciale (also known as rosacea fulminans) is an

unusual eruption that is not officially recognized as a rosacea variant. The disorder is characterized
by an abrupt onset of papules and suppurative nodules on the face [160]. Young women are most
commonly affected [161]. (See "Rosacea: Pathogenesis, clinical features, and diagnosis", section on
'Pyoderma faciale (rosacea fulminans)'.)
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Data on the treatment of pyoderma faciale are limited to reports of clinical experience. Patients can
be managed with a combination of prednisone and oral isotretinoin. Prednisone is often started at
0.5 to 1 mg/kg per day and tapered over a period of weeks, and isotretinoin is initiated around two
weeks after the start of prednisone therapy with low doses of 0.2 to 0.5 mg/kg per day [157,161,162].
During the steroid taper, the isotretinoin dose is slowly increased to 0.5 to 1 mg/kg per day as
tolerated. Some authors advocate treating until a cumulative dose of 150 mg/kg has been attained
[162]; others believe that isotretinoin can be discontinued once inflammatory lesions have resolved
[161]. We typically treat until a cumulative dose of 120 to 150 mg/kg has been attained, provided
treatment is tolerated.
Alternatives to the above regimen include initiation of minocycline or tetracycline (1 g per day) along
with a prednisone taper as above [161,163]. Successful treatment with dapsone has also been
reported [164].

provided separately. (See "Society guideline links: Rosacea".)
SUMMARY AND
RECOMMENDATIONS
●Rosacea is a common disorder that presents with a variety of clinical findings. The phenotype of
rosacea determines the approach to treatment. (See 'Patient assessment' above.)
●General measures to improve symptoms of flushing, erythema, and skin irritation can be beneficial
for patients with rosacea. Patients should be educated on the avoidance of triggers of flushing,
gentle skin care, and sun protection. Cosmetic camouflage is a useful adjunct for some patients.
(See 'Facial redness, flushing, skin sensitivity, and skin dryness' above.)
●Behavioral modifications may improve persistent facial erythema, telangiectasias, flushing, and
sensitive skin. If persistent facial erythema does not improve sufficiently with behavioral changes,
therapeutic interventions can be useful. For patients who desire a topical therapy for facial erythema
that can be self-administered, we suggest treatment with topical brimonidine (Grade 2A). Laser or
intense pulsed light are additional effective treatment options for facial erythema. Periodic
retreatment with laser or intense pulsed light is often necessary to maintain improvement. Facial
telangiectasias are best managed with laser or intense pulsed light therapy. (See 'Facial redness,
flushing, skin sensitivity, and skin dryness' above.)
●There are few data to support the efficacy of treatments used for papules and pustules of rosacea
(eg, topical metronidazole, topical azelaic acid, or subantimicrobial doxycycline) for persistent facial
erythema. In our experience, satisfactory improvement with these therapies is uncommon. (See
1122
'Pharmacologic therapy' above.)
●For patients with mild to moderate rosacea manifesting with papules and pustules, we suggest
treatment with topical metronidazole, azelaic acid, or topical ivermectin (Grade 2A) (see 'Mild to
moderate disease' above). The lower cost of metronidazole 0.75% gel (the least expensive
formulation of metronidazole) compared with azelaic acid and ivermectin favors the initial use of
metronidazole. We also favor metronidazole or ivermectin in patients who present with significant
facial sensitivity, due to the fairly frequent occurrence of irritation early in the course of therapy with
azelaic acid. Topical sodium sulfacetamide is an alternative topical therapy.
●For patients who present with numerous papules or pustules or who have milder disease that fails
to improve with topical agents, we suggest treatment with oral tetracycline, doxycycline, or
minocycline for 4 to 12 weeks (Grade 2B). Improvement may be maintained with topical agents or
subantimicrobial doxycycline. (See 'Moderate to severe disease' above and 'Maintenance therapy'
above.)
●Patients with refractory papules or pustules may benefit from treatment with oral isotretinoin. (See
'Refractory disease' above.)
●Ocular involvement in rosacea can result in damage to the ocular tissues. Patients with signs or
symptoms of ocular involvement should be referred to an ophthalmologist for further evaluation.
(See 'Ocular manifestations' above.)
●Childhood rosacea is managed similarly to rosacea in adults. However, the use of oral tetracyclines
should be avoided in children under the age of nine. (See 'Pediatric rosacea' above.)
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Official reprint from UpToDate®
www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Psoriasis: Epidemiology, clinical manifestations, and diagnosis

Author: Steven R Feldman, MD, PhD
Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Kristina Callis Duffin, MD
Deputy Editor: Abena O Ofori, MD
INTRODUCTION
Psoriasis is a common chronic inflammatory skin disease that may exhibit a variety of clinical
manifestations. Chronic plaque psoriasis, the most common subtype of psoriasis, is characterized by well-
demarcated, erythematous plaques with overlying, coarse scale (picture 1A-I). Other major subtypes of
psoriasis include guttate psoriasis, which typically presents as the acute onset of numerous small,
inflammatory plaques (picture 2A-C); pustular psoriasis, which may present as an acute, subacute, or
chronic pustular eruption (picture 3A-B); and erythrodermic psoriasis (picture 4A-B), which exhibits
cutaneous erythema and scale involving most or all of the body surface area. (See 'Clinical subtypes' below.)
Psoriasis has also been identified as a multisystem chronic inflammatory disorder associated with multiple
comorbidities. Psoriatic arthritis is a common comorbidity that should be screened for in all patients.
Examples of other comorbidities that are more common in individuals with psoriasis and may warrant
intervention include obesity, metabolic syndrome, hypertension, diabetes, and atherosclerotic disease. (See
"Comorbid disease in psoriasis".)
The epidemiology, clinical manifestations, and diagnosis of psoriatic skin disease will be reviewed here. In-
depth discussions of specific aspects of psoriasis are provided separately.
General principles:
● (See "Pathophysiology of plaque psoriasis".)

● (See "Treatment of psoriasis in adults".)
● (See "Comorbid disease in psoriasis".)
Clinical variants:
● (See "Nail psoriasis".)

● (See "Guttate psoriasis".)
1124
● (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)
● (See "Pustular psoriasis: Management".)
● (See "Erythrodermic psoriasis in adults".)
Special populations:
● (See "Treatment selection for moderate to severe plaque psoriasis in special populations".)
● (See "Management of psoriasis in pregnancy".)
● (See "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis".)
● (See "Psoriasis in children: Management of chronic plaque psoriasis".)
Psoriatic arthritis:
● (See "Clinical manifestations and diagnosis of psoriatic arthritis".)

● (See "Treatment of psoriatic arthritis".)
● (See "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis".)
● (See "Psoriatic juvenile idiopathic arthritis: Management and prognosis".)
EPIDEMIOLOGY
Psoriasis is a relatively common disorder that occurs in children and adults worldwide, though the
prevalence varies among populations. A systematic, worldwide review found the prevalence of psoriasis
ranged from 0.5 to 11.4 percent in adults and 0 to 1.4 percent in children [1]. The prevalence of psoriasis
tends to increase with increasing distance from the equator.
There is no clear gender predilection for psoriasis [2,3]. In addition, psoriasis can begin at any age, though it
is less common in children than adults. Peak ages for the onset of psoriasis are between 30 and 39 years
and between 50 and 69 years [2].
The incidence of psoriasis may be increasing. A population-based study in the United States found an
increase in the incidence of psoriasis between the years 1970 to 1974 (50.8 cases per 100,000) and 1995 to
1999 (100.5 cases per 100,000) [4]. A rise in incidence was also detected among children, increasing from
29.6 cases per 100,000 to 62.7 cases per 100,000 during the same time periods [5]. However, changes in
diagnostic patterns over time may also contribute to increasing rates of diagnosis [4].
RISK FACTORS
There are multiple proposed risk factors for psoriasis. Genetic predisposition is considered a key contributor,
and environmental and behavioral factors may also play roles [6]. In particular, elevated rates of smoking,
obesity, and alcohol use are found among individuals with psoriasis. Medications and infections have also
been identified as potential triggering or exacerbating factors for psoriasis. (See 'Genetic factors' below and
'Other factors' below.)
1125
Genetic factors — Support for a genetic contribution to psoriasis comes from the observation that
approximately 40 percent of individuals with psoriasis or psoriatic arthritis have a family history of the
disease [7], as well as the observation that the disease is more frequently concordant among monozygotic
twins than dizygotic twins [8-10]. Moreover, genome-wide association studies have identified multiple
susceptibility loci for psoriasis, many of which contain genes involved in regulation of the immune system
[11-17].
MHC genes — The psoriasis-susceptibility (PSORS1) locus within the major histocompatibility complex
(MHC) on chromosome 6p21 (location of the HLA genes) is considered a major genetic determinant of
psoriasis [18,19]. Among other MHC genes that have been associated with psoriasis, HLA-Cw6 is the most
important allele for susceptibility to early-onset psoriasis [20]. HLA-Cw6 also demonstrates a strong
association with guttate psoriasis. HLA-B17 may be associated with a propensity for psoriasis and more
severe psoriatic arthritis [21,22]. (See "Guttate psoriasis", section on 'Pathogenesis'.)
Other genes — MHC and HLA associations explain only a portion of genetic susceptibility to psoriasis.
Interleukin (IL) 23-related genes have been implicated in psoriasis, and this pathway, which involves Th17
cells, has been a target for drug development. (See "Pathophysiology of plaque psoriasis", section on
'Interleukin-23'.)
Genes that encode the shared subunit of the receptor for IL-12 and IL-23 have been identified as
susceptibility loci for psoriasis [16,23,24]. Certain receptor polymorphisms appear to predispose to, or
protect from, psoriasis [23,24]. In addition, the IL12B gene, which encodes the p40 subunit of IL-12 and IL-23,
as well as the IL23A gene, which encodes the p19 subunit of IL-23 and IL-39 [25], are strongly associated
with psoriasis [16].
Additional examples of genes involved in immune regulation that are linked to psoriasis include TNIP1 and
TNFAIP3, whose gene products act downstream of tumor necrosis factor (TNF)-alpha and regulate nuclear
factor kappa-B (NFkB) signaling [16]. Genes encoding IL-4 and IL-13, which modulate Th2 responses, and
beta defensins, which are involved in innate immunity, are also implicated [16,26].
Multiple other genes involved in the innate or adaptive immune systems may be associated with psoriasis
[17]. As an example, late-onset psoriasis (psoriasis with onset after age 40) may be associated with
polymorphisms in the IL1B gene [27]. Highly penetrant gain-of-function mutations in CARD14 can also lead to
psoriasis and psoriatic arthritis [28].
In addition, the LCE gene cluster on chromosome 1q21, which encodes cornified envelope proteins that are
important for epidermal cell differentiation, is a susceptibility locus for psoriasis [29]. A genome-wide scan
revealed that deletions of LCE3B and LCE3C, genes located within the LCE cluster, are associated with an
increased risk of psoriasis [30].
The generalized pustular psoriasis variant of psoriasis has been associated with distinct genetic mutations.
The role of genetics in generalized pustular psoriasis is reviewed separately. (See "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetics'.)
1126
Other factors — In addition to genetics, a variety of medical conditions, behavioral conditions, and
environmental exposures have been proposed as risk factors or exacerbating factors for psoriasis.
Examples of medical and behavioral risk factors linked to psoriasis include smoking, obesity, and alcohol
use. The relationship between psoriasis and these and other medical or behavioral conditions is reviewed in
detail separately. (See "Comorbid disease in psoriasis".)
Multiple drugs are associated with worsening psoriasis or psoriasis-like drug eruptions (table 1). The most
common implicated drugs are beta blockers, lithium, and antimalarial drugs. Paradoxically, TNF inhibitors,
drugs used for the treatment of psoriasis, are occasionally linked to the development of psoriasis-like
eruptions [31-34]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on
'Cutaneous reactions'.)
Infections, both bacterial and viral, may be associated with worsening of psoriasis. Poststreptococcal flares
of guttate psoriasis and the onset or worsening of psoriasis in association with HIV infection are recognized
contributors. (See "Guttate psoriasis", section on 'Streptococcal infection' and 'HIV-infected patients' below.)
The role of vitamin D status in psoriasis is uncertain, but low vitamin D levels have been observed in patients
with psoriasis [35]. A case-control study that compared 43 patients with psoriasis and 43 matched controls
with other nonphotosensitive dermatologic diseases found that serum levels of 25-hydroxyvitamin D were
lower in the patients with psoriasis even after adjusting for factors such as Fitzpatrick skin phototype (table
2) and estimated sun exposure [36]. (See "Vitamin D and extraskeletal health", section on 'Immune system'.)
Stress is often cited as an inciting or exacerbating factor for psoriasis. However, a systematic review and
meta-analysis of studies evaluating the relationship between antecedent psychologic stress and onset or
exacerbation of psoriasis found insufficient data to confirm an association [37]. The included studies were
primarily retrospective, had significant limitations, and yielded conflicting results. Further study is necessary
to clarify the impact of stress on the course of psoriasis.
PATHOPHYSIOLOGY
Historically, psoriasis was viewed as primarily a disease of hyperproliferation; however, it is now known that
psoriasis is a complex immune-mediated disease in which T lymphocytes, dendritic cells, and cytokines
(interleukin [IL] 23, IL-17, and tumor necrosis factor [TNF]) play a central role. A pathogenic role for observed
differences in the skin microbiota of psoriatic skin compared with normal skin remains to be confirmed
[38,39]. (See "Pathophysiology of plaque psoriasis".)
The typical clinical findings of scaling, induration, and erythema are the result of hyperproliferation and
abnormal differentiation of the epidermis, inflammatory cell infiltrates, and vascular dilatation. When
compared with a normal epidermis, this hyperproliferative state is characterized by:
● Increased numbers of epidermal stem cells
1127
● Increased numbers of cells undergoing DNA synthesis
● A shortened cell cycle time for keratinocytes (36 hours compared with 311 hours in normal skin)
● A decreased turnover time of the epidermis (4 days from basal cell layer to stratum corneum compared
with 27 days in normal skin)
Abnormal differentiation in psoriatic skin is evidenced by a delay in the expression of keratins 1 and 10 (seen
in normal skin) and an overexpression of keratins 6 and 16 (seen in reactive and healing skin).
The body of evidence demonstrating the importance of the immune system in the pathogenesis of psoriasis
is contributing to the development of new therapies for the disease. The availability of biologic agents that
work through targeted interference with specific cytokines has revolutionized psoriasis therapy. In addition,
new treatments are contributing to our understanding of the immune pathogenesis of the disease. The role
of the immune system in psoriasis is discussed in greater detail separately. (See "Pathophysiology of plaque
psoriasis" and "Treatment of psoriasis in adults", section on 'Biologic agents' and "Treatment of psoriasis in
adults", section on 'Emerging therapies'.)
Psoriasis occurs in a variety of clinical forms and may exhibit varying features based upon the affected body
area.
Clinical subtypes — The major subtypes of psoriasis include:
● Chronic plaque psoriasis

● Guttate psoriasis
● Pustular psoriasis
● Erythrodermic psoriasis
Chronic plaque psoriasis is the most common subtype. A population-based study of 1633 patients with
adult-onset psoriasis and 357 patients with pediatric-onset psoriasis found that chronic plaque psoriasis
accounted for 79 and 74 percent of cases of psoriasis, respectively [5]. A questionnaire study of 3179
women and 646 men in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS)
with physician-diagnosed psoriasis found that 55 to 60 percent reported plaque psoriasis [40].
Chronic plaque psoriasis — Patients with chronic plaque-type psoriasis usually present with
symmetrically distributed, cutaneous plaques (picture 1A-I). The scalp, extensor elbows, knees, and gluteal
cleft are common sites for involvement. The extent of involvement can range from limited, localized disease
to involvement of the majority of the body surface area. Involvement of intertriginous areas (inverse
psoriasis), the ear canal, umbilicus, palms, soles, or nails may also be present (picture 5A-B). (See 'Special
sites' below.)
1128
Psoriasis plaques are erythematous with sharply defined margins (picture 1A-I). In patients with highly
pigmented skin, postinflammatory hyperpigmentation may be prominent and may obscure erythema. The
plaques can range from less than 1 to more than 10 cm in diameter. A thick, silvery scale is usually present,
although bathing may remove the scale, and applications of emollients may make the scale temporarily
invisible.
The plaques may be asymptomatic, but pruritus is common. Palm or sole involvement can include painful
fissures (picture 6A-B). (See 'Palmoplantar psoriasis' below.)
Guttate psoriasis — Guttate psoriasis is characterized by the abrupt appearance of multiple small,
psoriatic papules and plaques (picture 2A-C). The papules and plaques are usually less than 1 cm in
diameter (giving rise to the name "guttate," which means "drop-like"). The trunk and proximal extremities are
the primary sites of involvement. (See "Guttate psoriasis".)
Guttate psoriasis typically occurs as an acute eruption in a child or young adult with no previous history of
psoriasis. Less commonly, a guttate psoriasis flare occurs in a patient with pre-existing psoriasis. There is a
strong association between recent infection (usually streptococcal pharyngitis) and guttate psoriasis. (See
"Guttate psoriasis", section on 'Streptococcal infection'.)
Pustular psoriasis — Pustular psoriasis is a form of psoriasis that can have life-threatening
complications. The most severe variant (the von Zumbusch-type of generalized pustular psoriasis) presents
with the acute onset of widespread erythema, scaling, and sheets of superficial pustules (picture 3A-B). This
form of psoriasis can be associated with malaise, fever, diarrhea, leukocytosis, and hypocalcemia. Renal,
hepatic, or respiratory abnormalities and sepsis are potential complications. (See "Pustular psoriasis:
Reported causes of pustular psoriasis include pregnancy, infection, and the withdrawal of oral
glucocorticoids. The term "impetigo herpetiformis" has been used to refer to pustular psoriasis of pregnancy.
(See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy' and "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'Precipitating factors'.)
Acrodermatitis continua of Hallopeau is a localized version of pustular psoriasis in which disease involves
the distal digits (picture 7). (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis",
section on 'Acrodermatitis continua of Hallopeau'.)
The categorization of palmoplantar pustulosis as a localized form of pustular psoriasis or as a distinct entity
is controversial (picture 8A-B). (See "Palmoplantar pustulosis: Epidemiology, clinical features, and
diagnosis".)
Erythrodermic psoriasis — Erythrodermic psoriasis is an uncommon manifestation that may be acute or

chronic. It is characterized by generalized erythema and scaling involving most or all of the body surface
area (picture 4A-B). Affected patients are at high risk for complications related to loss of adequate barrier
protection, such as infection (including sepsis) and electrolyte abnormalities secondary to fluid loss [41].
(See "Erythrodermic psoriasis in adults".)
1129
Special sites — Psoriasis involving intertriginous skin (inverse psoriasis), nails, and palms or soles can
exhibit unique features.
Inverse (intertriginous) psoriasis — "Inverse psoriasis" refers to a presentation involving the intertriginous
areas, including the inguinal, perineal, genital, intergluteal, axillary, or inframammary regions. This
presentation is called "inverse" since it is the reverse of the typical presentation of plaque psoriasis on
extensor surfaces.
Characteristic findings of inverse psoriasis include well-demarcated, smooth, shiny plaques with absent or
minimal scale that are often misdiagnosed as intertriginous fungal or bacterial infections (picture 9A-E).
Genital involvement, in particular, may have a significant negative effect on patient quality of life (picture
10A-B) [42]. (See "Approach to the patient with an intertriginous skin disorder".)
Nail psoriasis — Nail psoriasis is most often noted after the onset of psoriatic skin lesions but also may
occur concurrently or prior to the onset of psoriasis in other areas [43,44]. Nail disease is particularly
common in patients with psoriatic arthritis [43,45,46]. Occasionally, nail involvement is the only
manifestation of psoriasis [44,45]. (See "Nail psoriasis" and "Overview of nail disorders".)
The typical nail abnormality associated with nail matrix disease is pitting, consisting of a few to multiple tiny
pits scattered over the nail plate (picture 11). Other nail matrix findings include leukonychia, red spots on the
lunula, and crumbling of the nail plate.
When the nail bed is involved, a localized color change in the nail may occur that resembles the tan-brown
color of new motor oil, referred to as the "oil drop sign" (picture 12). Other nail bed findings reported to occur
in patients with psoriasis include onycholysis, subungual hyperkeratosis, and splinter hemorrhages.
[43,44,46]. Subungual hyperkeratosis and nail plate thickening can be confused with onychomycosis (picture
13). (See "Overview of nail disorders".)
Nail psoriasis is reviewed in detail separately. (See "Nail psoriasis".)
Palmoplantar psoriasis — Palmoplantar psoriasis is psoriasis involving the palms or soles. The classic
presentation consists of erythematous, hyperkeratotic plaques that may have associated fissures (picture
6A-D). Fissures are often painful and may be disabling. Concomitant nail psoriasis is common.
It is controversial whether palmoplantar pustulosis, a condition characterized by recurrent, pustular

eruptions on the palms or soles, is a variant of psoriasis or a distinct disease entity. Palmoplantar pustulosis
is reviewed separately. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis".)
Classic signs — The Koebner phenomenon and Auspitz sign are common findings in chronic plaque
psoriasis. However, the presence or absence of these signs does not confirm or exclude a diagnosis of
psoriasis [47].
Koebner phenomenon — The Koebner phenomenon describes the development of skin disease in sites of
skin trauma. This finding may also occur in other skin diseases, such as lichen planus and vitiligo.
1130
Auspitz sign — The Auspitz sign refers to the visualization of pinpoint bleeding after removal of scale
overlying a psoriatic plaque.
SPECIAL POPULATIONS
The characteristics of psoriasis may differ in certain populations, such as HIV-infected individuals, children,
and pregnant individuals.
HIV-infected patients — Psoriasis may be the presenting sign of HIV infection, or it can develop after the
diagnosis. Psoriasis associated with HIV infection is often severe, with palmar and plantar involvement, nail
disease, arthritis, and widespread, nearly erythrodermic disease (picture 14). Considerable clinical overlap
among HIV-associated psoriasis, psoriatic arthritis with HLA-B27 positivity, and reactive arthritis has led
some authors to view these entities as a disease continuum [48]. (See "Pathogenesis of spondyloarthritis".)
Children — Although psoriasis in adults and children can present similarly, there are characteristic features
in the pediatric population. (See "Psoriasis in children: Epidemiology, clinical manifestations, and
diagnosis".)
Psoriasis in infants often presents with involvement of the diaper area. Infants with diaper-area involvement
typically develop symmetrical, well-demarcated, erythematous patches with little scale (picture 15A-B).
Maceration may be present. Unlike irritant diaper dermatitis, the inguinal folds are usually involved. Affected
infants may also have psoriatic plaques in other body areas. These plaques are often smaller and thinner
than the psoriatic plaques in adult patients [49]. (See "Psoriasis in children: Epidemiology, clinical
manifestations, and diagnosis", section on 'Special sites'.)
The frequencies of specific features of the subtypes of psoriasis are notable in children. Scalp involvement
is a common and often initial presentation of chronic plaque psoriasis in children (picture 16) [50]. In
addition, children with chronic plaque psoriasis are more likely to have facial involvement than adults. The
most common presentation of generalized pustular psoriasis in children is the annular pustular psoriasis
variant [51]. Patients with generalized annular pustular psoriasis develop a recurring, subacute eruption of
annular or figurate, erythematous plaques with peripheral pustules and scale. (See "Psoriasis in children:
Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical presentation'.)
Pregnant individuals — Pregnant individuals with psoriasis may experience improvement, worsening, or
stability of psoriasis during pregnancy. Pregnant individuals may also develop pustular psoriasis of
pregnancy (formerly called impetigo herpetiformis), a rare form of generalized pustular psoriasis that usually
occurs during the third trimester of pregnancy. (See "Management of psoriasis in pregnancy", section on
'Special considerations' and "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)
ASSOCIATED DISORDERS
1131
Patients with psoriasis are at risk for psoriatic arthritis, an inflammatory musculoskeletal disease. A wide
variety of other conditions have also been associated with psoriasis, including systemic disorders,
psychiatric and psychosocial disorders, and ocular disease. (See "Comorbid disease in psoriasis".)
Psoriatic arthritis — Psoriatic arthritis is common in patients with psoriasis, though reported prevalence
estimates vary widely. Most patients with psoriatic arthritis have coincidental skin involvement, although
arthritis precedes the skin disease in a minority of cases. Associated nail involvement is common [43]. (See
"Clinical manifestations and diagnosis of psoriatic arthritis" and 'Nail psoriasis' above.)
Common symptoms of psoriatic arthritis include joint pain, joint stiffness (particularly morning stiffness),
and back pain [52]. Several clinical patterns of joint involvement have been identified [53]:
● Distal arthritis, characterized by involvement of the distal interphalangeal (DIP) joints (picture 17)
● Asymmetric oligoarthritis in which less than five small and/or large joints are affected in an asymmetric
distribution
● Symmetric polyarthritis, similar and at times indistinguishable from rheumatoid arthritis
● Arthritis mutilans, characterized by deforming and destructive arthritis (picture 18 and image 1)
● Spondyloarthropathy, including both sacroiliitis and spondylitis
Soft tissue inflammation manifesting as enthesitis (inflammation at the site of tendon insertion into bone),
tenosynovitis, and dactylitis ("sausage digits") are additional common findings in psoriatic arthritis. Psoriatic
arthritis is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of psoriatic
arthritis".)
Other comorbidities — Understanding of the prevalence of various comorbid conditions in individuals with
psoriasis is increasing. Examples of diseases reported to occur at a higher frequency in patients with
psoriasis include cardiovascular disease, malignancy, diabetes, hypertension, metabolic syndrome,
inflammatory bowel disease, serious infections, and autoimmune disorders [54-64].
The reasons for these associations are not well understood; both genetic and environmental causes are
postulated. Examples of factors that may contribute to the occurrence of comorbid disease in patients with
psoriasis include the effects of immune-mediated chronic inflammation, lifestyle factors, and the adverse
effects of systemic therapies. The comorbidities of psoriasis are reviewed separately. (See "Comorbid
disease in psoriasis".)
Ocular findings — Disorders of the eye, such as blepharitis, conjunctivitis, xerosis, corneal lesions, and
uveitis, may occur with increased frequency in patients with psoriasis. Symptoms of eye involvement include
ocular discomfort, flaking or crusting within the eyelashes, swollen eyelids, red eyes, visual changes, and
psoriatic lesions on the lids or lid margins [65].
1132
CLINICAL COURSE
The clinical course of psoriasis for an individual patient is unpredictable. Plaque psoriasis tends to be a
chronic disease [66]. However, there may be marked variability in severity over time [67]. Guttate psoriasis
may spontaneously remit, recur, or progress into chronic plaque psoriasis. Generalized pustular psoriasis
often runs an unstable and prolonged course without treatment. (See "Guttate psoriasis", section on 'Clinical
course' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical
course'.)
Psoriasis is a rare cause of mortality (eg, with widespread pustular or erythrodermic psoriasis), but there
were at least a few dozen deaths due to psoriasis in the United States annually before the introduction of
biologic medications [68]. In addition to mortality from severe disease, psoriasis is associated with
increased overall mortality [69]. Some deaths may be due to adverse effects from systemic therapies.
Psoriasis may contribute to more deaths through an increased risk of comorbid cardiovascular disease or
other disease. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on
'Clinical course' and "Comorbid disease in psoriasis".)
HISTOPATHOLOGY
Classic histologic findings of psoriasis include:
● Epidermal hyperplasia that is regular or uniform in degree
● Parakeratosis (retention of nuclei in the stratum corneum)
● Neutrophils in the stratum corneum and epidermis (microabscesses may be present in the stratum
corneum)
● Thinned or absent granular cell layer of the epidermis
● Thinning of the suprapapillary dermal plates
● Tortuous, dilated dermal papillary capillaries
Early lesions differ from established plaques and may only possess superficial, perivascular, lymphocytic
infiltrates and dilated, tortuous capillaries. Additionally, atypical cases and partially treated cases of
psoriasis can have histologic findings that are suggestive but not diagnostic.
Histologic features similar to psoriasis may be present in superficial fungal skin infections. Special stains for
fungal organisms aid with distinguishing psoriasis from fungal infections.
DIAGNOSIS
1133
A diagnosis of chronic plaque psoriasis can be made by physical examination in the vast majority of
patients. A skin biopsy can be helpful for challenging cases but is not usually necessary. There are no other
laboratory tests that confirm the diagnosis. Genetic testing is not used for the diagnosis of psoriasis.
The diagnostic approach for guttate, pustular, erythrodermic, and nail psoriasis is reviewed separately. (See
"Guttate psoriasis", section on 'Diagnosis' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis", section on 'Diagnosis' and "Erythrodermic psoriasis in adults", section on 'Diagnosis' and "Nail
psoriasis", section on 'Differential diagnosis'.)
● History and physical examination – A full skin examination that includes examination of the scalp, nails,
and anogenital skin should be offered to patients with suspected chronic plaque psoriasis. Supportive
examination findings include chronic, well-demarcated, inflamed plaques with coarse scale, particularly
when involvement of the scalp, ears, elbows, knees, and umbilicus is present. The recognition of
characteristic nail disease or inverse psoriasis in the intergluteal cleft or other sites can support a
diagnosis of psoriasis in difficult cases.
Helpful patient history questions may include inquiries regarding a family history of psoriasis and
exposure to medications that may induce or exacerbate psoriasis (table 1). (See 'Risk factors' above.)
● Skin biopsy – A skin biopsy may be performed if the diagnosis remains uncertain after the history and
physical examination. Typically, a 4 mm punch biopsy from involved skin is performed, though a shave
biopsy through the mid-dermis may also be adequate. A periodic acid-Schiff-diastase (PAS-D) stain of
the specimen may help distinguish psoriasis from a superficial fungal infection. (See "Skin biopsy
techniques", section on 'Punch biopsy' and 'Histopathology' above.)
ADDITIONAL EVALUATION
In addition to the evaluation above, patients with psoriasis should be assessed for signs or symptoms of
psoriatic arthritis and other comorbidities [70]. (See 'Associated disorders' above.)
Joint guidelines from the American Academy of Dermatology and the National Psoriasis Foundation
recommend routine screening for signs and symptoms of psoriatic arthritis to facilitate the earliest possible
detection [70]. Screening questions can include asking about the presence of joint pain, joint stiffness
(particularly morning stiffness), and back pain (which patients may not recognize as a manifestation of joint
pain) [52]. (See "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Diagnosis'.)
Assessment for other comorbidities is reviewed separately. (See "Comorbid disease in psoriasis", section on
'Evaluation and management'.)
The proportion of patients with psoriasis and ocular disorders is not definitively known, and guidelines for
screening for ocular involvement in patients with psoriasis have not been established. Asking patients about
ocular symptoms at each follow-up visit may help to identify patients with ocular involvement. In addition,
1134
some authors have suggested routine ophthalmic examinations every one to two years in patients with
severe psoriasis [65]. (See 'Ocular findings' above.)
The differential diagnosis of chronic plaque psoriasis varies according to the clinical presentation. Key
disorders that may be mistaken for chronic plaque psoriasis include seborrheic dermatitis, lichen simplex
chronicus, atopic dermatitis, and nummular eczema. The differential diagnoses for guttate, pustular,
erythrodermic, and nail psoriasis are reviewed separately. (See "Guttate psoriasis", section on 'Differential
diagnosis' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on
'Differential diagnosis' and "Erythrodermic psoriasis in adults", section on 'Differential diagnosis' and "Nail
psoriasis", section on 'Differential diagnosis'.)
● Seborrheic dermatitis – Seborrheic dermatitis usually presents with erythematous patches with
overlying scale (picture 19A-C). In individuals with dark skin, the erythema may be less visible (picture
19B, 19D). Both psoriasis and seborrheic dermatitis commonly involve the scalp, ears, and intertriginous
areas. Features that support a diagnosis of seborrheic dermatitis include the characteristic fine, greasy
scale typically evident in nonintertriginous locations and involvement of classic areas such as the
eyebrows, nasolabial folds, central chest, or postauricular area. The presence of nail changes or
characteristic changes of psoriasis in other areas helps distinguish psoriasis from seborrheic
dermatitis. (See "Seborrheic dermatitis in adolescents and adults" and "Cradle cap and seborrheic
dermatitis in infants".)
● Lichen simplex chronicus – Lichen simplex chronicus describes skin changes that occur secondary to
excessive scratching of the skin. An underlying cause of pruritus or scratching (eg, atopic dermatitis,
arthropod bite, or psychologic disorder) is often present. Patients develop plaques of thickened skin that
exhibit accentuated skin markings (picture 20). Overlying scale or hyperpigmentation may be present.
Sites where the patient cannot reach are unaffected. Lichen simplex chronicus can occur in
combination with psoriasis when psoriasis lesions are very itchy. (See "Pruritus: Etiology and patient
evaluation", section on 'Secondary skin disorders'.)
● Atopic dermatitis – Atopic dermatitis is a common skin disorder associated with the development of
pruritus and often excoriated papules and patches that may exhibit erythema, hyperpigmentation, or
scale (picture 21A-B). Localized areas of skin lichenification (thickening) are common. The
characteristic thick, coarse scale and sharp, raised, well-defined borders of psoriasis are typically
absent. In older children and adults, atopic dermatitis tends to involve skin flexures. Infants often have
facial or scalp involvement (picture 22). Unlike psoriasis, the diaper area is typically spared. (See "Atopic
dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)
● Nummular eczema – Nummular eczema (also known as nummular dermatitis) typically presents with
well-demarcated, round plaques 1 to 10 cm in diameter (picture 23A-C). The plaques are often
1135
erythematous with overlying scale, crust, or small fissures and have indistinct borders, unlike psoriasis.
The trunk and extremities are the usual sites of involvement. The face and scalp are spared. (See
"Nummular eczema".)
● Superficial fungal infections – Superficial fungal infections (eg, tinea corporis, tinea pedis, cutaneous
candidiasis) may present with erythematous plaques (with or without pustules) that may be mistaken
for psoriasis (picture 24A-B). Nail changes related to onychomycosis can also be confused with nail
psoriasis (picture 25). A potassium hydroxide (KOH) preparation or biopsy can be useful for confirming
fungal infection. (See "Dermatophyte (tinea) infections" and "Onychomycosis: Epidemiology, clinical
Other less common disorders that should be considered in the differential diagnosis of chronic plaque
psoriasis include subacute cutaneous lupus erythematosus, pityriasis rubra pilaris, crusted scabies, and
cutaneous T cell lymphoma.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Psoriasis".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer
the four or five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable
with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Psoriasis (The Basics)")
● Beyond the Basics topics (see "Patient education: Psoriasis (Beyond the Basics)" and "Patient
education: Psoriatic arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
1136
● Psoriasis is a common chronic inflammatory skin disease that has also been identified as a
multisystem inflammatory disorder associated with multiple comorbidities.
● Psoriasis affects males and females equally. Psoriasis can begin at any age; however, onset during
adulthood is most frequent. (See 'Epidemiology' above.)
● Psoriasis is a complex immune-mediated disease. Genetic factors play an important role, and multiple
genes have been associated with susceptibility to psoriasis. The psoriasis-susceptibility (PSORS1)
locus within the major histocompatibility complex (MHC) on chromosome 6p21 is considered a major
genetic determinant of this disease. (See 'Pathophysiology' above and "Pathophysiology of plaque
psoriasis".)
● There are multiple clinical subtypes of psoriasis. Chronic plaque psoriasis, the most common form of
psoriasis, most often presents with sharply defined, erythematous plaques with overlying, coarse scale
(picture 1A-I). The scalp, extensor elbows, knees, and gluteal cleft are common locations for chronic
plaque psoriasis. Other major subtypes include guttate psoriasis, pustular psoriasis, and erythrodermic
psoriasis. (See 'Clinical manifestations' above.)
● Individuals with psoriasis are at risk for psoriatic arthritis and multiple other comorbidities. Examples of
other comorbidities linked to psoriasis include obesity, metabolic syndrome, hypertension, diabetes, and
atherosclerotic disease. (See 'Other comorbidities' above and "Comorbid disease in psoriasis".)
● A diagnosis of psoriasis can be made by physical examination in the vast majority of patients.
Occasionally, a skin biopsy is needed to rule out other conditions. (See 'Diagnosis' above.)
1137
GRAPHICS
Psoriasis vulgaris
Well-demarcated, erythematous, scaly plaques are present on the neck and scalp.
1138
Plaque psoriasis
An erythematous plaque with coarse scale is present on the knee of this patient with
psoriasis.
1139
Plaque psoriasis
Well-demarcated, raised, erythematous plaques with a silvery-white, scaly surface are

characteristic of plaque psoriasis.
1140
Plaque psoriasis
A large, infiltrated, erythematous plaque with well-demarcated margins in a patient with plaque psoriasis.
1141
Multiple large plaques with silver scale on the back.
1142
Plaque psoriasis
Multiple well-demarcated, erythematous, and hyperpigmented plaques on the back and buttocks.
1143
Plaque psoriasis
Well-demarcated, erythematous, and hyperpigmented plaques with coarse scale on the thighs.
1144
Plaque psoriasis
Erythematous, scaly plaques on the chest and abdomen.
1145
Plaque psoriasis
Well-demarcated, scaly, erythematous papules and plaques on the back.
1146
Guttate psoriasis
Numerous erythematous, scaly papules on the back.
1147
Guttate psoriasis
Multiple erythematous papules with scale on the back.
1148
Guttate psoriasis
Multiple discrete, well-demarcated, pink, scaly papules on the trunk following a streptococcal infection.
1149
Diffuse erythema, numerous pustules, and scale on the buttocks and posterior thighs.
1150
Pustular psoriasis
Widespread, erythematous patches, desquamation, and pustules in pustular psoriasis.
1151
Erythrodermic psoriasis
Diffuse erythema and scale on the legs.
1152
Diffuse erythema and scale on the arm.
1153
Reported causes of psoriasiform drug eruptions
Common
Psychoactive drugs (lithium)
Antihypertensives (beta blockers)
Antimalarials (chloroquine, hydroxychloroquine, quinidine)
Nonsteroidal anti-inflammatory drugs, antibiotics (tetracycline)
Uncommon
Tumor necrosis factor inhibitors (infliximab, adalimumab, etanercept, certolizumab pegol) [1,2]
Antifungals (terbinafine) [3]
Rare
Antihypertensives (clonidine)
Antiarrhythmics (digoxin, amiodarone)
Antiepileptics (carbamazepine, valproic acid)
Psychoactives (fluoxetine)
Antihypertensives/diuretics (captopril, chlorthalidone, diltiazem, nifedipine, nicardipine, [4] acetazolamide)
Antibiotics (penicillin, amoxicillin, ampicillin)
Opioids (morphine)
Anesthetics (procaine)
Antihistamines (cimetidine, ranitidine*)
Heavy metals (gold, mercury)
Hormonal agents (oxandrolone, progesterone)
Fibrates (gemfibrozil)
Antithyroid (potassium iodide)
Cytokines/cytokine inducers (GM-CSF, imiquimod)
GM-CSF: granulocyte macrophage colony-stimulating factor.

* Ranitidine has been withdrawn from the United States market.
References:
1. Wollina U, Hansel G, Koch A, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature
including a series of six new patients. Am J Clin Dermatol 2008; 9:1.
2. Cullen G, Kroshinsky D, Cheifetz AS, Korzenik JR. Psoriasis associated with antitumour necrosis factor therapy in inflammatory bowel disease: a new series
and a review of 120 cases from the literature. Aliment Pharmacol Ther 2011; 34:1318. doi:10.1111/j.1365-2036.2011.04866.x.
3. Gupta AK, Sibbald RG, Knowles SR, et al. Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: four case
reports and a review of drug-induced psoriasis. J Am Acad Dermatol 1997; 36:858.
4. Kitamura K, Kanasashi M, Suga C, et al. Cutaneous reactions induced by calcium channel blocker: high frequency of psoriasiform eruptions. J Dermatol
1993; 20:279.
Reproduced with permission from: Ahronowitz I, Fox L. Severe drug-induced dermatoses. Semin Cutan Med Surg 2014; 33:49. Copyright © 2014 Frontline Medical
Communications.
1154
1155
Psoriasis
Erythematous, scaly plaque at the umbilicus.
1156
Psoriasis
Erythematous and scaly plaque involving the ear.
1157
Palmoplantar plaque psoriasis
Erythematous, scaly plaques on the palms in a patient with psoriasis.
1158
Palmoplantar psoriasis
Erythematous, scaly plaques with fissures on the palms and soles.
1159
Acrodermatitis continua of Hallopeau
Erythema, pustules, and nail dystrophy are present on the distal finger.
1160
Pustules within an erythematous, scaly plaque on the lateral heel.
1161
Multiple brown macules and pustules are present in an erythematous, hyperkeratotic

plaque on the plantar foot.
1162
Inverse psoriasis
Shiny, erythematous, well-demarcated plaques in the axilla.
1163
Inverse psoriasis
Well-demarcated, erythematous plaque in the axilla.
1164
Inverse psoriasis
Well-demarcated, erythematous plaques with some overlying scale in the inframammary creases.
1165
Inverse psoriasis
Shiny, erythematous plaques within skin folds of the suprapubic region and inguinal creases. Erythematous, scaly plaques on the scrotum.
1166
Inverse psoriasis
Shiny, erythematous plaque within skin fold of the groin and associated scrotal involvement.
1167
Psoriasis
Erythematous, scaly plaque on the glans penis.
1168
Psoriasis
Round plaque with scale on the glans penis.
1169
Nail pits in psoriasis
Numerous pits are present on the nail of this patient with psoriasis.
1170
Oil drop sign and distal onycholysis in psoriasis
Discoloration of the nail plate and distal onycholysis (separation of the nail plate from the
nail bed) are present in this patient with psoriasis.
1171
Nail psoriasis with subungual hyperkeratosis
Marked subungual hyperkeratosis is present on several nails of this patient with psoriasis.
1172
Palmar psoriasis
A scaly, erythematous patch on the palm of a patient with plaque psoriasis.
1173
Palmoplantar psoriasis
Thick, hyperkeratotic plaques on the pressure areas of the soles in a patient with palmoplantar
psoriasis. Note the nail involvement.
Courtesy of Akiharu Kubo, MD, PhD.
1174
Psoriasis
Confluent, scaly, erythematous papules and plaques on the back of a patient with AIDS.
1175
Psoriasis
Erythematous plaques in the diaper area in an infant with psoriasis.
1176
Psoriasis
Erythema and maceration in the diaper area of an infant with psoriasis. Note involvement of the inguinal fold.
1177
Psoriasis
Scaly, erythematous plaque on the scalp of a child.
1178
Distal interphalangeal joint involvement in psoriatic arthritis
Psoriatic arthritis with distal joint involvement in the third and fifth digits (arrow).
Onycholysis is also seen in most of the fingernails.
Courtesy of Dafna D Gladman, MD.
1179
Arthritis mutilans
Arthritis mutilans in psoriatic arthritis with marked deformity and destruction of digits.
Courtesy of Peter H Schur, MD.
1180
Arthritis mutilans in psoriatic arthritis
Radiograph demonstrating marked deformity and destruction of the hand digits in a patient
with classic psoriatic arthritis and arthritis mutilans.
Courtesy of Peter H Schur, MD.
1181
Facial redness and scale involving the nasolabial folds and central face.
Reproduced with permission from: Goodheart HP. Goodheart's photoguide of common skin disorders,
2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003 Lippincott Williams &
Wilkins.
1182
Intertriginous seborrheic dermatitis
Intertriginous seborrheic dermatitis of the axilla in an HIV-positive patient with secondary

folliculitis.
1183
Diffuse erythema and scaling of the scalp.
1184
Seborrheic dermatitis of the face and beard area
Erythematous and scaly patches on the face and beard area.
1185
Lichen simplex chronicus
Areas of thickened and hyperpigmented skin from chronic rubbing on the ankle of a patient with
lichen simplex chronicus.
1186
Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings) of the
knee flexures in a 22-year-old woman.
1187
dermatitis.
1188
Confluent erythema, microvesiculation, papules, crust, and scale on the face of an infant.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds), Color Atlas and
Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York 1997. Copyright © McGraw-Hill.
1189
Nummular eczema
Nummular eczema of the thigh typically presenting as round, coin-shaped, erythematous, scaly plaques.
1190
Nummular eczema
A plaque of nummular eczema with erythema, vesiculation, and crusting.
1191
Nummular eczema
These coin-shaped, scaly lesions on the thigh show evidence of postinflammatory

hyperpigmentation.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders,
Wilkins.
1192
Tinea corporis
Annular plaque with scale on the knee.
1193
Candidal intertrigo
Erythematous plaque with satellite papules and pustules in the abdominal and inguinal folds.
1194
Distal subungual onychomycosis
1195
Pathophysiology of plaque psoriasis

Authors: Andrew Blauvelt, MD, MBA, Benjamin D Ehst, MD, PhD
Section Editor: Kristina Callis Duffin, MD
INTRODUCTION
Psoriasis is a complex immune-mediated inflammatory disease that occurs in genetically

susceptible individuals and presents with the development of inflammatory plaques on the skin
(picture 1A-B). Although early concepts of the pathogenesis of psoriasis focused primarily on
keratinocyte hyperproliferation, dysregulation of the immune system is now recognized as a critical
event in this disease. The evolving knowledge of the role of the immune system in psoriasis has had
a significant impact on treatment development. Many new and emerging therapeutic agents target
specific immunologic aspects of psoriatic disease. (See "Treatment of psoriasis in adults".)
The pathophysiology of plaque psoriasis will be discussed here. The epidemiology, genetics, clinical
features, diagnosis, and management of psoriasis, as well as the pathogenesis of the less common
subtype of pustular psoriasis, are reviewed separately. (See "Psoriasis: Epidemiology, clinical
manifestations, and diagnosis" and "Treatment selection for moderate to severe plaque psoriasis in
special populations" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)
OVERVIEW
Involvement of the immune system in psoriasis was first indicated in early studies that identified
complex infiltrates of leukocytes involved in both innate and adaptive immunity in psoriatic skin [1,2].
Subsequent studies have supported the concept that interactions between dendritic cells, T cells,
keratinocytes, neutrophils, and the cytokines released from immune cells likely contribute to the
initiation and perpetuation of the cutaneous inflammation that is characteristic of psoriasis [3]. A
1196
basic sequence of the immunologic events that are theorized to occur in psoriasis is described
below [3]:
● Antigenic stimuli contribute to the activation of plasmacytoid dendritic cells and other innate
immune cells in the skin.
● Proinflammatory cytokines produced by innate immune cells, including interferon (IFN)-alpha,

stimulate the activation and migration of various myeloid dendritic cells in the skin.
● Myeloid dendritic cells produce cytokines, in particular interleukin (IL)-23, that stimulate the
attraction, differentiation, and activation of T cells.
● Recruited T cells produce cytokines, importantly IL-17A, which synergizes with other cytokines
to stimulate keratinocytes to proliferate and produce proinflammatory antimicrobial peptides
and cytokines.
● Cytokines produced by immune cells and keratinocytes perpetuate the inflammatory process via
participation in positive feedback loops.
The specific components of this pathway are reviewed below.
THE INNATE IMMUNE RESPONSE
The cellular components of the innate immune system that have been linked to the pathophysiology
of psoriasis include the professional antigen-presenting cells (APCs), dendritic cells and
macrophages, as well as neutrophils. The cytokines produced by these cells that appear to play
major roles in the development of psoriasis include interferon (IFN)-alpha, tumor necrosis factor
(TNF)-alpha, and interleukin (IL)-23. Modulating the production of these inflammatory cytokines and
the innate immune cells responsible for their production with the small molecule phosphodiesterase
4 (PDE4) inhibitor apremilast and the small molecule Janus kinase (JAK) and tyrosine kinase 2
(Tyk2) inhibitors tofacitinib and BMS-986165, respectively, has demonstrated benefit in the treatment
of psoriasis [4-6]. (See "Treatment of psoriasis in adults", section on 'Emerging therapies' and
"Treatment of psoriasis in adults", section on 'Apremilast'.)
Cellular components
Dendritic cells — Two types of dendritic cells (plasmacytoid dendritic cells and various myeloid
dendritic cells) have been implicated as contributors to psoriasis.
● Plasmacytoid dendritic cells – Plasmacytoid dendritic cells are a unique type of dendritic cell
largely absent from normal human skin but are greatly increased in number in early lesions of
1197
psoriasis [7]. These cells are the primary producers of IFN-alpha, a key cytokine involved in the
initiation phase of autoimmune responses and antiviral immunity. (See 'Interferon-alpha' below.)
Upregulation of IFN-alpha has been detected in early psoriatic lesions [8]. In addition, in a mouse
xenograft model of psoriasis, the development of psoriatic lesions was dependent on IFN-alpha
production by plasmacytoid dendritic cells [9].
● Myeloid dendritic cells – The numbers of myeloid dendritic cells are markedly elevated in
psoriatic skin. In particular, an inflammatory subset of myeloid dendritic cells (including TNF-
alpha and iNOS-expressing dendritic cells [TIP-DCs], 6-sulfo LacNAc dendritic cells [slanDCs],
and epidermal dendritic cells [eDCs]) recruited in response to the release of IFN-alpha and other
proinflammatory cytokines and chemokines has been detected in lesional psoriatic skin [10-15].
Myeloid dendritic cells are potent APCs that produce an array of inflammatory cytokines that
influence T cell activity, such as TNF-alpha (see 'Tumor necrosis factor-alpha' below). Myeloid
dendritic cells also produce IL-23, a cytokine that causes the differentiation of precursor CD4+
cells into Th17 cells, and IL-12, a cytokine that stimulates the development of Th1 cells and
effector CD8+ T cells [14-16] (see 'Interleukin-23' below and 'Interleukin-12' below). Myeloid
dendritic cells also affect keratinocytes and the skin vasculature through the production of IL-20
(a modulator of keratinocyte function) and nitric oxide (a vasodilating agent) [17]. (See
'Keratinocytes' below and 'Vascular changes' below.)
Macrophages and neutrophils — The importance of macrophages in psoriasis in humans is not

well understood. Macrophages accumulate in psoriatic skin near the basement membrane [18] and
may contribute to psoriasis through antigen presentation to T cells as well as cytokine production.
The depletion of macrophages can reverse psoriasis-like skin changes in mouse models [19].
Neutrophils are prominent in lesions of psoriasis, and are found in collections throughout the
epidermis that are referred to as Munro microabscesses. The neutrophil chemoattractant IL-8 is
highly elevated in psoriatic skin [20,21]. Like macrophages, neutrophils are believed to participate in
psoriatic inflammation. Studies highlight their potential role as producers of IL-17A, an important
cytokine with multiple effects in psoriatic plaques [22]. (See 'Interleukin-17A' below.)
Cytokines
Interferon-alpha — Type I interferon pathways are upregulated in early lesions of psoriasis [8].
IFN-alpha present in psoriatic skin is largely derived from plasmacytoid dendritic cells [8]. (See
'Dendritic cells' above.)
Evidence in support of a key role for IFN-alpha in psoriasis includes the observation that systemic
treatment with IFN-alpha can exacerbate psoriasis [23,24]. In addition, topical treatment with
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imiquimod, which induces local production of IFN-alpha in the skin, has stimulated the development
of psoriasis in humans and psoriasis-like disease in mice [25,26]. Furthermore, mice that lack a
transcription factor that represses type I interferon signaling develop psoriasis-like disease [27].
Tumor necrosis factor-alpha — TNF-alpha is a critical proinflammatory cytokine common to many

inflammatory disease states, including psoriasis [28]. Activated dendritic cells, Th17 and Th1 cells,
and keratinocytes in psoriatic skin produce TNF-alpha and respond to its effects. TNF-alpha also
functions synergistically with other cytokines to promote disease pathogenesis.
The following observations support an important role for TNF-alpha in psoriasis:
● Elevated levels of TNF-alpha are found in lesional skin of psoriatic patients [29].
● Dramatic clinical improvement of psoriasis is seen with pharmacologic inhibitors of TNF-alpha

(infliximab, adalimumab, etanercept, and certolizumab pegol) [30-33].
● Removal of circulating TNF-alpha via the administration of etanercept (a TNF-alpha inhibitor)

results in decreased numbers of dendritic cells and T cells along with a reduction of epidermal
hyperplasia in psoriatic skin [12].
The central role of TNF-alpha in both innate and adaptive immune responses makes this cytokine a
key target for therapeutic blockade. (See "Treatment of psoriasis in adults", section on 'Biologic
agents'.)
Interleukin-23 — IL-23 is the regulatory cytokine responsible for proliferation and survival of Th17
cells, which is an increasingly important T cell subset in many autoimmune diseases, including
psoriasis and Crohn's disease [34-36]. IL-23 is produced by myeloid dendritic cells and at low levels
by keratinocytes [37,38]. Production of this cytokine by dendritic cells can occur through toll-like
receptor signaling pathways [39,40]. (See "Toll-like receptors: Roles in disease and therapy".)
The importance of IL-23 to the pathogenesis of psoriasis has been demonstrated by the following:
● In psoriatics, IL-23 is elevated in lesions of psoriasis compared with unaffected skin and
localizes to dermal dendritic cells and keratinocytes; levels of IL-23 fall with effective treatment
of psoriasis [41-45].
● Injection of IL-23 into normal mouse skin produces changes that are clinically and histologically
similar to psoriasis; this process depends on downstream production of IL-22 and IL-17A
[41,46,47]. Blockade of IL-23 in a mouse model prevented development of psoriasis in human
xenografted skin from patients with psoriasis [48].
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● Polymorphisms in the genes encoding a component of the IL-23 receptor, IL23R, and the p40 and
p19 subunits of IL-23 have been linked to psoriasis [49].
● Several monoclonal antibodies bind selectively to the p19 subunit of IL-23 (guselkumab,
tildrakizumab, risankizumab, and mirikizumab), thereby blocking IL-23-mediated effects on Th17
cells. These drugs are highly effective for psoriasis [50-53]. Additionally, the biologic agent
ustekinumab, which inhibits both IL-23 and IL-12 signaling by binding the shared p40 subunit of
these cytokines, is effective for psoriasis [54]. (See "Treatment of psoriasis in adults", section on
'Ustekinumab'.)
● BMS-986165 inhibits IL-23 receptor-mediated signaling by selective blockade of Tyk2, a tyrosine

kinase acting downstream of the IL-23 receptor. Treatment with this drug has resulted in
improvement of psoriasis in clinical trials [6].
Interleukin-12 — IL-12, like IL-23, is produced by activated myeloid dendritic cells, and this
cytokine promotes the differentiation of Th1 cells. Indirect evidence for a contributory role for IL-12 in
psoriasis comes from findings of increased Th1 cells and IFN-gamma (a product of Th1 cells) in
psoriatic skin [55,56]. However, the degree to which IL-12 contributes to psoriasis is brought into
question by the failure of a study to detect upregulation of the p35 subunit of IL-12 in psoriatic skin
[43]. Additionally, preclinical mouse models suggest a regulatory or protective role for IL-12 in
counteracting the IL-23/Th17 immunologic pathway [57]. It is possible that ustekinumab, an effective
biologic agent for psoriasis that targets both IL-12 and IL-23 [48,54], may function primarily through
the drug's effects on the IL-23 pathway. (See 'T helper type 1 cells' below and 'Interleukin-23' above
and "Treatment of psoriasis in adults", section on 'Ustekinumab'.)
THE ADAPTIVE IMMUNE RESPONSE
The importance of T cells and their effector cytokines in psoriasis was established early on with the
success of medications that inhibit global T cell responses, such as cyclosporine [58]. Therapies that
block T cell activation or induce T cell death, such as alefacept (an inhibitor of the T cell-activating
interaction between LFA3 on antigen-presenting cells (APCs) and CD2 on T cells that is no longer
commercially available), have been effective for psoriasis [59]. In addition, injection of lymphocytes
from psoriatics can induce psoriatic features in nonlesional human skin transplanted onto severe
combined immunodeficient (SCID) mice [60]. Inhibition of inflammatory cytokine production via
phosphodiesterase 4 (PDE4) blockade or Janus kinase (JAK)/tyrosine kinase 2 (Tyk2) inhibition in
lymphocytes has improved psoriasis as well [5,6,61,62]. (See "Treatment of psoriasis in adults",
section on 'Emerging therapies' and "Treatment of psoriasis in adults", section on 'Apremilast'.)
Cellular components
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CD4+ T cells — CD4+ helper T cells are found throughout dermal inflammatory infiltrates in
psoriatic skin [63]. Data in support of a role for these cells include the finding that the injection of
CD4+ (but not CD8+) T cells from patients with psoriasis into graft sites on SCID mice transplanted
with human skin induces psoriatic changes in the engrafted skin [64]. In addition, clinical
improvement has occurred in patients with psoriasis treated with monoclonal antibodies against the
CD4+ molecule on T cells [65].
The Th17 subset of CD4+ T cells, and to a lesser extent Th1 and Th22 cells, has been implicated in
psoriasis. Early investigational studies presumed a dominating role for Th1 cells; however, Th17 cells
are now believed to play the more critical role. The effects of these cells and other components of
the adaptive immune system in psoriasis are reviewed below.
T helper type 17 cells — The discovery of Th17 cells has led to important insights on the
pathophysiology of psoriasis and new target-specific approaches to treatment. Th17 cells develop in
psoriatic skin under the polarizing effects of IL-1, IL-6, transforming growth factor (TGF)-beta, and IL-
23 produced by inflammatory dendritic cells [66] (see 'Dendritic cells' above). The activation of Th17
cells by IL-23 stimulates these cells to produce IL-17A and IL-22, cytokines that promote keratinocyte
activation and growth [46,67,68]. (See 'Interleukin-17A' below and 'Interleukin-22' below.)
The following study results highlight the role of these cells in psoriasis:
● Th17 cells produce an array of proinflammatory cytokines, including IL-17A, IL-17F, IL-21, IL-22,
IL-6, and TNF-alpha [36], all of which have been linked to psoriasis.
● Th17 cells are found in lesional skin and at elevated levels in the circulation in patients with
psoriasis, and IL-17A is abundantly expressed by these cells [55,69,70].
● Transgenic mice overexpressing the p19 subunit of IL-23, a key factor for Th17 cell functioning,
have severe widespread inflammatory disease that includes inflammation of the skin [71].
● Effective therapies for psoriasis, such as phototherapy, cyclosporine, etanercept, and infliximab,
have all been shown to modulate the Th17 pathway in psoriasis [12,70,72-74].
● Selective targeting of IL-17A (the main effector cytokine produced by Th17 cells) by
secukinumab and ixekizumab, as well as duel blockade of IL-17A and IL-17F by bimekizumab,
leads to dramatic improvement in psoriasis [75-77]. Similar success in clearing psoriatic skin is
seen with blockade of the IL-17RA, a subunit of the IL-17A receptor, by brodalumab [78]. (See
"Treatment of psoriasis in adults", section on 'Secukinumab' and "Treatment of psoriasis in
adults", section on 'Emerging therapies'.)
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Affecting Th17 cells via inhibition of IL-23 or the IL-23 receptor also is a promising therapeutic
approach for psoriasis [50,79,80]. Ustekinumab, a highly effective drug that is in use for psoriasis, is
a monoclonal antibody that binds to p40, a subunit of both IL-23 and IL-12, which leads to death of
Th17 cells. Similarly, guselkumab, tildrakizumab, risankizumab, and mirikizumab are selective
blockers of IL-23 that show high efficacy in clinical practice and clinical trials. Agents that interrupt
JAK/STAT signaling pathways (key intracellular events in Th17 cytokine production) are also under
investigation for the treatment of psoriasis [5,6,62].
T helper type 1 cells — Th1 cells produce an array of proinflammatory cytokines, including IFN-
gamma, IL-2, and TNF-alpha [81]. IFN-gamma, the prototypic cytokine produced by these cells, can
promote psoriasis-like changes in nonlesional psoriatic skin [82]. Of note, infliximab, an effective
anti-TNF therapy for psoriasis, is also capable of inhibiting IFN-gamma production by Th1 cells [83].
IL-12, a cytokine produced by activated myeloid dendritic cells, promotes the differentiation of Th1
cells. The degree to which IL-12-mediated effects contribute to psoriasis is uncertain [43]. (See
'Dendritic cells' above and 'Interleukin-12' above.)
CD8+ T cells — Cytotoxic CD8+ T cells are found primarily in the epidermis of psoriatic skin and
are generally considered to play a less prominent role in psoriasis than CD4+ T cells [84]. Although
they produce cytolytic enzymes, their role in psoriasis is speculated to involve the elaboration of
inflammatory cytokines, including IL-17A [85-88]. Interestingly, clonal restriction of resident memory
epidermal T cells seems limited to the CD8+ compartment [89]. This finding might suggest a link
between viral or self-antigens in the epidermis and triggering of psoriasis, since these types of MHC
class I-restricted antigens are typically presented to CD8+ T cells, and not CD4+ T cells [90,91].
In addition, resident memory T cells that are long-lived CD69+, CD103+, IL-17A-producing epidermal
CD8+ T cells have been linked to the recurrence of psoriasis in previously healed skin [92]. Further
research on these cells may result in therapeutic strategies to target them, perhaps leading to greater
long-term control of psoriasis in the future.
Regulatory T cells — CD18-knockout mice that are deficient in regulatory T cells develop skin with
features of psoriasis [93]. T regulatory cells have also been found to limit psoriasiform inflammation
in imiquimod-induced mouse skin via modulation of IFN-alpha [94]. Additionally, defects in the
suppressive function of regulatory T cells have been found in psoriasis lesions [95]. In the absence
of properly functioning regulatory cells, downregulation of immune responses is inadequate. This
may contribute to unchecked inflammation in psoriasis.
Cytokines
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Interleukin-17A — IL-17A, an effector cytokine produced by Th17 cells, is elevated in lesions of
psoriasis and serum of patients with psoriasis [41,96]. IL-17A has many functions that are relevant to
psoriasis, including the activation, recruitment, and inhibition of apoptosis in neutrophils; the
enhancement of angiogenesis; the promotion of the release of other inflammatory cytokines (TNF-
alpha, IL-1, and IL-6); and the direct activation of keratinocytes leading to increased production of
chemokines [46,68,97-103]. Therapeutic agents for psoriasis that block IL-17A production or the
downstream effects of IL-17 are commercially available. The anti-IL-17A monoclonal antibodies
secukinumab and ixekizumab have shown efficacy results equivalent to or better than other available
biologic agents for moderate to severe plaque psoriasis [75,76]. Bimekizumab, a monoclonal
antibody that blocks IL-17A and its close homolog IL-17F, shows promising results in clinical trials
[77]. Similarly, high efficacy results in psoriasis are achieved with brodalumab, an antibody that
blocks the binding of IL-17A to its receptor [78].
Interleukin-22 — IL-22 levels are increased in the blood of patients with psoriasis and in psoriatic
plaques. Treatment of psoriasis decreases these levels [70,96,104].
IL-22 is produced by Th17 cells and Th22 cells. This cytokine stimulates the growth and activation of
keratinocytes and has little effect on immune cells. In keratinocytes, IL-22-mediated signaling via
STAT3 stimulates cell hyperproliferation, secretion of antimicrobial peptides, and production of
matrix metalloproteinases that support increased cell mobility [47,104-107]. Molecular therapies that
target IL-22 are in clinical trials [108].
KERATINOCYTES
A role for epidermal keratinocytes as triggers for the initiation of psoriasis is a subject of much
debate. Keratinocyte-derived antimicrobial peptides (AMPs), including beta-defensins, cathelicidins,
and psoriasin (S100A7), may be induced by trauma, and are upregulated in psoriatic epidermis early
in the course of lesion development [109]. AMPs have both chemoattractant and immunomodulatory
effects on dendritic cells and T cells and may contribute to cutaneous inflammation. Similarly, the
melanocyte-derived ADAMTS-like protein 5 may also function as an antigenic trigger of the IL-17
pathway in psoriatics [110]. One theory on the initiation of psoriasis involves the upregulation of the
AMP cathelicidin LL-37 in skin. LL-37 may bind self DNA and stimulate the production of IFN-alpha
by plasmacytoid dendritic cells through Toll-like receptor (TLR)-9 [111]. LL-37 has also been shown to
be antigenic in psoriasis; LL-37 stimulates both CD4+ and CD8+ T cells in an HLA-restricted manner
[112].
Keratinocyte hyperplasia characteristic of psoriasis may develop because of the effects of cytokines
produced by immune cells. IL-22 is produced by Th17 cells and promotes many of the epidermal
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changes that occur in psoriatic lesions (see 'Interleukin-22' above). Additionally, IL-20 production by
keratinocytes plays an important synergistic role downstream of IL-22.
Both IL-22 and IL-20 are highly expressed in psoriatic skin and promote alterations in epidermal
thickness, maturation defects, and upregulation of AMPs [113,114]. A role for IL-20 in psoriasis is
supported by the observation that blocking IL-20 in a SCID xenotransplant model of psoriasis
induces resolution of psoriasis and blocks initiation of disease [115]. Therapeutics directed against
both IL-22 and IL-20 have been tested in early clinical trials [108].
The cytokines and chemokines produced by activated keratinocytes contribute to the sustainment of
the inflammatory response in psoriasis via their effects on innate and adaptive immune cells. Topical
vitamin D analogs as well as topical and oral retinoids primarily affect this pathway in psoriasis.
Methotrexate was originally thought to modulate the epidermal component of psoriasis as well,
although current thinking suggests that its direct effects on the immune system are more important.
(See "Treatment of psoriasis in adults", section on 'Topical vitamin D analogs' and "Treatment of
psoriasis in adults", section on 'Tazarotene' and "Treatment of psoriasis in adults", section on
'Methotrexate'.)
VASCULAR CHANGES
Endothelial cells within psoriatic plaques express elevated levels of vascular endothelial growth
factor (VEGF), prostaglandins, and nitric oxide, all contributing to the characteristic leaky and
tortuous vessels that are abundant in psoriatic skin [116,117]. Transgenic mice overexpressing VEGF
in the epidermis have been found to develop psoriasiform skin changes [118].
The activated vasculature promotes attraction and transmigration of the leukocytes discussed
above. Antiangiogenic agents have demonstrated some success in psoriasis patients, but more
investigation is needed [119].
ENVIRONMENTAL FACTORS
Medications, trauma, alcohol, cigarette smoking, stress, and infections have all been linked to the
onset of autoimmune inflammatory conditions and are also known to trigger psoriasis. The current
understanding of this process is rudimentary.
A proposed pathogenic model highlights the possibility of innate recognition of conserved

sequences in microbes through TLR signaling as one possible explanation for infectious triggers.
The TLR-7/8 antagonist imiquimod can induce a psoriasis-like skin disease in mice through
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production of IFN-alpha by plasmacytoid dendritic cells. This process is dependent on the Th17
pathway [26].
SUMMARY
● Psoriasis is a complex immune-mediated disorder that presents as inflammatory plaques in the

skin (picture 1A-B). Dysregulation or alteration of components of the innate and adaptive
immune systems, keratinocyte function, and vascular structure contribute to the manifestations
of this disease. (See 'Overview' above.)
● Plasmacytoid and myeloid dendritic cells are key contributors to development of inflammation in
psoriasis. IFN-alpha produced by plasmacytoid dendritic cells stimulates the activation of
myeloid dendritic cells, which contribute to the adaptive immune response through the
activation of T cells. (See 'The innate immune response' above.)
● IL-23 and IL-12 produced by activated myeloid dendritic cells promote the development of Th17
and Th1 cells, respectively. Th17 cells play a major role in the pathogenesis of psoriasis. (See
'The adaptive immune response' above.)
● Keratinocytes may contribute to the initiation of psoriasis via the production of antimicrobial
peptides. Epidermal hyperplasia is driven by cytokines that stimulate keratinocyte activation and
proliferation. (See 'Keratinocytes' above.)
● Knowledge of the pathophysiology of psoriasis is evolving. Advances in the understanding of

the mechanisms of disease will likely contribute to the development of new therapeutic agents
and improved patient outcomes. (See 'Introduction' above and "Treatment of psoriasis in
adults".)
1205
GRAPHICS
Plaque psoriasis
psoriasis.
1206
Inverse psoriasis
A well-defined, erythematous plaque in the inframammary area.
Wilkins.
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Nail psoriasis
Author: April W Armstrong, MD, MPH
INTRODUCTION
Psoriasis is a common, chronic, inflammatory disease that has skin, nail, and systemic manifestations. Nail
psoriasis results from psoriatic involvement of the nail bed or nail matrix.
Patients with nail psoriasis can develop a wide variety of nail changes, such as pitting, onycholysis,
subungual hyperkeratosis, and nail discoloration (picture 1A-E). Patients may find the appearance of psoriatic
nails psychologically distressing, and extensive cases may confer significant morbidity and functional
impairments. Therefore, managing nail psoriasis is an integral part of psoriasis therapy.
The clinical manifestations, diagnosis, and management of nail psoriasis will be reviewed here. The diagnosis
and treatment of other manifestations of psoriasis are reviewed separately. (See "Psoriasis: Epidemiology,
clinical manifestations, and diagnosis" and "Treatment of psoriasis in adults".)
EPIDEMIOLOGY
Nail psoriasis occurs in both adults and children [1,2]. The prevalence of nail psoriasis among patients with
psoriasis is estimated to be 10 to 55 percent [3]. In most patients, nail involvement follows or is concurrent
with the onset of cutaneous psoriasis [4]. Occasionally, nail psoriasis is the sole manifestation of psoriasis at
the time of clinical presentation [5].
Nail psoriasis is also strongly associated with psoriatic arthritis. It has been estimated that 80 to 90 percent
of patients with psoriatic arthritis develop nail involvement [6,7]. This finding may be related to the proximity
of the nail to the distal interphalangeal (DIP) joint, a site of predilection of psoriatic arthritis (picture 2A). The
enthesis of extensor tendon crossing the DIP joint is linked to the nail root and nail matrix [8]. (See "Clinical
manifestations and diagnosis of psoriatic arthritis".)
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Some studies suggest that psoriatic arthritis is more tightly associated with psoriatic nail involvement than
cutaneous psoriasis alone [6]. However, not all studies have corroborated this finding [9-12].
PATHOGENESIS
Nail psoriasis results from psoriatic inflammation involving the nail matrix or nail bed. The nail matrix is
responsible for the formation of the nail plate and is located primarily beneath the proximal nail fold, with the
distal one-third visible as the lunula (picture 3 and figure 1). The proximal nail matrix forms the superficial
portion of the nail plate. More distal portions of the nail matrix (intermediate and ventral portions) form the
deeper portion of the nail plate (figure 2).
The nail bed lies directly beneath the nail plate and extends from the distal end of the lunula to the
hyponychium (picture 3 and figure 1). The nail bed contributes epithelial cells to the ventral portion of the nail
plate and plays an important role in the adherence of the nail plate to the nail bed [13]. Nail anatomy and
physiology is discussed in greater detail separately. (See "Overview of nail disorders", section on 'Anatomy
and physiology of the nail unit'.)
The site of psoriasis in the nail apparatus leads to specific effects on nail formation and determines the
clinical manifestations. Clinical manifestations related to nail matrix involvement include [13]:
● Pitting: Proximal matrix involvement resulting in clusters of parakeratotic cells in the nail plate.
Sloughing of the parakeratotic cells leads to nail plate depressions.
● Leukonychia: Intermediate and ventral nail matrix involvement.
● Red spots in lunula: Intermediate and ventral nail matrix involvement.
● Nail plate crumbling: Severe involvement of the entire nail matrix.
Clinical manifestations related to nail bed involvement include [13]:
● Oil drop discoloration: Nail bed involvement located entirely within the nail bed.
● Onycholysis: Nail bed involvement near the hyponychium.
● Subungual (nail bed) hyperkeratosis: Nail bed involvement resulting in accumulation of cells under the
nail plate.
● Splinter hemorrhages: Nail bed involvement resulting in capillary rupture in the dermis beneath the nail
plate.
Genetic contributions to the development of nail psoriasis are not well understood. The HLA-Cw6 allele is
strongly associated with cutaneous psoriasis [14]. However, psoriatic nail disease may align closer to
dysregulation in innate immunity. Therefore, psoriatic nail disease may have a different contribution from
innate immunity and adaptive immunity compared with skin-limited disease [15,16].
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Patients with nail psoriasis may present with involvement of a single nail, multiple nails, both fingernails and
toenails, fingernails only, or toenails only [17]. More than one manifestation of nail psoriasis may be present in
a single nail or in different nails in an individual patient. The physical changes in nail psoriasis are reviewed
below:
● Pitting (picture 1A): Punctate depressions in the nail plate
● Leukonychia (picture 4): White discoloration in the nail plate
● Red spots in lunula: Pink to red punctate areas within the lunula
● Nail plate crumbling (picture 1B): Fragility and disintegration of the nail plate
● Oil drop discoloration (picture 1E): Irregular areas of yellow or pink discoloration, also known as "salmon
patches"
● Onycholysis (picture 1C): Distal separation of the nail plate from the nail bed
● Subungual hyperkeratosis (picture 1D): Gray-white accumulation of keratinous material overlying the nail
bed
● Splinter hemorrhages (picture 1C): Linear areas of hemorrhage visible through the nail plate
Other manifestations include onychorrhexis (longitudinal ridges and distal splitting of the nail plate) and Beau
lines (transverse grooves) [13]. Patients with nail psoriasis may experience associated pain, psychological
distress, and functional impairments resulting in interference with activities of daily living [17].
HISTOPATHOLOGY
Classic histologic features of nail psoriasis overlap with those of cutaneous psoriasis and include [18]:
● Mild to moderate hyperkeratosis

● Foci of parakeratosis
● Spongiosis
● Psoriasiform epidermal hyperplasia (evident in transverse sections)
● Neutrophilic inflammation
● Dilated, tortuous, inflamed capillaries in the papillary dermis
In addition, there may be a loss of granular layer in the hyponychium and hypergranulosis in the nail matrix
and nail bed [18].
DIAGNOSIS
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The diagnosis of nail psoriasis is usually established by review of the patient history and performance of a
physical examination. Testing for fungal infection is often necessary to rule out onychomycosis as an
alternative cause of nail dystrophy. A biopsy of the nail unit is not necessary in most cases.
Patient history — Because most patients with nail psoriasis have concomitant cutaneous psoriasis or
psoriatic arthritis, the patient history should include assessment for a personal history of these disorders or
signs or symptoms of these disorders. A strong family history of psoriasis may also raise suspicion for nail
psoriasis in the occasional patient who presents without other manifestations of psoriasis. (See "Psoriasis:
Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Clinical
manifestations and diagnosis of psoriatic arthritis", section on 'Major clinical features'.)
Physical examination — A full skin examination should be performed, including examination of the nails,
scalp, and anogenital skin, to assess for nail changes and cutaneous psoriasis. Nail findings that warrant
strong consideration of a diagnosis of nail psoriasis include nail pitting, distal onycholysis, oil drop
discoloration of the nail plate, and subungual hyperkeratosis. Performance of a nail examination is reviewed
in detail separately. (See "Overview of nail disorders", section on 'Nail evaluation'.)
Nail psoriasis is a common finding in patients with psoriatic arthritis and an evaluation for signs of psoriatic
arthritis is prudent [5]. Swelling or tenderness of the joints (particularly the DIP joints of the hands or feet) or
dactylitis (diffuse swelling of an entire digit) may indicate associated arthritis (picture 2A-B). (See "Clinical
manifestations and diagnosis of psoriatic arthritis", section on 'Joint manifestations'.)
Evaluation for fungal infection — Clinical features of nail psoriasis overlap with onychomycosis, and in some
cases it can be difficult to distinguish between these disorders clinically. In addition, nails affected by nail
psoriasis may be predisposed to secondary fungal infection. A nail plate clipping for periodic acid-Schiff
(PAS) staining, potassium hydroxide (KOH) preparation, or fungal culture is usually performed to assess the
possibility of primary or secondary onychomycosis. (See "Onychomycosis: Epidemiology, clinical features,
and diagnosis", section on 'Diagnosis'.)
Biopsy — In contrast to the evaluation for fungal infection, nail bed and nail matrix biopsies to detect
histologic changes consistent with psoriasis are usually not performed because the diagnosis of nail
psoriasis usually can be made with relative certainty based upon the patient history and clinical examination.
Nail bed and nail matrix biopsies are performed in very select circumstances where the diagnosis is
uncertain. (See "Nail biopsy: Indications and techniques".)
Other diseases may present with nail changes that resemble nail psoriasis. Onychomycosis is the most
common disorder in the differential diagnosis because of shared clinical features with nail psoriasis and the
high frequency of this condition. Examples of disorders in the differential diagnosis include:
● Onychomycosis – Nail psoriasis can be difficult to distinguish from onychomycosis, particularly when
subungual hyperkeratosis or nail crumbling is present (picture 5A-B). Other manifestations, such as nail
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pitting, oil drop discoloration, and onycholysis, are more common in nail psoriasis than in
onychomycosis. A periodic acid-Schiff (PAS) stain on a nail clipping, fungal culture, or potassium
hydroxide (KOH) preparation can identify onychomycosis. Of note, secondary fungal infection can occur
in a psoriatic nail. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis".)
● Lichen planus – Nail involvement in lichen planus usually manifests as thin, grooved, or ridged nail plates
(picture 6). In some instances, scarring of the cuticle can result in formation of pterygium (picture 7).
Lichen planus may also involve the skin or mucosa. The classic cutaneous manifestations of lichen
planus are pruritic, violaceous, polygonal papules or plaques. Mucosal lichen planus may present as
painful erosions, reticular white plaques, or hyperkeratotic plaques. (See "Lichen planus", section on
'Clinical features' and "Vulvar lichen planus" and "Oral lichen planus: Pathogenesis, clinical features, and
diagnosis", section on 'Clinical manifestations'.)
● Alopecia areata – Nail pitting, trachyonychia (linear ridging), onychorrhexis (longitudinal fissuring), and
other nail abnormalities may occur in patients with alopecia areata, a form of hair loss characterized by
nonscarring patchy hair loss on the scalp or other areas of the body (picture 8A-B). Severe cases can
manifest as loss of all scalp hair (alopecia totalis) or body hair (alopecia universalis). (See "Alopecia
areata: Clinical manifestations and diagnosis", section on 'Clinical features'.)
● Pityriasis rubra pilaris – Pityriasis rubra pilaris (PRP) is an uncommon skin disorder that most commonly
presents with hyperkeratotic follicular papules, orange-red plaques, and palmoplantar hyperkeratosis.
The cutaneous plaques of PRP typically have fine overlying scale rather than the coarse scale
characteristically present in psoriasis. The nails in PRP can become thickened and the distal edges
sometimes display splinter hemorrhages (picture 9). (See "Pityriasis rubra pilaris".)
TREATMENT
The severity of nail involvement plays an important role in determining the approach to treatment (algorithm
1). In clinical practice, consideration of the number of nails involved, associated symptoms, and level of
functional impairment is often used to assess severity of disease. (See 'Mild nail psoriasis' below and
'Moderate to severe nail psoriasis' below.)
Although infrequently used in clinical practice, clinical studies evaluating nail psoriasis therapies often use a
version of the Nail Psoriasis Severity Index (NAPSI) to assess the severity of nail psoriasis and the response
to treatment [19]. To identify the NAPSI score, individual nails are divided into four quadrants and each
quadrant is assigned a score of 1 for the presence of signs of nail matrix psoriasis and a score of 1 for the
presence of signs of nail bed psoriasis. Therefore, the maximum total NAPSI score per nail is 8, and the
maximum total score for all nails is 160. Alternatively, each quadrant of a single target nail can be assessed.
A modified version of the NAPSI has also been validated and used for assessment of a single target nail. The
modified NAPSI assigns a severity score of 0 to 3 for each quadrant of the target nail [20].
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General measures — Patient education is an important part of therapy. The slow pace of nail growth leads to
prolonged treatment courses and a delay in achieving the desired effect. Also, treatment can be challenging
and improvement is often incomplete. Clear communication with the patient may foster realistic expectations
for treatment results and may promote adherence to therapy.
Gentle hand and foot care may help to minimize symptoms. Recommendations include [5]:
● Avoid trauma to the nails (eg, manicures, nail biting)

● Wear protective gloves during exposure to wet work or harsh chemicals
● Dry nails and periungual skin thoroughly after washing or bathing
● Apply emollients regularly
● Keep nails trimmed
In particular, in patients with onycholysis, trimming the nails reduces risk for additional traumatic separation
of the nail plate from the nail bed. Trimming nails also facilitates application of topical treatments to the
hyponychium [21].
Clinical photographs are useful for following the response to treatment. Photographs can be taken at baseline
and at follow-up visits.
Mild nail psoriasis — Topical therapy is the preferred initial mode of treatment for mild nail psoriasis (nail
psoriasis limited to one or two nails and without significant symptoms or functional impairment). Topical
treatment achieves a sufficient response for some patients and minimizes risk for serious treatment-related
side effects. Although topical therapy is widely used, studies on efficacy are limited.
Systemic therapy is typically reserved for patients with more extensive nail involvement and patients who fail
to respond to topical therapy. However, because many systemic treatments used for psoriasis and psoriatic
arthritis are also effective for nail psoriasis, patients with mild nail psoriasis who receive systemic treatment
for other manifestations may experience improvement in nail disease. (See 'Moderate to severe nail psoriasis'
below.)
First-line therapy — First-line therapies for mild nail psoriasis include monotherapy with a topical
corticosteroid, monotherapy with a topical vitamin D analog, and combination treatment with a topical
corticosteroid and topical vitamin D analog.
Topical corticosteroids and topical vitamin D analogs — High-potency topical corticosteroids, topical
vitamin D analogs such as calcipotriol (ie, calcipotriene), and combination treatment with a topical vitamin D
analog and a high-potency topical corticosteroid are common initial interventions for mild nail psoriasis [22].
Therapy with these agents takes advantage of the immunomodulatory and antiproliferative effects of vitamin
D and the antiinflammatory effects of corticosteroids [5].
When feasible, we prescribe combination therapy with a topical corticosteroid and topical vitamin D analog
(eg, calcipotriol) as the initial treatment. In our experience, this approach has seemed most likely to yield
some improvement.
1213
● Efficacy – Placebo-controlled randomized trials evaluating the efficacy of topical calcipotriol or topical
corticosteroid monotherapy and topical calcipotriol/topical corticosteroid combination therapy are
lacking. Examples of studies evaluating these medications include:
• In an investigator-blind trial, 40 adults with fingernail psoriasis were randomly assigned to treatment
with calcipotriol 0.005%/betamethasone dipropionate 0.05% ointment once daily or calcipotriol
0.005% ointment twice daily for 12 weeks [23]. Eight patients left the study prior to completion for
reasons unrelated to treatment. At the end of the 12-week treatment period, the investigator's global
evaluation revealed at least moderate improvement in 8 of 15 patients (53 percent) treated with
calcipotriol/betamethasone dipropionate and 9 of 17 patients (53 percent) treated with calcipotriol
alone. NAPSI scores were similarly reduced in the two groups.
• A randomized, double-blind trial that compared the efficacy of twice-daily treatment with calcipotriol
ointment (50 mcg/g) to twice-daily combination treatment with betamethasone dipropionate and
salicylic acid ointment in 58 adults with psoriatic subungual hyperkeratosis (29 with fingernail
psoriasis and 44 with toenail psoriasis) found that both regimens reduced subungual hyperkeratosis
[24]. Mean reductions in fingernail subungual hyperkeratosis in the calcipotriol and the
betamethasone dipropionate/salicylic acid-treated patients were 26 percent and 30 percent,
respectively, after three months. Mean reductions in toenail subungual hyperkeratosis were 20 and
23 percent, respectively. The differences were not statistically significant.
In addition to these randomized trials, uncontrolled studies and case series report efficacy of treatment
with once-daily calcipotriol/betamethasone dipropionate ointment [25], weekday calcipotriol treatment
combined with weekend clobetasol therapy [26], and twice-daily topical calcipotriol monotherapy [27].
● Administration – Twice-daily application of topical calcipotriol 0.005% ointment or a high-potency (group

1) topical corticosteroid or, alternatively, once-daily application of a combination ointment containing
topical calcipotriol and a high-potency topical corticosteroid (eg, betamethasone dipropionate) are
appropriate regimens for nail psoriasis (table 1). An alternative to use of a combination product is once-
daily application of topical calcipotriol and a high-potency (group 1 or 2) topical corticosteroid
successively on the skin.
Patients should apply a thin layer of the product to the nail plate, hyponychium, and proximal and lateral
nail folds. For patients with fingernail psoriasis prescribed once-daily treatment, application before
bedtime will allow the medication to remain on the skin. The use of an occlusive dressing at night is
encouraged to aid in absorption of the medication.
Our initial course of treatment is typically three months followed by clinical assessment. If no signs of
response are evident after three to six months, we proceed with a trial of a second-line therapy. (See
'Second-line therapy' below.)
● Adverse effects – Topical calcipotriol and topical corticosteroid therapy are generally well tolerated.
Cutaneous atrophy is a well-known side effect of topical corticosteroids, particularly with occlusion.
1214
Systemic adverse effects are unlikely with the limited area of application in the treatment of nail
psoriasis. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Second-line therapy — Limited data suggest that topical tacrolimus and topical tazarotene, agents used for
the treatment of cutaneous psoriasis, can improve nail psoriasis. For both treatments, signs of improvement
are expected within the first three to six months of treatment. (See "Treatment of psoriasis in adults", section
on 'Calcineurin inhibitors' and "Treatment of psoriasis in adults", section on 'Tazarotene'.)
Topical tacrolimus — Tacrolimus is a nonsteroidal topical calcineurin inhibitor that exerts its action by
down-regulating antigen-specific T-cell activity and proinflammatory cytokine production. Support for the use
of topical tacrolimus is derived from a small open-label trial performed in 21 patients with fingernail psoriasis
in which one hand was randomly assigned to once-daily application of tacrolimus 0.1% ointment to the nail
folds of affected nails and the contralateral hand was given no treatment [28]. After 12 weeks, the reduction in
mean single-hand NAPSI scores compared with baseline was greater in the tacrolimus group (reduced from
23 to 10) than in the no-treatment group (reduced from 19 to 16).
Topical tacrolimus 0.1% ointment is applied once daily to the periungual skin (hyponychium, lateral nail folds,
and proximal nail folds) and is usually well tolerated. One patient in the open-label trial stopped therapy after
nine weeks due to the development of acute paronychia [28].
Topical tazarotene — Tazarotene is a third-generation topical retinoid that can improve nail psoriasis
[29-31]. A vehicle-controlled randomized trial that evaluated tazarotene therapy in 31 adults with fingernail
psoriasis found a modest but greater reduction in onycholysis, as compared with placebo, with use of
tazarotene 0.1% gel nightly for up to 24 weeks with or without occlusion [32]. Tazarotene also reduced nail
pitting when used under occlusion.
In addition, a trial that randomly assigned 46 patients to either treatment with tazarotene 0.1% cream applied
nightly under occlusion or treatment with clobetasol propionate 0.05% cream applied with the same regimen
for 12 weeks found that both treatments were associated with improved NAPSI scores for pitting,
onycholysis, hyperkeratosis, and salmon patches [31]. Of note, 14 patients dropped out of the study prior to
completion. An urgent need for systemic therapy prompted exiting of the study for 10 of these patients.
Tazarotene 0.1% gel or cream is usually applied once daily to the nail plate and periungual skin. An occlusive
dressing is often used. Treatment is generally well tolerated; however, prolonged use under occlusion may be
associated with skin redness and irritation. Periungual pyogenic granulomas may be a rare complication [33].
Refractory cases — Patients with mild nail involvement who fail to respond to topical therapy may benefit
from interventions used for patients with moderate to severe nail psoriasis. However, the risks and benefits of
more aggressive treatment must be considered carefully. (See 'Moderate to severe nail psoriasis' below.)
Moderate to severe nail psoriasis — Moderate to severe nail psoriasis is nail psoriasis associated with
marked nail dystrophy involving more than two nails or nail psoriasis associated with significant symptoms or
functional impairment.
1215
First-line therapy — Systemic therapy with a biologic agent is the preferred first-line treatment for
moderate to severe nail psoriasis. The highest-quality evidence on nail psoriasis treatment resides in trials
assessing biologic therapy.
Biologic TNF-alpha inhibitors — Tumor necrosis factor-alpha (TNF-alpha) inhibitors used for the
treatment of cutaneous psoriasis and psoriatic arthritis are also effective for nail disease. Adalimumab [34-
44], etanercept [39-42,44-46], infliximab [29,39-42,44,47-52], certolizumab pegol [53], and golimumab [54,55]
have all demonstrated moderate to high efficacy for psoriatic nail disease.
● Efficacy – Examples of randomized trials that have evaluated the efficacy of biologic TNF-alpha
inhibitors are reviewed below:
• Adalimumab – In a 16-week, randomized, placebo-controlled trial (n = 72) that evaluated the efficacy
of adalimumab (80 mg loading dose followed by 40 mg every other week during weeks 1 to 15) for
moderate to severe chronic plaque psoriasis on the hands or feet, effects on nail psoriasis were
evaluated as a secondary endpoint [35]. After 16 weeks, the mean percentage improvement in the
NAPSI score in target fingernails was significantly higher among patients treated with adalimumab
than among patients in the placebo group (50 versus 8 percent). In another phase 3 randomized trial,
217 patients with moderate to severe plaque psoriasis and moderate to severe fingernail psoriasis
were treated with adalimumab (80 mg loading dose followed by 40 mg every other week) or placebo
for 26 weeks [56]. The primary endpoint was an improvement of ≥75 percent in the modified NAPSI
score compared with baseline. After 26 weeks, more patients in the adalimumab group than those in
the placebo group achieved the primary endpoint (47 and 3 percent, respectively).
• Etanercept – A 24-week randomized, open-label, dose-comparison trial (n = 72) that compared the
efficacy of etanercept 50 mg twice weekly for 12 weeks, then once weekly for 12 weeks to the
efficacy of etanercept 50 mg once weekly for 24 weeks in adults with moderate to severe plaque
psoriasis found that both regimens were effective for nail psoriasis that had failed to respond to at
least one form of systemic therapy [45]. The mean target nail NAPSI score decreased similarly in the
biweekly/once-weekly group and the once-weekly group (-4.3, 95% CI -4.9 to -3.7 and -4.4, 95% CI -5.0
to -3.7, respectively).
• Infliximab – The effect of infliximab therapy on nail psoriasis was evaluated in a 50-week
randomized, placebo-controlled, cross-over trial in which patients with moderate to severe plaque
psoriasis were randomly assigned to infliximab (5 mg/kg at weeks 0, 2, and 6 followed by every eight
weeks) or placebo until week 22, with a placebo crossover to infliximab at week 24. Analysis of the
305 patients with nail psoriasis revealed a 57 percent reduction in the mean NAPSI score at week 24
in the infliximab group versus a 4 percent increase in NAPSI score in the placebo group [51].
• Certolizumab pegol – Benefit of certolizumab pegol for nail psoriasis was demonstrated in a
placebo-controlled trial that evaluated the effect of certolizumab pegol on signs and symptoms in
patients with psoriatic arthritis [53]. Patients were randomly assigned to a 400 mg certolizumab
pegol loading dose given at weeks 0, 2, and 4 followed by 200 mg given every two weeks, the same
1216
loading dose followed by 400 mg given every four weeks, or placebo. The effect on nail psoriasis
was evaluated as a secondary endpoint. At week 24, the mean change in the target nail modified
NAPSI score was greater in the certolizumab pegol 200 mg and 400 mg groups than in the placebo
group (-1.6, -2.0, and -1.1 respectively).
• Golimumab – A trial in which patients with psoriatic arthritis were randomly assigned to every-four-
week injections of golimumab 100 mg, golimumab 50 mg, or placebo evaluated the effect on nail
psoriasis as a secondary endpoint [54]. At week 24, the median percent improvement in target nail
NAPSI score was 54 percent in the 100 mg group, 33 percent in the 50 mg group, and 0 percent in
the placebo group.
Studies comparing the efficacy of different TNF-alpha inhibitors for nail psoriasis have yielded mixed
results [39-42,44]. Additional study is necessary to confirm the relative efficacy of these therapies.
● Administration – Because the comparative efficacy of different TNF-alpha inhibitors is unclear, selection
of a specific TNF-alpha inhibitor is based upon factors such as treatment availability, treatment cost,
clinician familiarity with specific agents, patient preferences, and contraindications. The presence of
other manifestations of psoriasis also influences treatment selection. Adalimumab, etanercept, and
infliximab are indicated for the treatment of both cutaneous psoriasis and psoriatic arthritis, and
golimumab and certolizumab pegol are indicated for the treatment of psoriatic arthritis. (See "Treatment
of psoriasis in adults", section on 'Biologic agents' and "Treatment of psoriatic arthritis".)
The biologic TNF-alpha inhibitors can be given via subcutaneous injection, with the exception of
infliximab, which requires intravenous infusion. Pending additional data to determine optimal dosing for
nail psoriasis, the doses used are similar to those used for cutaneous psoriasis or psoriatic arthritis. (See
"Treatment of psoriasis in adults", section on 'Biologic agents' and "Treatment of psoriatic arthritis".)
An initial response to TNF-alpha inhibitor therapy is usually evident within the first few months of
treatment. Long-term therapy may be necessary to maintain remission of nail disease.
There are insufficient data to determine the best approach to patients who fail to improve. In the event of
treatment failure with a particular agent, treatment with an alternative TNF-alpha inhibitor or ustekinumab
may be attempted. (See 'Ustekinumab' below.)
● Adverse effects – There are multiple potential adverse effects of TNF-alpha inhibition, including injection
site reactions, infusion reactions, neutropenia, infections, demyelinating disease, heart failure, skin
disorders, malignancy, and autoimmune disorders. The adverse effects are reviewed in detail separately.
(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
Ustekinumab — Ustekinumab, an inhibitor of p40 subunit of IL-12/23, is effective for the treatment of
cutaneous psoriasis, psoriatic arthritis, and nail psoriasis [57-61]. (See "Treatment of psoriasis in adults",
section on 'Ustekinumab' and "Treatment of psoriatic arthritis", section on 'Ustekinumab'.)
1217
● Efficacy – In a randomized trial that compared the impact of ustekinumab 45 mg, ustekinumab 90 mg,
and placebo in 545 patients with nail psoriasis, NAPSI scores were significantly improved by 12 weeks
after the start of treatment [58]. The percentage in improvements in NAPSI scores were 26.7 percent
[95% CI 18.5-35.0] for ustekinumab 45 mg, 24.9 percent [95% CI 17.8-32.0] for ustekinumab 90 mg, and
11.8 percent [95% CI 4.2-19.3] for placebo. Improvement in nail psoriasis continued to progress among
patients who continued ustekinumab treatment beyond 12 weeks, approaching 50 percent reductions in
NAPSI by 24 weeks.
● Administration – Ustekinumab is self-administered as a subcutaneous injection. Clinical improvement is

usually evident within three months. Our suggested dosing for nail psoriasis in adults is similar to the
dosing used for the treatment of psoriasis. Patients weighing less than 100 kg are given 45 mg initially
and 4 weeks later, followed by 45 mg every 12 weeks. Patients weighing more than 100 kg are given 90
mg initially, 4 weeks later, and then every 12 weeks thereafter. As with TNF-alpha inhibitors, continued
treatment may be necessary to maintain remission of nail disease.
● Adverse effects – Increased risk for infection is a potential adverse effect of ustekinumab. Side effects of
ustekinumab are reviewed in detail separately. (See "Treatment of psoriasis in adults", section on
'Ustekinumab'.)
Secukinumab — Secukinumab is a monoclonal antibody that inhibits the IL-17A ligand. It is effective for
the treatment of psoriasis, psoriatic arthritis, and nail psoriasis [62-64]. (See "Treatment of psoriasis in adults",
section on 'Secukinumab'.)
● Efficacy – The TRANSFIGURE trial, in which 198 patients with moderate to severe plaque psoriasis and
moderate to severe nail psoriasis were randomly assigned to secukinumab 300 mg, secukinumab 150
mg, and placebo groups (each given once weekly at week 0, 1, 2, 3, and 4, and then every four weeks
thereafter), found both secukinumab dose regimens superior to placebo for improving nail psoriasis [64].
The mean percentage reductions in NAPSI at week 16 for secukinumab 300 mg, secukinumab 150 mg,
and placebo were 45, 38, and 11 percent, respectively. Moreover, nail improvement continued beyond 16
weeks when all patients received open-label secukinumab; at week 32, the mean reduction in NAPSI for
patients receiving secukinumab 300 mg and secukinumab 150 mg were 63 and 53 percent, respectively.
● Administration – Secukinumab is self-administered as a subcutaneous injection. The suggested dosing

for nail psoriasis is the same as that for plaque psoriasis: 300 mg at weeks 0, 1, 2, 3, and 4, and then
every four weeks thereafter.
● Adverse effects – Secukinumab may increase risk for superficial fungal infections. A possible
association between secukinumab and increased risk for development of inflammatory bowel disease
(IBD) has been reported [65]; however, a pooled safety analysis of over 7000 patients treated for
psoriasis, psoriatic arthritis, or ankylosing spondylitis in 21 clinical trials found the occurrence of IBD
uncommon and did not detect increases in exposure-adjusted incidence rates over time [64]. Additional
study is necessary to confirm whether secukinumab increases risk for IBD.
1218
Ixekizumab — Ixekizumab is a monoclonal antibody that targets the IL-17A ligand. In addition to nail
psoriasis, ixekizumab has demonstrated efficacy for psoriasis and psoriatic arthritis. (See "Treatment of
psoriasis in adults", section on 'Ixekizumab'.)
● Efficacy – Efficacy of ixekizumab for nail psoriasis was evaluated in a subgroup analysis in UNCOVER-3,
a trial in which patients with moderate to severe psoriasis were randomly assigned to ixekizumab (80 mg
every four weeks after an initial 160 mg dose), ixekizumab (80 mg every two weeks after an initial 160 mg
dose), etanercept (50 mg twice weekly), or placebo [66]. At the end of the 12-week randomized phase,
greater improvement in the mean percent NAPSI occurred in patients with nail psoriasis in the
ixekizumab every four weeks and ixekizumab every two weeks groups (37 and 35 percent improvement,
respectively) compared with patients with nail psoriasis in the etanercept and placebo groups (20 percent
improvement and 34 percent worsening, respectively). After week 12, patients were continued on or
transitioned to open-label ixekizumab given every four weeks. By week 60, the mean percent
improvement in NAPSI was greater than 80 percent, and more than 50 percent of patients had complete
resolution of nail psoriasis.
● Administration – Ixekizumab is given through subcutaneous injection. The initial dose is 160 mg,
followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12. Subsequently, ixekizumab is given every four weeks.
● Adverse effects – Ixekizumab may increase risk for superficial fungal infections. A small number of
patients on ixekizumab experienced exacerbation of IBD, although this appears to be uncommon [65,67].
Additional study is necessary to determine whether ixekizumab therapy promotes IBD.
Second-line therapy — Biologic therapy is considered the most effective therapy for moderate to severe
nail psoriasis. However, various factors (eg, cost, patient preference, contraindications) may contribute to the
need to use alternative therapies. Alternative therapies for patients who will not receive biologic agents
include methotrexate, apremilast, and local interventions such as topical medications, intralesional
corticosteroids, and pulsed dye laser therapy. However, our experience suggests that local interventions may
be most useful as adjuncts to systemic biologic therapy. (See 'First-line therapy' above.)
Methotrexate — Methotrexate is one of the oral treatment options for patients who are unable to receive
biologic therapy due to cost, lack of availability, or other factors. Moderate improvement in nail psoriasis after
methotrexate therapy has been demonstrated in randomized trials [68,69].
Methotrexate is usually administered as an oral or intramuscular injection. Typical doses for adults range
from 7.5 mg to 25 mg given once weekly.
Potential side effects of methotrexate include gastrointestinal distress, hepatotoxicity, hematologic toxicity,
and pulmonary toxicity. Monitoring for hematologic and liver abnormalities is necessary during treatment.
Methotrexate is teratogenic and should not be taken during pregnancy. (See "Major side effects of low-dose
methotrexate" and "Treatment of psoriasis in adults", section on 'Hepatotoxicity and liver biopsy' and
"Treatment of psoriasis in adults".)
1219
Apremilast — Apremilast is an oral phosphodiesterase 4 inhibitor used in the treatment of plaque
psoriasis. Data from two similar phase III, randomized, placebo-controlled studies evaluating the efficacy of
apremilast for moderate to severe plaque psoriasis (ESTEEM 1 and ESTEEM 2) indicate that apremilast also
improves nail psoriasis [70]. In the trials, a total of 1255 patients with moderate to severe plaque psoriasis
were randomly assigned to either apremilast (30 mg twice daily) or placebo in a 2:1 ratio. Approximately two-
thirds of the trial patients had associated nail psoriasis. At week 16, a 23 percent reduction in the mean target
nail NAPSI score was detected in the apremilast group in ESTEEM 1 compared with a 7 percent increase in
the placebo group. In ESTEEM 2, there were 29 and 7 percent mean reductions in target nail NAPSI scores in
the apremilast and placebo groups at 16 weeks, respectively. A limitation of the trials is that baseline
randomization was not stratified for nail psoriasis. (See "Treatment of psoriasis in adults", section on
'Apremilast'.)
Apremilast is administered in a dose titration schedule to minimize risk for drug-induced diarrhea. Examples
of other side effects include nausea, upper respiratory infection, headache, and weight loss. There is a
possible slight increase in risk for depression. (See "Treatment of psoriasis in adults", section on 'Apremilast'.)
Topical therapy — Topical therapies used for mild nail disease, such as topical tazarotene, topical
calcipotriol, high-potency topical corticosteroids, and topical tacrolimus have limited efficacy for moderate to
severe nail disease. Clinical experience suggests that these agents may be most helpful as adjuncts to
systemic therapy. Treatment regimens are similar to the regimens used for mild nail disease. (See 'Mild nail
psoriasis' above.)
Intralesional corticosteroids — Open-label studies suggest that intralesional corticosteroid therapy is

moderately effective in treating specific psoriatic nail dystrophies, particularly abnormalities of the nail matrix
[29]. Although there is a long history of use of intralesional corticosteroids for this indication, efficacy data are
limited. No randomized trials have been performed.
The efficacy of intralesional corticosteroid injections can vary depending on dosing amount and frequency
[29]. Typically, 0.05 to 0.3 mL of triamcinolone acetonide (2.5 to 10 mg/mL) is injected with a 30-gauge needle
at multiple sites in the proximal nail fold at monthly intervals for up to five months [29]. Initial signs of
improvement are usually evident within the first three months. (See "Intralesional corticosteroid injection".)
The main drawback of intralesional corticosteroid injection is that it can be very painful, and the procedure is
generally not very well tolerated. Use of a needleless injector may reduce the pain associated with
intralesional injection. Improvement in nail psoriasis has been reported in open studies evaluating
corticosteroid delivery with needleless injectors [29,71].
Pulsed dye laser — The 595 nm pulsed dye laser is occasionally used to treat psoriatic nails [72,73]. A
randomized left-right trial that compared the efficacy of two different pulsed dye laser settings (6 versus 0.45
ms pulse duration) in 20 patients with bilateral fingernail psoriasis found similar and statistically significant
reductions in NAPSI scores with both regimens [73]. Patients were given six treatments at one-month
intervals.
1220
Pulsed dye laser treatments are typically given once monthly for six months. Signs of improvement are
expected within the first few treatments [73].
Side effects of pulsed dye laser therapy include petechiae, transient hyperpigmentation, moderate to severe
pain and burning sensations. Longer pulse durations do not appear to result in greater efficacy and may
cause greater side effects [72,73]. Patients may relapse or experience remissions of 15 months or longer after
the completion of treatment [73].
Additional therapies — A variety of other interventions may improve nail psoriasis. However, additional data
are necessary prior to a recommendation for the use of these agents as first- or second-line therapies.
● Oral tofacitinib – Tofacitinib, an oral Janus kinase inhibitor, appears effective for nail psoriasis. In two
identical phase 3 trials, patients with moderate to severe plaque psoriasis were randomly assigned in a
2:2:1 ratio to tofacitinib 5 mg, tofacitinib 10 mg, or placebo given twice daily [74]. In a post-hoc analysis of
the 1196 patients with nail involvement, more patients in the tofacitinib 5 mg and 10 mg groups achieved
at least a 50 percent improvement in NAPSI score than patients in the placebo group (34, 44, and 12
percent, respectively). Complete clearance (100 percent improvement in NAPSI score) occurred in 10, 18,
and 5 percent of patients, respectively.
● Topical cyclosporine – Topical cyclosporine may be effective. A trial in which 16 adults were randomly
assigned to treatment with cyclosporine in 70% maize oil solution or maize oil alone found a higher rate
of improvement in patients given topical cyclosporine [75].
● Topical indigo naturalis – Indigo naturalis, a Chinese herb, may be a promising treatment for nail
psoriasis [76,77]. A 24-week, split-body randomized trial that compared twice-daily application of indigo
naturalis extract in oil to twice-daily topical calcipotriol solution (50 mcg/mL) in 33 patients with bilateral
fingernail psoriasis found greater improvement in disease severity scores on nails treated with indigo
naturalis than in nails treated with calcipotriol [77]. The greatest improvement occurred in onycholysis
and subungual hyperkeratosis.
● Oral acitretin and cyclosporine – Limited data suggest that acitretin and cyclosporine, therapies with a
long history of use in the treatment of psoriasis, have some efficacy for nail disease [68,78]. However,
efficacy of acitretin in nail psoriasis is modest, at best. Cyclosporine is not appropriate for long-term use
in nail psoriasis due to its associated nephrotoxicity. (See "Treatment of psoriasis in adults", section on
'Retinoids' and "Treatment of psoriasis in adults", section on 'Systemic calcineurin inhibitors'.)
● Phototherapy – Phototherapy is typically not recommended as first- or second-line treatment due to

limited evidence for its efficacy in nail psoriasis [79,80].
Treatment of children — Nail disease can occur in both children and adults. In children, the treatment of nail
disease is typically limited to topical treatment options, such as topical corticosteroids, vitamin D analogs,
calcineurin inhibitors, and tazarotene because of safety concerns. Oral medications are typically not
recommended to treat nail psoriasis in children. For severe nail disease, etanercept may be used in the
pediatric population.
1221
Links to society and government-sponsored guidelines from selected countries and regions around the world
are provided separately. (See "Society guideline links: Psoriasis".)
● Nail psoriasis is characterized by nail deformities that result from psoriatic involvement of the nail matrix
or the nail bed. Nail psoriasis is common in patients with psoriatic arthritis or cutaneous psoriasis.
Proximity to the distal interphalangeal joint may contribute to the relationship between nail psoriasis and
psoriatic arthritis. (See 'Epidemiology' above and 'Pathogenesis' above.)
● The location of psoriasis in the nail apparatus influences the clinical presentation. Psoriasis involving the
nail matrix results in pitting, leukonychia, red spots in the lunula, or nail plate crumbling. Nail bed
involvement results in oil drop discoloration, onycholysis, subungual hyperkeratosis, or splinter
hemorrhages (picture 1A-E). (See 'Clinical manifestations' above.)
● The diagnosis of nail psoriasis can usually be made based upon recognition of the characteristic clinical
features, particularly if concomitant psoriasis or psoriatic arthritis is present. Onychomycosis can closely
resemble nail psoriasis and an evaluation for fungal infection is often necessary. Of note, psoriatic nails
may develop concomitant fungal infection. (See 'Differential diagnosis' above.)
● The severity of nail psoriasis influences the approach to treatment (algorithm 1). For patients with mild
nail psoriasis (psoriasis limited to two or fewer nails without significant symptoms or functional
impairment) we recommend topical therapy, rather than systemic therapy, as initial treatment (Grade 1B).
We typically prescribe combination therapy with a high-potency topical corticosteroid and topical vitamin
D analog (eg, calcipotriol). Monotherapy with a high-potency topical corticosteroid and monotherapy with
a topical vitamin D analog are alternative first-line treatments. (See 'Mild nail psoriasis' above.)
● Patients with moderate to severe psoriasis (nail psoriasis associated with marked nail dystrophy
involving more than two nails, significant symptoms, or functional impairment) often require systemic
therapy to achieve satisfactory improvement. For these patients, we suggest treatment with a biologic
TNF-alpha inhibitor, ustekinumab, secukinumab, or ixekizumab (Grade 2A). (See 'Moderate to severe nail
psoriasis' above.)
1222
GRAPHICS
1223
Nail psoriasis
Crumbling of the nail plate resulting in loss of part of the dystrophic nail in a patient with nail psoriasis.
1224
Nail psoriasis
Onycholysis with erythema of the nail bed and splinter hemorrhages in a patient with nail psoriasis.
1225
Nail psoriasis with subungual hyperkeratosis
Marked subungual hyperkeratosis is present on several nails of this patient with psoriasis.
1226
1227
Psoriatic arthritis
This photograph of the hand of a patient with psoriatic arthritis shows characteristic early nail
separation (onycholysis), swelling, and erythema of the index and little finger distal
interphalangeal joints.
Reproduced with permission from Daniel Z Sands, MD, MPH.
1228
Nail anatomy
1229
Anatomy of the nail apparatus
1230
Nail growth: Direction of matrix cell differentiation and movement
1231
Leukonychia (white patches or striae of the nail plate)
1232
Psoriatic arthritis
This photograph of the foot of a patient with psoriatic arthritis shows the early separation of
the nails (onycholysis), swelling of the entire second toe (dactylitis), and some psoriatic skin
lesions.
Reproduced with permission from Daniel Z Sands, MD, MPH.
1233
Distal subungual onychomycosis
1234
Totally dystrophic onychomycosis
Total destruction of the nail with a ridged, hyperkeratotic nail bed is present in this patient with
totally dystrophic onychomycosis.
1235
Trachyonychia induced by lichen planus
Nail plate roughness, longitudinal ridging, and pitting.
1236
Lichen planus of the nails, permanent nail dystrophy leading to pterygium and
anonychia
Permanent nail dystrophy resulting in anonychia and pterygium (extension and adherence of the proximal
nail fold to the nail bed secondary to scarring of the nail matrix).
1237
Nail pitting
Numerous pits are present in this nail from a patient with alopecia areata.
1238
Trachyonychia
Rough surfaces of nail plates with longitudinal ridging are present in this patient with
trachyonychia secondary to alopecia areata.
1239
Nail abnormalities in pityriasis rubra pilaris
Nail thickening and subungual hyperkeratosis in patient with pityriasis rubra pilaris.
1240
Treatment algorithm for nail psoriasis
TNF: tumor necrosis factor.

* Nail psoriasis limited to 1 or 2 nails and without significant symptoms or functional impairment.
¶ Nail psoriasis associated with marked nail dystrophy involving more than 2 nails or nail psoriasis associated with significant symptoms or functional
impairment.
1241
Comparison of representative topical corticosteroid preparations (classified according to the US system)
Available strength(s),
Brand names
Potency group* Corticosteroid Vehicle type/form percent
(United States)
(except as noted)
Super-high potency Betamethasone Gel, lotion, ointment Diprolene 0.05

(group 1) dipropionate, augmented (optimized)
Clobetasol propionate Cream, gel, ointment, Temovate 0.05

solution (scalp)
Cream, emollient base Temovate E 0.05
Lotion, shampoo, spray Clobex 0.05

aerosol
Solution (scalp) Cormax 0.05
Diflucortolone valerate (not Ointment, oily cream Nerisone Forte (United 0.3
available in United States) Kingdom, others)
Flurandrenolide Tape (roll) Cordran 4 mcg/cm 2
Halobetasol propionate Cream, lotion, ointment Ultravate 0.05
High potency Amcinonide Ointment Cyclocort ¶, Amcort ¶ 0.1

(group 2)
Betamethasone Ointment Diprosone ¶ 0.05
dipropionate
Cream, augmented Diprolene AF 0.05
formulation (AF)
Desoximetasone Cream, ointment, spray Topicort 0.25
Gel Topicort 0.05
Diflorasone diacetate Ointment ApexiCon ¶, Florone ¶ 0.05
Cream, emollient ApexiCon E 0.05
Fluocinonide Cream, gel, ointment, Lidex ¶ 0.05

solution
Halcinonide Cream, ointment Halog 0.1
Halobetasol propionate Lotion Bryhali 0.01
High potency Amcinonide Cream Cyclocort ¶, Amcort ¶ 0.1

(group 3)
Lotion Amcort ¶ 0.1
Betamethasone Cream, hydrophilic Diprosone ¶ 0.05

dipropionate emollient
Betamethasone valerate Ointment Valisone ¶ 0.1
Foam Luxiq 0.12
Desoximetasone Cream Topicort LP ¶ 0.05
Diflorasone diacetate Cream Florone ¶ 0.05
Diflucortolone valerate (not Cream, oily cream, Nerisone (Canada, United 0.1
available in United States) ointment Kingdom, others)
Fluocinonide Cream aqueous emollient Lidex-E ¶ 0.05
Fluticasone propionate Ointment Cutivate 0.005
Triamcinolone acetonide Cream, ointment Aristocort HP ¶, Kenalog ¶, 0.5

Triderm
Medium potency Betamethasone Spray Sernivo 0.05

(group 4) dipropionate
1242
Clocortolone pivalate Cream Cloderm 0.1
Fluocinolone acetonide Ointment Synalar ¶ 0.025
Hydrocortisone valerate Ointment Westcort 0.2
Mometasone furoate Cream, lotion, ointment, Elocon ¶ 0.1

solution
Triamcinolone acetonide Cream Kenalog ¶, Triderm 0.1
Ointment Kenalog ¶ 0.1
Aerosol spray Kenalog 0.2 mg per 2 second spray
Lower-mid potency Betamethasone Lotion Diprosone ¶ 0.05

Betamethasone valerate Cream Beta-Val, Valisone ¶ 0.1
Desonide Ointment DesOwen, Tridesilon ¶ 0.05
Gel Desonate 0.05
Fluocinolone acetonide Cream Synalar ¶ 0.025
Fluticasone propionate Cream, lotion Cutivate 0.05
Hydrocortisone butyrate Cream, lotion, ointment, Locoid, Locoid Lipocream 0.1

solution
Hydrocortisone probutate Cream Pandel 0.1
Hydrocortisone valerate Cream Westcort ¶ 0.2
Prednicarbate Cream (emollient), Dermatop 0.1

ointment
Triamcinolone acetonide Lotion Kenalog ¶ 0.1
Low potency Alclometasone Cream, ointment Aclovate 0.05

Betamethasone valerate Lotion Beta-Val ¶, Valisone ¶ 0.1
Desonide Cream DesOwen, Tridesilon ¶ 0.05
Foam Verdeso 0.05
Fluocinolone acetonide Cream, solution Synalar ¶ 0.01
Shampoo Capex 0.01
Oil Δ Derma-Smoothe/FS Body, 0.01

Derma-Smoothe/FS Scalp
Triamcinolone acetonide Cream, lotion Kenalog ¶, Aristocort ¶ 0.025
Least potent Hydrocortisone (base, ≥2%) Cream, ointment Hytone, Nutracort ¶ 2.5
(group 7)
Lotion Hytone, Ala Scalp, 2
Scalacort
Hydrocortisone (base, <2%) Ointment Cortaid, Cortizone 10, 1

Hytone, Nutracort
Cream Cortaid ¶, Cortizone 10, 1

Hytone, Synacort
Gel Cortizone 10 1
Lotion Aquanil HC, Sarnol-HC, 1

Cortizone 10
1243
Spray Cortaid 1
Solution Cortaid, Noble, Scalp Relief 1
Cream, ointment Cortaid 0.5
Hydrocortisone acetate Cream MiCort-HC 2.5
Lotion Nucort 2
US: United States.

* Listed by potency according to the US classification system: group 1 is the most potent, group 7 is the least potent. Other countries use a different
classification system with only four or five groups.
¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available generically in the
United States.
Δ 48% refined peanut oil.
Data from:
2. Tadicherla S, Ross K, Shenefelt D. Topical corticosteroids in dermatology. Journal of Drugs in Dermatology 2009; 12:1093.
3. U.S. Food & Drug Administration Approved Drug Products with Therapeutic Equivalence (Orange Book). Available at:
https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm (Accessed on June 18, 2017).
1244
Guttate psoriasis
Author: Stephanie Mehlis, MD
INTRODUCTION
Psoriasis is a common skin disorder characterized by the development of inflammatory plaques on

the skin. The spectrum of clinical manifestations of psoriasis is wide and includes chronic plaque,
guttate, inverse, erythrodermic, pustular, and nail variants of the disease. (See "Psoriasis:
Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
Patients with guttate psoriasis typically present with the acute onset of numerous small,
inflammatory, scaly plaques on the trunk and extremities (picture 1A-B). Guttate psoriasis is most
common among children and young adults, and a preceding history of streptococcal infection is
often present.
The epidemiology, clinical manifestations, and treatment of guttate psoriasis will be reviewed here.
Other manifestations of psoriasis are discussed separately. (See "Psoriasis: Epidemiology, clinical
manifestations, and diagnosis" and "Treatment of psoriasis in adults".)
EPIDEMIOLOGY
Psoriasis occurs in 0.6 to 4.8 percent of the general population [1], with chronic plaque psoriasis as
the most common clinical presentation. Estimates of the proportion of patients with psoriasis who
develop guttate disease vary widely; many studies cite a prevalence of less than 30 percent among
patients with psoriasis [2-6].
Guttate psoriasis is most frequently diagnosed in children and young adults under the age of 30;
however, older individuals may also be affected [7-9]. As an example, in a Spanish study that
1245
compared 1092 patients in whom psoriasis began between the ages of 0 and 30 years with 662
patients with disease onset later in life, patients in the younger-onset group were significantly more
likely to have the guttate variant (15 versus 7 percent) [8].
A sex predilection for guttate psoriasis has not been established. Both males and females may
develop this disease.
RISK FACTORS
Genetic and environmental factors likely contribute to the development of guttate psoriasis. The class
I human leukocyte antigen HLA-Cw6 (in particular, the HLA Cw*0602 allele) and beta-hemolytic
streptococci are the primary factors linked to the development of this disease.
Genetics — The HLA-Cw*0602 allele is strongly associated with psoriasis [10]. In a meta-analysis of
18 studies with approximately 3400 patients with psoriasis and 3300 healthy controls, participants
who were positive for HLA-Cw*0602 were more than four times more likely to have psoriasis than
participants who were negative for the allele (odds ratio 4.55, 95% CI 3.65-5.67) [11].
The association between psoriasis and the HLA-Cw*0602 allele appears to be particularly strong
among patients with guttate psoriasis [5,12-16]. Examples of studies in support of an association
include:
● In an Icelandic study that evaluated the correlation between HLA-Cw6 status and disease
characteristics in patients with familial psoriasis, 31 of 33 patients (94 percent) whose
symptoms began as an acute guttate eruption demonstrated HLA-Cw6 positivity [16]. An
extension of this study that included patients without a family history of psoriasis (n = 1019)
found the prevalence of guttate disease was significantly greater among HLA-Cw*0602 positive
patients than among HLA-Cw*0602 negative patients (11 versus 3 percent) [14].
● In a Swedish case-control study, 56 of 77 patients with guttate psoriasis (73 percent) were
positive for the HLA-Cw*0602 allele compared with 39 or 371 controls (11 percent) [12].
● In a United Kingdom study of 29 patients with guttate psoriasis and 604 controls, the HLA-
Cw*0602 allele was detected in all patients with guttate psoriasis compared with only 20 percent
of controls [15].
● A Chinese study found that HLA-Cw*0602 was strongly associated with guttate psoriasis; the
guttate presentation accounted for 21 percent of psoriasis cases in HLA-Cw*0602 positive
patients with psoriasis and 9 percent of psoriasis cases in HLA-Cw*0602 negative patients with
psoriasis [5].
1246
Streptococcal infection — Streptococcal infection often precedes the onset of guttate psoriasis [7,17-
21]. A link between these entities is supported by studies that have documented a relationship
between new-onset guttate psoriasis and acute streptococcal pharyngitis in 56 to 97 percent of
patients [18]. In addition, perianal streptococcal infection has preceded guttate psoriasis in children
[22,23]. The cutaneous manifestations of guttate psoriasis typically develop two to three weeks after
an associated streptococcal infection [7].
New-onset guttate psoriasis may be more likely to be associated with streptococcal infections than
guttate psoriasis that develops in patients with preexisting chronic plaque psoriasis. In a prospective
study, 19 of 33 patients (58 percent) with acute guttate psoriasis versus 7 of 27 patients (26 percent)
with guttate exacerbations of chronic psoriasis had serologic evidence for recent streptococcal
infection [19].
Other infections — Case reports have documented the development of guttate psoriasis following
varicella [24,25] and Pityrosporum folliculitis [26,27]. A Koebner phenomenon, in which wound healing
triggers hyperproliferative changes in the skin, may be a factor in these cases. Guttate psoriasis has
also developed in the site of a tattoo, a finding consistent with the theory of Koebnerization [28].
Drugs — Guttate psoriasis has been reported after treatment with tumor necrosis factor (TNF)-alpha
inhibitors in case reports and case series [29-33]. The reason for this paradoxical observation is
unclear but may involve disruption of the cytokine milieu, leading to unopposed interferon production
[31].
PATHOGENESIS
The pathophysiology of guttate psoriasis is not well understood. Interplay between genetic and
environmental factors leading to an aberrant immune response in the skin may contribute to disease
development.
As noted above, strong associations between guttate psoriasis, streptococcal infection, and HLA-
Cw*0602 positivity have been detected in patients with guttate psoriasis (see 'Risk factors' above).
Examples of proposed mechanisms for the relationship between guttate psoriasis and streptococcal
infection include [34]:
● Cross-reactivity between streptococcal M-proteins (the major pathogenic antigens on beta-

hemolytic streptococci) presented to immune cells in the tonsils and structurally similar type I
keratins in the epidermis (K16 and K17) trigger a T cell-mediated autoimmune response.
● Streptococcal superantigens in the tonsils may augment the expression of the skin-homing
cutaneous lymphocyte antigen (CLA) on effector T cells, contributing to the migration of T cells
1247
into the skin; CD4+ cells migrate into the dermis, and CD8+ cells migrate into the epidermis. A
study that found identical T cell receptor gene rearrangement in tonsils and psoriatic skin in
patients with streptococcal-induced psoriasis supports direct migration of CLA+ cells in the
tonsils to the skin [35].
● An innate immune-mediated inflammatory response occurs as a consequence of the binding of

peptidoglycan or other streptococcal antigens to cell receptors.
The observed association between guttate psoriasis and HLA-Cw*0602 may be related to interactions
between streptococci and this molecule [12]. In an in vitro study, homologous peptides from K17 and
streptococcal M-protein that were predicted to bind to HLA-Cw6 were better able to stimulate
interferon (IFN)-gamma production in T cells (mostly CD8+ T cells that also demonstrated CLA) from
patients with psoriasis than T cells obtained from patients without psoriasis [36]. Moreover, the
greatest responses were detected in T cells derived from HLA-Cw*0602 positive patients with
psoriasis.
Another ex vivo study supports a role for interactions between streptococci and HLA-Cw*0602.
Coculture of CLA+ T cells and autologous epidermal cells from patients with guttate psoriasis in the
presence of Streptococcus pyogenes led to a higher Th17 response (higher production of interleukin
[IL]-17A and IL-17F than IFN-gamma) with cells from carriers of HLA-Cw*0602 who had psoriasis
flares associated with pharyngitis than with cells from HLA-Cw*0602 positive or negative patients
who did not have flares associated with pharyngitis [37]. Th17 cells play an important role in the
pathogenesis of psoriasis. (See "Pathophysiology of plaque psoriasis", section on 'T helper type 17
cells'.)
Clinical evidence of a relationship between HLA-Cw*0602 status, guttate psoriasis, and streptococcal
infection was detected in a study of 439 patients with plaque psoriasis, 143 patients with guttate
psoriasis, and 454 healthy controls. Patients with guttate psoriasis who were positive for HLA-
Cw*0602 were more likely to have a positive streptococcal throat swab than patients who were HLA-
Cw*0602 negative (odds ratio 3.5, 95% CI 1.5-8.7) [13]. A difference in throat swab positivity rates
based upon HLA-Cw*0602 status was not detected among the healthy controls.
Guttate psoriasis is characterized by the acute eruption of numerous small, erythematous papules
and plaques. The term "guttate" is utilized to refer to the discrete, drop-like appearance of skin
lesions. The eruption may present as a new-onset disorder in patients without a history of psoriasis
or as a new presentation of psoriasis in patients with preexisting chronic plaque-type disease [19].
1248
Individual lesions usually measure between 2 and 15 mm in diameter and demonstrate fine, overlying
scale (picture 1A-B). The trunk and proximal extremities are classically involved, although lesions
may also occur in other sites, such as the scalp, hands, feet, and nails [7]. Pruritus and
postinflammatory hyperpigmentation may occur.
DIAGNOSIS
Clinical examination is usually sufficient for the diagnosis of guttate psoriasis. A skin biopsy can be
used to support the diagnosis in difficult cases.
Histopathology — The histopathologic findings of guttate psoriasis vary with the age of the lesion
[38]. The findings in early lesions may be nondiagnostic, demonstrating mild acanthosis, papillary
dermal edema, capillary dilatation, and a sparse lymphocyte-predominant dermal infiltrate.
Mature lesions more closely resemble the pathology findings in chronic plaque psoriasis. Such
lesions have parakeratosis alternating with hyperkeratosis, epidermal acanthosis, rete ridge
elongation, and collections of neutrophils in the epidermis that are also known as Munro
microabscesses. Dermal findings include dilated, tortuous vessels and a superficial perivascular
infiltrate containing lymphocytes, neutrophils, and macrophages.
Laboratory tests — No serologic tests provide a definitive diagnosis of guttate psoriasis. Routine
assessment for evidence of a streptococcal infection in patients without infectious symptoms is
controversial because a benefit of antibacterial therapy in guttate psoriasis is unproven [39]. In our
opinion, laboratory testing is not necessary in patients without active signs or symptoms of
streptococcal infection.
Patients who present with symptoms suggestive of streptococcal pharyngitis or other forms of
streptococcal infection should be evaluated with appropriate laboratory studies to facilitate the
identification and treatment of these conditions. Symptoms of streptococcal pharyngitis include sore
throat, tonsillar exudate, tender cervical adenitis, and fever. (See "Evaluation of acute pharyngitis in
adults" and "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features
and diagnosis", section on 'Diagnosis'.)
Differential diagnosis — Multiple disorders may present with clinical features that resemble guttate
psoriasis. In most cases, the clinical history and physical examination are sufficient for differentiating
guttate psoriasis from other diseases. Occasionally, laboratory studies are needed to assist with
diagnosis.
Examples of disorders in the differential diagnosis of guttate psoriasis include:
1249
● Pityriasis rosea – Pityriasis rosea presents with the acute eruption of multiple oval inflammatory
plaques (picture 2A-C). Like guttate psoriasis, the trunk and proximal extremities are prominent
sites of involvement. The classic features of a "Christmas tree" pattern distribution and collarette
of scale can be useful clues for the identification of pityriasis rosea. At least 50 percent also
develop a large, oval plaque (also known as a herald plaque) prior to the development of the
widespread eruption. (See "Pityriasis rosea".)
● Tinea corporis – Extensive tinea corporis may present with numerous annular plaques on the
skin (picture 3A-B). Peripheral scale and central clearing are commonly seen. A potassium
hydroxide (KOH) preparation is useful for diagnosis. (See "Dermatophyte (tinea) infections",
section on 'Tinea corporis'.)
● Secondary syphilis – Secondary syphilis is characterized by the development of erythematous to

brown macules, papules, or small plaques in a generalized distribution (picture 4A-B).
Involvement of the palms and soles suggests the possibility of this diagnosis. Serologic findings
and histopathologic examination are also useful for diagnosis. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in HIV-uninfected patients", section on 'Clinical
manifestations'.)
● Pityriasis lichenoides chronica – Pityriasis lichenoides chronica is an uncommon skin disorder

that presents with recurrent crops of erythematous to brown papules on the trunk and proximal
extremities (picture 5). Lesions often demonstrate an adherent (micaceous) scale. Pruritus may
or may not be present. The disorder is most common in children and young adults.
● Small plaque parapsoriasis – Small plaque parapsoriasis is a rare condition in which multiple
small, oval patches with fine scale develop on the trunk and proximal extremities. The eruption
may be asymptomatic or mildly pruritic.
● Nummular dermatitis – Nummular dermatitis (also known as nummular eczema) may present
with single or multiple oval, inflammatory plaques (picture 6A-B). Pruritus is typically prominent.
Serous drainage may be present. (See "Overview of dermatitis (eczema)", section on 'Nummular
eczema'.)
Although the cutaneous features of viral exanthems and maculopapular drug eruptions tend to differ
from guttate psoriasis, the clinical scenarios in which guttate psoriasis develops (a new, widespread
skin eruption in a patient with a recent history of upper respiratory symptoms or a history of
streptococcal pharyngitis treated with antibiotics) may lead to consideration of these diagnoses
(picture 7A-B). Recognition of the well-defined plaques with adherent scale that are characteristic of
guttate psoriasis is useful for distinguishing this diagnosis.
1250
CLINICAL COURSE
Guttate psoriasis may spontaneously remit, typically over the course of several weeks to several
months, may intermittently recur, or may persist and progress into chronic plaque psoriasis
[7,21,40,41]. Few data are available on the prognosis of guttate psoriasis, precluding reliable
predictions about the disease course in individual patients.
Disease remission was the most common course followed in a retrospective study of 36 patients
with childhood or adult-onset guttate psoriasis who lacked a preceding history of psoriasis [7].
Complete remission lasting for at least one year occurred in 22 patients (61 percent) with a mean
time to disease clearance of 3.9±2.4 months, and the remaining 14 patients progressed to chronic
plaque-type disease. Of note, three patients in the remission group had recurrence after one year. A
wide variety of treatments for guttate psoriasis were utilized in the patients in this study.
Disease remission also was the most common course in a retrospective study of 79 patients with
guttate psoriasis and no prior history of psoriasis who were followed for a least one year (median
follow-up period of five years). In this study, 20 patients (25 percent) progressed to plaque psoriasis
[42]. The results of a molecular probe for streptococci appeared to correlate with risk for plaque
psoriasis; however, additional data are necessary to confirm this finding. Among the 31 patients who
had the molecular probe performed, none of the five patients who developed plaque psoriasis had a
positive molecular probe for streptococci compared with 16 of 26 patients (62 percent) who did not
develop plaque psoriasis. A similar correlation with antistreptolysin O titers was not detected.
Further study is necessary to determine whether a preceding history of guttate psoriasis is

associated with greater severity of chronic plaque-type disease [21].
TREATMENT
The treatments used for guttate psoriasis overlap with those utilized for chronic plaque psoriasis.
Although many treatments for chronic plaque psoriasis have been extensively studied, investigations
focused specifically on treatment results in guttate psoriasis are limited [43-45]. (See "Treatment of
psoriasis in adults".)
Given the possibility for spontaneous remission of guttate psoriasis within several weeks or several
months, foregoing treatment is an option for patients who prefer to avoid therapy. However, since the
time required for disease remittance is unpredictable and persistence of psoriasis is not uncommon,
in our experience, many patients elect to proceed with treatment. (See 'Clinical course' above.)
1251
First-line treatments for guttate psoriasis include phototherapy and topical agents. Although
systemic antibiotic therapy has been advocated by some authors, the value of such treatment is
unclear [39]. In addition, data on the efficacy of tonsillectomy, which aims to permanently remove a
focus of streptococcal infection, are limited. Patients who progress to chronic plaque psoriasis can
be managed according to the treatment approach for this variant. (See "Treatment of psoriasis in
adults", section on 'Approach'.)
First-line therapies
Phototherapy — Ultraviolet (UV) phototherapy is considered a first-line therapy for guttate

psoriasis. This designation is primarily due to its documented efficacy in other forms of psoriasis, its
relative safety, and the ability to easily treat large body surface areas. The options for full-body
phototherapy for psoriasis include narrowband ultraviolet B (UVB), broadband UVB, and psoralen plus
ultraviolet A (PUVA) phototherapy.
The efficacy of phototherapy for plaque psoriasis is well documented, with narrowband UVB
considered the preferred form of phototherapy [46,47]. Narrowband UVB has been more effective
than broadband UVB in multiple small, prospective, split-body studies of patients with plaque-type
psoriasis [46,48]. Although a randomized trial that compared narrowband UVB with a selective
broadband UVB device in 100 patients with plaque-type psoriasis found a difference of efficacy in
favor of narrowband UVB that was not statistically significant (56 versus 40 percent of patients
achieved disease clearance), the study was underpowered to detect a difference [49]. PUVA was
significantly more effective than narrowband UVB in a randomized trial (n = 93). However, the
requirement for strict photoprotection following treatment makes PUVA a less favorable choice for
therapy [50]. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light' and "Psoralen plus
ultraviolet A (PUVA) photochemotherapy".)
Formal study of the efficacy of phototherapy in guttate psoriasis is limited since most psoriasis
studies that have included patients with this variant have failed to stratify treatment results according
to the type of psoriasis [43]. A prospective uncontrolled study in which 67 adults with guttate
psoriasis were treated with narrowband UVB for guttate psoriasis supports benefit in this population;
52 (78 percent) achieved at least 90 percent improvement in the Psoriasis Area and Severity Index
score, and 46 (88 percent) of those patients maintained this response during 18 months of follow-up
without treatment [51]. Patients received an average of 20 treatments.
Potential adverse effects of phototherapy include burns, pruritus, and premature skin aging.
Increased risks for squamous cell carcinoma and possibly melanoma are associated with long-term
PUVA therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Skin
cancer'.)
1252
Patients without access to phototherapy may experience improvement in guttate psoriasis with
cautious outdoor sun exposure. The efficacy of this intervention has not been formally evaluated.
Based upon clinical experience, 5 to 10 minutes of noontime sun exposure without sunscreen is
typically sufficient. Sunburns should be avoided.
Topical corticosteroids and vitamin D analogs — Multiple randomized trials have supported the
efficacy of topical corticosteroids and topical vitamin D analogs for chronic plaque psoriasis [52].
These agents have not been formally evaluated specifically in guttate disease [43].
A potential impediment to topical treatment of guttate psoriasis is the often widespread nature of the
disease, which can make the application of topical agents impractical. Thus, phototherapy is usually
preferred for the treatment of patients with numerous lesions. Topical agents may be used as an
adjunct to phototherapy. (See 'Phototherapy' above.)
Cutaneous atrophy is a potential adverse effect of topical corticosteroid therapy. To minimize this
risk, low-potency agents are typically used on atrophy-prone sites, such as the face and intertriginous
areas (table 1). Medium- to high-potency agents may be applied to lesions on the trunk or extremities.
Topical corticosteroids are typically applied to active lesions once to twice daily for around two
weeks. Longer courses may be utilized if necessary; however, monitoring for adverse effects is
essential. (See "Treatment of psoriasis in adults", section on 'Corticosteroids' and "Topical
Topical vitamin D analogs, such as calcitriol or calcipotriene, may be used alone or in conjunction
with topical corticosteroid therapy. Cutaneous irritation is the most common adverse effect of these
agents. (See "Treatment of psoriasis in adults", section on 'Topical vitamin D analogs'.)
Refractory disease — In a minority of patients, guttate psoriasis recurs multiple times per year or fails
to improve with phototherapy or topical therapies. Although few data are available to support their
use, tonsillectomy and systemic therapies used for chronic plaque psoriasis have been utilized in the
management of these patients.
Tonsillectomy — Resolution of recurrent Streptococcus-associated guttate or chronic plaque

psoriasis following tonsillectomy has been documented, including in a small randomized trial
performed with patients with chronic plaque psoriasis and in case reports and uncontrolled studies
[53-56]. In one uncontrolled study, five out of six patients with guttate psoriasis that flared with
episodes of tonsillitis had complete clearance of the disease after tonsillectomy, and the remaining
patient had a lesser degree of improvement [57]. Two of seven patients with chronic plaque psoriasis
cleared.
1253
Based upon the available data, it is conceivable that tonsillectomy may be effective for some patients
with recurrent, tonsillitis-associated guttate psoriasis. However, data are insufficient to recommend
the routine use of tonsillectomy, and further studies are necessary to evaluate the efficacy of this
treatment [56]. (See "Tonsillectomy in adults" and "Tonsillectomy and/or adenoidectomy in children:
Indications and contraindications".)
Systemic psoriasis therapies — Based upon efficacy demonstrated in chronic plaque psoriasis,
treatment with systemic immunomodulatory and immunosuppressive therapies utilized for chronic
plaque psoriasis may be attempted in patients with persistent disease that fails to respond to first-
line therapies. However, there is a lack of published evidence on the efficacy of these treatments,
specifically in guttate psoriasis [43,44]. (See "Treatment of psoriasis in adults", section on 'Systemic
therapies'.)
Other interventions
Systemic antibiotics — Due to the well-accepted association between streptococcal infection and
guttate psoriasis, antibiotic therapy has been proposed as a treatment for this disease (see
'Streptococcal infection' above). However, data on the efficacy of antibiotic therapy are limited and
conflicting.
Evidence in support of antistreptococcal antibiotics is limited to a few uncontrolled studies that

document improvement in guttate or plaque-type psoriasis after treatment with macrolides or
treatment with rifampin given with or without other antistreptococcal agents [58-61]. The few
randomized trials performed are of low quality and have not yielded favorable results [62]. In a
randomized trial in 20 patients with psoriasis (19 with guttate psoriasis) that compared 14 days of
treatment with penicillin V or erythromycin (both 250 mg four times daily) plus rifampin (300 mg
twice daily) during the final five days of therapy with a 14-day treatment regimen consisting of
penicillin or erythromycin monotherapy, neither treatment approach reduced disease severity [63].
A potential role for rifampin therapy resurfaced in a subsequent prospective uncontrolled study of 52
patients with guttate psoriasis. Monotherapy with rifampin (600 mg per day) for 60 days was
associated with reductions of psoriasis severity scores regardless of the presence or absence of
evidence of recent streptococcal infection. Based upon this finding, the authors postulated that
immunomodulatory effects of rifampin may have contributed to the observed effect [61].
Overall, data remain insufficient to support a routine recommendation for antibiotic therapy for skin
disease in guttate psoriasis [54,62]. However, patients with active sources of streptococcal infection
(eg, streptococcal pharyngitis or perianal streptococcal infection) should be treated with antibiotic
therapy to resolve these infections as indicated. (See "Treatment and prevention of streptococcal
pharyngitis".)
1254
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Psoriasis".)
● Guttate psoriasis is a variant of psoriasis that is characterized by the presence of small,

erythematous papules and plaques on the skin. Guttate psoriasis is most frequently diagnosed in
adolescents and young adults but may occur in other age groups. (See 'Epidemiology' above.)
● Genetic and environmental factors likely contribute to the development of guttate psoriasis. The
HLA-Cw*0602 allele has been strongly linked to this disorder, and streptococcal infection often
precedes its development. The latency period between streptococcal infection and the
appearance of skin lesions is typically two to three weeks. (See 'Risk factors' above.)
● The relationship between streptococcal infection and guttate psoriasis is not fully understood.
Cross-reactivity between streptococcal and epidermal antigens, stimulatory effects of
streptococcal superantigens, and/or the induction of an innate immune response by
streptococcal components may be involved. (See 'Pathogenesis' above.)
● The skin lesions of guttate psoriasis are typically 2 to 15 mm in diameter with overlying, fine
scale (picture 1A-B). The trunk and proximal extremities are the principle sites of involvement.
● The diagnosis of guttate psoriasis can usually be made by clinical examination. In difficult cases,
a skin biopsy may be used to support the diagnosis and rule out other conditions. (See
'Diagnosis' above.)
● Guttate psoriasis may spontaneously remit over the course of several weeks to months or may
persist and progress to chronic plaque disease. The course of the disease is unpredictable. (See
'Clinical course' above.)
● For patients with widespread lesions of guttate psoriasis who desire treatment, we suggest
treatment with narrowband ultraviolet B (UVB) phototherapy (Grade 2B). Topical corticosteroids,
topical vitamin D analogs, and other forms of phototherapy are alternative treatments. (See 'First-
line therapies' above.)
● Treatment with the systemic immunomodulatory and immunosuppressive agents utilized for
plaque psoriasis may be attempted in patients with guttate psoriasis that fails to improve with
1255
phototherapy and topical therapies. The efficacy of such treatment in guttate psoriasis has not
been well studied. (See 'Systemic psoriasis therapies' above.)
● The use of tonsillectomy and systemic antibiotic therapy for the treatment of the skin
manifestations of guttate psoriasis is controversial. Further study is necessary to explore the
efficacy of these interventions. These interventions are not recommended for routine treatment
of guttate psoriasis. (See 'Treatment' above.)
1256
GRAPHICS
Guttate psoriasis
1257
Guttate psoriasis
Multiple erythematous papules with scale on the back.
1258
Pityriasis rosea
Pityriasis rosea. Here the "Christmas tree" pattern is evident.
Wilkins.
1259
Pityriasis rosea
Erythematous plaques with trailing collarettes of scale.
1260
Pityriasis rosea
Erythematous papules and oval plaques are present on the trunk. A larger herald patch is on the right midback.
1261
Tinea corporis
Multiple annular, erythematous plaques with peripheral scale are present.
1262
Tinea corporis
This annular lesion with a raised erythematous border, central clearing, and slight scale
was consistent with tinea corporis.
Wilkins.
1263
Secondary syphilis
Multiple slightly scaly, erythematous papules are present on the trunk of this patient with
papular secondary syphilis.
1264
Secondary syphilis
Maculopapular rash on the palms, which rarely can be pustular, in a patient with secondary
syphilis. Patients can be quite contagious at this stage.
Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A Color Atlas and Text,
Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.
http://www.lww.com
1265
Pityriasis lichenoides chronica
Multiple small papules with adherent scale are present in this patient with pityriasis
lichenoides chronica.
1266
Nummular eczema

hyperpigmentation.
Wilkins.
1267
Nummular eczema
"Coin-shaped" patches and plaques are located on the legs.
Wilkins.
1268
Viral exanthem
Multiple erythematous macules are present on the skin of this patient with a viral
exanthem.
1269
Exanthematous (morbilliform) drug eruption
Numerous erythematous macules and papules are present in this child with a morbilliform
drug eruption.
1270
Available
Brand names
Potency group* Corticosteroid Vehicle type/form strength(s), percent
(United States)
(except as noted)


solution (scalp)

aerosol
Diflucortolone valerate Ointment, oily cream Nerisone Forte (United 0.3

(not available in United Kingdom, others)
States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12
Diflucortolone valerate Cream, oily cream, Nerisone (Canada, 0.1

(not available in United ointment United Kingdom, others)
States)
Fluocinonide Cream aqueous Lidex-E ¶ 0.05

emollient
1271
Triamcinolone acetonide Cream, ointment Aristocort HP ¶, 0.5

Kenalog ¶, Triderm


solution
Aerosol spray Kenalog 0.2 mg per 2 second

spray

Gel Desonate 0.05
Hydrocortisone butyrate Cream, lotion, ointment, Locoid, Locoid 0.1

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01
Oil Δ Derma-Smoothe/FS 0.01

Body, Derma-
Smoothe/FS Scalp
¶ ¶
1272
Least potent Hydrocortisone (base, Cream, ointment Hytone, Nutracort ¶ 2.5

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

* Listed by potency according to the US classification system: group 1 is the most potent, group 7 is the least potent. Other countries use a
different classification system with only four or five groups.
¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available
generically in the United States.
Data from:
1273
Treatment of psoriasis in adults

Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Kristina Callis Duffin, MD
INTRODUCTION
Psoriasis is a common chronic skin disorder typically characterized by erythematous papules and
plaques with a silver scale, although other presentations occur. Most cases are not severe enough to
affect general health and are treated in the outpatient setting. Rare life-threatening presentations can
occur that require intensive inpatient management.
This topic reviews the treatment of psoriatic skin disease. The epidemiology, clinical manifestations,
and diagnosis of psoriatic skin disease are discussed in detail separately, as are psoriatic arthritis
and the management of psoriasis in pregnant women, children, and special populations. (See
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Treatment of psoriatic
arthritis" and "Pathogenesis of psoriatic arthritis" and "Clinical manifestations and diagnosis of
psoriatic arthritis" and "Management of psoriasis in pregnancy" and "Psoriasis in children:
Management of chronic plaque psoriasis" and "Treatment selection for moderate to severe plaque
psoriasis in special populations".)
APPROACH
Psoriasis is a chronic disease that can have a significant effect on quality of life. Therefore,
management of psoriasis involves addressing both psychosocial and physical aspects of the
disease.
Numerous topical and systemic therapies are available for the treatment of the cutaneous
manifestations of psoriasis. Treatment modalities are chosen on the basis of disease severity,
1274
relevant comorbidities, patient preference (including cost and convenience), efficacy, and evaluation
of individual patient response [1]. Although medication safety plays an important role in treatment
selection, this must be balanced by the risk of undertreatment of psoriasis, leading to inadequate
clinical improvement and patient dissatisfaction [2,3].
The desired outcome of treatment differs for individual patients and is dependent upon factors such
as patient preferences regarding the preferred amount of disease control and tolerance of specific
treatments. A reasonable goal is minimal to no skin involvement achieved with a well-tolerated
treatment regimen. A panel of psoriasis experts convened by the National Psoriasis Foundation
identified the acceptable response for plaque psoriasis after three months of treatment as either less
than 3 percent body surface area (BSA) involvement or 75 percent improvement compared with
baseline and the target response after six months as 1 percent BSA [4].
Psychosocial aspects — Psoriasis can be a frustrating disease for the patient and the provider. The
clinician needs to be empathetic and spend adequate time with the patient. It may be helpful for the
clinician to touch the patient when appropriate to communicate physically that the skin disorder is
neither repulsive nor contagious.
Clinicians should lay out reasonable aims of treatment, making it clear to the patient that the primary
goal of treatment is control of the disease. Although treatment can provide patients with high
degrees of disease improvement, there is no cure for psoriasis.
Educating the patient about psoriasis is important and referral to an organization such as the
National Psoriasis Foundation is often helpful.
Psoriasis may affect patients' perceptions of themselves and this can potentially initiate or
exacerbate psychologic disorders such as depression [5,6]. Patients with limited skin disease may
still have significant psychosocial disability [7]. Some patients with psoriasis may benefit from
counseling and/or treatment with psychoactive medications.
Choice of therapy — For most patients, the initial decision point around therapy will be between
topical and systemic therapy. However, even patients on systemic therapy will likely continue to need
some topical agents. Topical therapy may provide symptomatic relief, minimize required doses of
systemic medications, and may even be psychologically cathartic for some patients.
For purposes of treatment planning, patients may be grouped into limited disease and moderate to
severe disease categories. Limited skin disease can often be managed with topical agents, while
patients with moderate to severe disease may need phototherapy or systemic therapy. The location
of the disease and the presence of psoriatic arthritis also affect the choice of therapy. Psoriasis of
the hand, foot, or face can be debilitating functionally or socially and may deserve a more aggressive
1275
treatment approach. The treatment of psoriatic arthritis is discussed separately. (See "Treatment of
psoriatic arthritis".)
Moderate to severe psoriasis is typically defined as involvement of more than 5 to 10 percent of the
BSA (the entire palmar surface, including fingers, of one hand is approximately 1 percent of the BSA
[8]) or involvement of the face, palm or sole, or disease that is otherwise disabling. Patients with
more than 5 percent BSA affected are generally candidates for phototherapy or systemic therapy,
since application of topical agents to a large area is not usually practical or acceptable for most
patients. Attempts to treat extensive disease with topical agents alone are often met with failure, can
add cost, and lead to frustration in the patient-clinician relationship. However, topical agents are
useful adjuncts for resistant, localized lesions in patients who are getting phototherapy or systemic
agents for extensive involvement.
There is ample evidence of efficacy of the newer systemic therapies ("biologics"); however, cost is a
major consideration with these agents. Established therapies such as methotrexate and
phototherapy continue to play a role in the management of moderate to severe plaque psoriasis.
(See 'Biologic agents' below.)
The management of patients with extensive or recalcitrant disease is a challenge even for
experienced dermatologists. However, the availability of biologic medications has reduced the
challenge considerably.
The concept that many patients with psoriasis in the United States do not receive sufficient
treatment to control the disease is suggested by an analysis of surveys performed by the National
Psoriasis Foundation between 2003 and 2011 [2]. Among the 5604 survey respondents with
psoriasis, 52 percent expressed dissatisfaction with their treatment. Many survey respondents
received no treatment, including 37 to 49 percent of respondents with mild psoriasis, 24 to 36
percent of respondents with moderate psoriasis, and 9 to 30 percent of respondents with severe
psoriasis; selection bias and the particular population that was surveyed may have contributed to the
high observed rate of undertreatment. Further studies will be useful for clarifying the reasons for
these observations and for determining the value of interventions to increase the accessibility of
treatment.
Widespread pustular disease requires aggressive treatment, which may include hospitalization.
Therapeutic approaches to generalized pustular psoriasis and psoriatic arthritis are discussed
separately. (See "Pustular psoriasis: Management" and "Treatment of psoriatic arthritis".)
Limited disease — Limited plaque psoriasis responds well to topical corticosteroids and
emollients. Alternatives include vitamin D analogs, such as calcipotriene and calcitriol, tar, and
topical retinoids (tazarotene). For facial or intertriginous areas, topical tacrolimus or pimecrolimus
1276
may be used as alternatives or as corticosteroid sparing agents, though improvement may not be as
rapid. Localized phototherapy is another option for recalcitrant disease.
Combinations of potent topical corticosteroids (table 1) and either calcipotriene, calcitriol,

tazarotene, or UVB phototherapy are commonly prescribed by dermatologists. Calcipotriene in
combination with Class I topical corticosteroids is highly effective for short-term control.
Calcipotriene alone can then be used continuously and the combination with potent corticosteroids
used intermittently (on weekends) for maintenance. A combination product containing calcipotriene
and betamethasone dipropionate is available for this use. Similarly, a combination product
containing tazarotene and halobetasol propionate is available. With proper adherence, considerable
improvement with topical therapies may be seen in as little as one week, though several weeks may
be required for full benefits.
Because adherence to topical treatment can be a major hurdle, keeping the treatment regimen
simple and using treatment vehicles that the patient finds acceptable is often beneficial [9].
Moderate to severe disease — Severe psoriasis requires phototherapy or systemic therapies such
as retinoids, methotrexate, cyclosporine, apremilast, or biologic immune modifying agents. Biologic
agents used in the treatment of psoriasis include the anti-tumor necrosis factor (TNF) agents
adalimumab, etanercept, infliximab, and certolizumab pegol; the anti-interleukin (IL)-12/IL-23
antibody ustekinumab; the anti-IL-17 antibodies secukinumab and ixekizumab; the anti-IL-17
receptor antibody brodalumab; and the anti-IL-23/IL-39 antibodies guselkumab and tildrakizumab.
Improvement usually occurs within weeks. Patients with severe psoriasis generally require care by a
dermatologist.
Intertriginous psoriasis — In general, intertriginous (inverse) psoriasis should be treated with

class VI and VII low potency corticosteroids (table 1) due to an increased risk of corticosteroid-
induced cutaneous atrophy in the intertriginous areas. Very short-term use of more potent topical
corticosteroids may also be acceptable and can help reduce the complexity of the treatment regimen
when patients are prescribed high-potency topical corticosteroids for use on other parts of the body.
Topical calcipotriene or calcitriol and the topical calcineurin inhibitors tacrolimus or pimecrolimus
are additional first-line treatments [10,11]. These agents may be used alone or in combination with
topical corticosteroids as corticosteroid sparing agents for long term maintenance therapy.
Calcipotriene, tacrolimus, and pimecrolimus are more expensive options than topical corticosteroids.
Some concerns have been raised about the safety of the calcineurin inhibitors. (See 'Calcineurin
inhibitors' below and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on
'Inverse (intertriginous) psoriasis'.)
1277
Scalp psoriasis — The presence of hair on the scalp can make topical treatment of psoriasis
challenging because patients may find certain products messy or difficult to apply. Recognizing the
patient's preference for a drug vehicle may help to improve adherence to therapy. For many patients,
solution, shampoo, lotion, gel, foam, or spray vehicles are preferable to thicker creams or ointments
for use on the scalp.
Topical corticosteroids are the primary topical agents used for psoriasis on the scalp [12]. Support
for the use of these agents is evident in a systematic review of randomized trials that found that very
potent or potent topical corticosteroids are more effective treatments for scalp psoriasis than topical
vitamin D analogs [13]. Combining a corticosteroid and vitamin D analog may offer additional benefit;
in the systematic review, combination treatment with a potent topical corticosteroid and a vitamin D
analog appeared slightly more effective than potent topical corticosteroid monotherapy. However, in
clinical practice, complicating the treatment regimen with more than one topical product may reduce
the likelihood of consistent adherence to the treatment regimen. Thus, we usually prescribe a topical
corticosteroid alone as initial therapy. Commercial betamethasone dipropionate-calcipotriene
combination products are available but are more expensive than most topical corticosteroid
preparations.
Other topical therapies used for psoriasis (eg, tazarotene, coal tar shampoo, anthralin) and
intralesional corticosteroid injections also may be beneficial for scalp involvement, though data on
efficacy specifically in scalp disease are limited [12]. Salicylic acid can be a helpful adjunctive
treatment because of its keratolytic effect, but prescribing it alongside a separate topical
corticosteroid makes the treatment regimen more complicated and, therefore, could adversely affect
adherence to treatment. Phototherapy (eg, excimer laser) and systemic agents are additional
treatment options for patients who cannot achieve sufficient improvement with topical agents [12].
Guttate psoriasis — The management of guttate psoriasis is reviewed separately. (See "Guttate
psoriasis", section on 'Treatment'.)
Generalized pustular psoriasis — The management of generalized pustular psoriasis is reviewed

separately. (See "Pustular psoriasis: Management".)
Localized pustular psoriasis — Localized pustular psoriasis (palms and soles) is difficult to treat.
Approaches include potent topical corticosteroids and topical bath psoralen plus UVA phototherapy
(PUVA). (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
Data are limited on the use of systemic retinoids for localized pustular psoriasis. However, these
drugs appear to be particularly effective in the treatment of pustular psoriasis, and we consider them
first line therapy. Acitretin is the retinoid that is used most often for this indication. Acitretin is a
potent teratogen and should not be used in women who might become pregnant. Pregnancy is
1278
contraindicated for three years following acitretin therapy (see 'Retinoids' below). Methotrexate,
cyclosporine, apremilast, and the array of biologics for psoriasis can also be used.
Nail psoriasis — Although nail involvement alone is uncommon, many patients with psoriasis
have disease that involves the nails. The management of nail psoriasis is reviewed in detail
separately. (See "Nail psoriasis", section on 'Treatment'.)
Erythrodermic psoriasis — There is no high-quality evidence to support specific recommendations

for the management of erythrodermic psoriasis. Based upon data from open-label or retrospective
studies and case reports, a panel of experts suggested that patients with severe, unstable disease
should be treated with cyclosporine or infliximab due to the rapid onset and high efficacy of these
agents [14]. Patients with less acute disease can be treated with acitretin or methotrexate as first-line
agents. The panel advised against the use of systemic glucocorticoids due to the perceived potential
for these drugs to induce a flare of psoriasis upon withdrawal of therapy. (See 'Systemic therapies'
below.)
Data are limited on the efficacy of biologic agents other than infliximab for the treatment of
erythrodermic psoriasis. Etanercept was effective in an open-label study of 10 patients [15], and case
reports have documented successful treatment with adalimumab and ustekinumab [16,17].
In general, patients with erythrodermic psoriasis should be cared for by a dermatologist and may
require hospitalization and/or combinations of systemic treatments. Topical therapies, such as mid-
potency topical corticosteroids, emollients, wet dressings, and oatmeal baths can be used in
concordance with systemic treatment to manage symptoms [14]. Long-term maintenance therapy
for psoriasis is required.
Children — The immediate and long-term adverse effects of therapies for psoriasis are of particular
concern in the pediatric population. Although many agents used in the treatment of adult psoriasis
have also been used for children, high-quality studies on the efficacy and safety of therapies for
psoriasis in children are limited. The management of psoriasis in children is reviewed separately.
(See "Psoriasis in children: Management of chronic plaque psoriasis".)
Concomitant psoriatic arthritis — Patients with psoriasis should be assessed periodically for signs
and symptoms of psoriatic arthritis. The concomitant presence of psoriatic arthritis and moderate to
severe psoriasis favors the selection of treatments that are effective for both skin and joint disease.
(See "Clinical manifestations and diagnosis of psoriatic arthritis" and "Treatment of psoriatic
arthritis".)
Special populations — The treatment of psoriasis in pregnant women and patients with hepatitis B,
hepatitis C, human immunodeficiency virus infection, latent tuberculosis, or malignancy is reviewed
1279
separately. (See "Treatment selection for moderate to severe plaque psoriasis in special populations"
and "Management of psoriasis in pregnancy".)
There is an association between psoriasis and inflammatory bowel disease. Biologics such as
infliximab, adalimumab, and ustekinumab can be effective for both diseases. Etanercept and the
anti-IL-17 biologics secukinumab, brodalumab, and ixekizumab are effective for psoriasis but should
be used with caution in patients with inflammatory bowel disease because these drugs may
exacerbate inflammatory bowel disease [18].
Referral — Referral to a dermatologist should be considered in the following settings:
● Confirmation of the diagnosis is needed.
● The response to treatment is inadequate as measured by the clinician, patient, or both.
● There is significant impact on quality of life.
● The primary care clinician is not familiar with the treatment modality recommended such as
PUVA, phototherapy, or immunosuppressive medications.
● The patient has widespread severe disease.
● In cases of psoriatic arthritis, referral and/or collaboration with a rheumatologist is indicated.

(See "Treatment of psoriatic arthritis".)
TOPICAL THERAPIES
Patient adherence may be the largest barrier to treatment success with topical therapies [9]; early
patient follow-up (within a week of initiating treatment) may improve adherence. Published
guidelines for the treatment of psoriasis with topical therapies are available [19].
Emollients — Hydration and emollients are valuable and inexpensive adjuncts to psoriasis treatment.
Keeping psoriatic skin soft and moist minimizes the symptoms of itching and tenderness.
Additionally, maintaining proper skin hydration can help prevent irritation and thus the potential for
subsequent Koebnerization (development of new psoriatic lesions at sites of trauma).
The most effective are ointments such as petroleum jelly or thick creams, especially when applied
immediately after a hydrating bath or shower. In practice, however, whichever moisturizer the patient
finds most appealing may be the best choice.
Corticosteroids — Topical corticosteroids remain the mainstay of topical psoriasis treatment despite
the development of newer agents [20]. The mechanism of action of corticosteroids in psoriasis is not
1280
fully understood. Corticosteroids exert anti-inflammatory, antiproliferative, and immunosuppressive
actions by affecting gene transcription.
The inherent potency of a topical corticosteroid is frequently reported using a I to VII scale based on
vasoconstrictive assays (table 1). Although ointments are sometimes thought to be inherently more
effective because of their occlusive properties, this is not uniformly correct. In practice, the
efficacy/potency of a topical corticosteroid is dependent on many factors, including application site,
plaque thickness, how well the vehicle delivers the active drug molecule, how well that drug molecule
activates corticosteroid receptors, and, perhaps most importantly, compliance.
To minimize adverse effects and maximize compliance, the site of application needs to be
considered in choosing the appropriately potent corticosteroid:
● On the scalp or in the external ear canal, potent corticosteroids in a solution vehicle (eg,
fluocinonide 0.05% or clobetasol propionate 0.05%) are frequently indicated. Clobetasol 0.05%
shampoo, foam, or spray can also be used for scalp involvement. Patients who use scalp oils or
ointments for general hair care (a common practice among individuals with Afro-textured hair)
may prefer an oil or ointment vehicle for scalp involvement.
● On the face and intertriginous areas, a low-potency ointment or cream (eg, over-the-counter
hydrocortisone 1% or prescription-strength 2.5%) is often sufficient.
● For thick plaques on extensor surfaces, potent preparations (eg, betamethasone 0.05% or
clobetasol propionate 0.05%) are often required.
The typical regimen consists of twice daily application of topical corticosteroids. Most patients will
show a rapid decrease in inflammation with such therapy, but complete normalization of skin or
lasting remission is unpredictable.
Topical corticosteroids generally can be continued as long as the patient has thick active lesions.
Skin atrophy from topical corticosteroids usually is not a problem unless the medication is
continuously applied after the skin has returned to normal thickness or if areas without psoriasis are
exposed. Once clinical improvement occurs, the frequency of application should be reduced [19]. For
patients in whom lesions recur quickly, topical corticosteroids can be applied intermittently (such as
on weekends only) to maintain improvement. The addition of noncorticosteroid topical treatments
can also facilitate the avoidance of long-term daily topical corticosteroids. (See 'Limited disease'
above.)
The risks of cutaneous and systemic side effects associated with chronic topical corticosteroid use
are greater with high-potency formulations compared with lower-potency formulations. Data support
limiting the continuous application of Class I topical corticosteroids to two to four weeks; thus, close
1281
clinician supervision should be employed if longer treatment durations are required (table 1) [19].
Data are less clear regarding treatment durations for less potent topical corticosteroids. Side effects
of topical corticosteroids, including the potential for suppression of the hypothalamic axis, are
discussed separately. (See "Pharmacologic use of glucocorticoids" and "Topical corticosteroids: Use
and adverse effects".)
The cost of topical corticosteroids varies widely. The price of a 60 gram tube of a potent
corticosteroid brand name product can be hundreds of dollars. There are generic preparations in
each potency class that have reduced the cost somewhat, though generic prices in the United States
are rising [21]. Examples of available generics include, in order of increasing potency, hydrocortisone
2.5%, triamcinolone 0.1%, fluocinonide 0.05%, betamethasone dipropionate 0.05%, and clobetasol
0.05%.
Different formulations have been developed in an effort to enhance the delivery of topical
corticosteroids. Betamethasone valerate in a foam had superior efficacy for scalp psoriasis and was
preferred, on average, by patients when compared with betamethasone valerate lotion [22]. The foam
becomes a liquid on contact with skin and is also well tolerated by patients with trunk and extremity
psoriasis [23]. A clobetasol propionate spray is also available; like foams, sprays are easy to apply to
large areas [24]. The main advantage of these newer preparations is likely greater patient
acceptance, which may translate into greater adherence; the main disadvantage is cost.
Topical vitamin D analogs — Topical vitamin D analogs for the treatment of psoriasis include
calcipotriene (calcipotriol), calcitriol, and tacalcitol. Although topical vitamin D analogs are effective
as monotherapy for some patients, a systematic review found that combination therapy with a
topical corticosteroid is more effective than either treatment alone [25].
Until 2009, calcipotriene was the only topical vitamin D analog available in the United States.
Calcipotriene is obtainable as a cream, solution, ointment, or foam, or as a combination ointment,
suspension, or foam with betamethasone dipropionate. Topical calcitriol ointment has been
prescribed in Europe for years, and is now available in the United States. When compared with
calcipotriene, calcitriol appears to induce less irritation in sensitive areas of the skin (eg, skin folds)
[26].
Calcipotriene — Calcipotriene (calcipotriol) is an established therapy in psoriasis. The precise

mechanism is not clear, but a major effect is the hypoproliferative effect on keratinocytes [27]. An
immune modulating effect has been postulated for calcipotriene, but has not been shown to be
significant in psoriasis to date [28].
In a systematic review of randomized controlled trials, calcipotriene was at least as effective as

potent (not super-potent) topical corticosteroids, calcitriol, short contact dithranol, tacalcitol, coal tar
1282
and combined coal tar 5%, allantoin 2%, and hydrocortisone 0.5% [29]. Only potent topical
corticosteroids appeared to have comparable efficacy at eight weeks. Skin irritation is the main
adverse event associated with calcipotriene.
Combined use of calcipotriene and superpotent corticosteroids increases clinical response and
tolerance in clinical trials compared with either agent used alone [30-32]. One regimen employed
daily use of both calcipotriene ointment and halobetasol ointment for two weeks, followed by
weekend use of the halobetasol ointment and weekday use of calcipotriene [30]. This regimen
produced six-month remission maintenance in 76 percent compared with 40 percent with weekend
halobetasol alone. A similar regimen with calcipotriene ointment and clobetasol propionate foam
also appears to be effective [33].
In addition, a randomized trial found that an ointment preparation that combines calcipotriene with
betamethasone dipropionate (0.064%) was effective with once-daily usage and more effective than
once-daily therapy with either betamethasone or calcipotriene [34]; this combination preparation may
cost more than $400 for a 60 g tube. An oil formulation of the combined product was developed for
scalp use. A foam formulation of the combination is also available and may be easier to apply, but
this formulation may cost more than $1000 for 60 g. Patients who use topical corticosteroids in
combination with calcipotriene must be monitored for adverse effects as with corticosteroid
monotherapy. (See 'Corticosteroids' above.)
Thus, topical calcipotriene may be used as an alternative or adjunct to topical corticosteroid therapy.
It is applied twice daily when used as monotherapy. No controlled trials guide how best to use topical
corticosteroids in conjunction with calcipotriene. Once daily use of each may be adequate. Acidic
products can inactivate topical calcipotriene, and some topical corticosteroids may be acidic. A
reasonable approach to combination therapy is to have patients apply topical calcipotriene and
topical corticosteroids each once daily at different times of day.
Other than skin irritation, side effects of topical calcipotriene are usually minimal; the risk of
hypercalcemia is low when the drug is used appropriately [35]. However, topical calcipotriene is more
expensive than many generic potent corticosteroids.
Calcitriol — The mechanism of action of calcitriol is thought to be similar to that of calcipotriene

and involves the drug's ability to inhibit keratinocyte proliferation and stimulate keratinocyte
differentiation [36]. In addition, calcitriol inhibits T cell proliferation and other inflammatory
mediators [36]. In two randomized trials with a total of 839 patients with mild to moderate plaque
psoriasis, calcitriol 3 mcg/g ointment was more effective than vehicle [37]. At the end of the study
periods (up to eight weeks), 39.6 and 32.7 percent of the calcitriol groups versus 21.2 and 12 percent
of the vehicle groups exhibited at least marked global improvement.
1283
In a systematic review, calcipotriene and calcitriol were equally effective [25]. However, on sensitive
or intertriginous areas of the skin, calcitriol appears to be less irritating than calcipotriene. An
intraindividual randomized trial of 75 patients compared treatment with calcitriol 3 mcg/g ointment
to calcipotriene 50 mcg/g ointment for mild to moderate psoriasis on facial, hairline, retroauricular,
and flexural areas [26]. Perilesional erythema, perilesional edema, and stinging or burning sensations
were significantly lower in the areas treated with calcitriol. A 52-week open-label study of the safety
of calcitriol ointment did not reveal an adverse effect on calcium homeostasis [38].
Similar to calcipotriene, calcitriol ointment is more expensive than many generic potent topical
corticosteroids. The drug is applied twice daily.
Tar — The use of tar is a time-honored modality for treating psoriasis, although newer (and less
messy) treatment options have reduced its popularity. The precise mechanism of action of tar is not
known but may involve aryl hydrocarbon receptors [39]. Tar has apparent anti-inflammatory and
antiproliferative effects [40].
Tar can be helpful as an adjunct to topical corticosteroids. There are no commercially available
corticosteroid/tar combinations. Tar products are available without a prescription in the form of
shampoos, creams, lotions, ointments, and oils. Newer products include a solution and a foam.
Some patients may prefer the less messy formulations.
Tar can also be compounded into creams and ointments. A commonly used compound is 2% or 3%
crude coal tar in triamcinolone cream 0.1% applied twice daily to individual plaques. An alternative is
4 to 10% LCD (liquor carbonis detergens, a tar distillate) in triamcinolone cream or ointment, used
similarly. A preparation of 1% tar in a fatty-acid based lotion may be superior to conventional 5% tar
products [41] and appears to have efficacy similar to that of calcipotriene [42].
Topical tar preparations, including shampoos, creams, and other preparations, can be used once
daily. Patients should be warned that tar products have the potential to stain hair, skin, and clothing.
It may help to use them at night and wear inexpensive night clothes (eg, old pajamas) as tar products
tend to be messy. Patients may also find the odor of tar products unpleasant.
For shampoos, the emphasis should be on making sure the product reaches the scalp. Tar shampoo
should be left in place for 5 to 10 minutes before rinsing it out.
Tazarotene — Tazarotene is a topical retinoid that was safe and effective in two randomized, vehicle-
controlled trials that included 1303 patients with psoriasis [43]. The 0.1% cream was somewhat more
effective than 0.05% cream, but with a slightly higher rate of local side effects. In another study,
once-daily administration of tazarotene gel, 0.05% or 0.1%, compared favorably with twice-daily
administration of topical fluocinonide 0.05% [44]. Absorption of tazarotene was minimal over the 12-
1284
week course of the study, suggesting that systemic toxicity is unlikely during long-term therapy. A
small uncontrolled study of short contact tazarotene found that a 20 minute application followed by
washing appeared to be less irritating than traditional use, and seemed to have similar efficacy [45].
Irritation limits use of tazarotene by itself; the irritation is reduced by concomitant treatment with a
topical corticosteroid [46].
Treatment with tazarotene is often combined with topical corticosteroid therapy to minimize skin
irritation. A combination product containing halobetasol propionate and tazarotene is available. In
two phase III trials, 418 patients with moderate to severe plaque psoriasis were randomly assigned in
a 2:1 ratio to once-daily application of either halobetasol propionate 0.01% plus tazarotene 0.045%
lotion or vehicle for eight weeks [47]. At week 8, 36 and 45 percent of patients in the halobetasol
propionate plus tazarotene groups achieved at least a two-grade improvement in the Investigator's
Global Assessment score and clear or almost clear disease status. In contrast, only 7 and 13 percent
of patients in the vehicle groups achieved this endpoint. Halobetasol propionate 0.01%-tazarotene
0.045% lotion is commercially available; it may cost more than $800 for 100 g.
Calcineurin inhibitors — Topical tacrolimus 0.1% and pimecrolimus 1% are effective in the treatment
of psoriasis in sensitive areas [48-51]. Facial and intertriginous areas may be well suited to these
treatments, which can allow patients to avoid or minimize chronic topical corticosteroid use:
● In an eight-week randomized trial in 167 patients ages 16 and older, twice-daily treatment of
intertriginous and facial lesions with tacrolimus 0.1% ointment resulted in more patients
achieving clearance of lesions or excellent improvement compared with placebo (65 versus 32
percent) [52].
● In an eight-week randomized trial in 57 adults with moderate to severe inverse psoriasis, twice-
daily treatment with pimecrolimus 1% cream resulted in more patients clearing or almost
clearing lesions compared with placebo (71 versus 21 percent) [53].
Topical tacrolimus and pimecrolimus are generally well tolerated when used to treat facial and
intertriginous psoriasis [52,53]. However, corticosteroid therapy may be more effective, at least
compared with pimecrolimus. This was suggested in a four-week randomized trial in 80 patients with
intertriginous psoriasis that compared various therapies applied once daily [54]. Betamethasone
valerate 0.1% was more effective than pimecrolimus 1%.
In 2005, the US Food and Drug Administration (FDA) issued an alert about a possible link between
topical tacrolimus and pimecrolimus and cases of lymphoma and skin cancer in children and adults
[55], and in 2006 placed a "black box" warning on the prescribing information for these medications
[56]. No definite causal relationship has been established; however, the FDA recommended that
these agents only be used as second line agents for atopic dermatitis. Subsequent studies have not,
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however, found evidence of an increased risk of lymphoma [57,58]. (See "Treatment of atopic
dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)
Anthralin — Topical anthralin (also known as dithranol) is an effective treatment for psoriasis and
has been utilized since the early 20th century [59-61]. The mechanism of action of anthralin in
psoriasis is not well understood, but may involve anti-inflammatory effects and normalization of
keratinocyte differentiation [19].
Skin irritation is an expected side effect of anthralin that can limit the use of this therapy. This side
effect and the ability of anthralin to cause permanent red-brown stains on clothing and temporary
staining of skin have contributed to a decline in the use of anthralin therapy.
In order to minimize irritation, anthralin treatment is usually prescribed as a short-contact regimen

that is titrated according to patient tolerance. For example, treatment may begin with concentrations
as low as 0.1% or 0.25% applied for 10 to 20 minutes per day, with weekly step-wise increases in
duration to reach a total contact time up to one hour [62]. Then, weekly, serial increases in the
concentration of anthralin can be performed (eg, 0.5, 1, and 2%) based upon patient tolerance and
lesion response. Additionally, application to surrounding unaffected skin should be avoided.
Petrolatum or zinc oxide may be applied to uninvolved surrounding skin as a protectant prior to
application. After the desired contact period has elapsed, anthralin should be washed off the treated
area [19].
In the United States, anthralin is commercially marketed only as a 1% or 1.2% cream or a 1%

shampoo. Thus, in the outpatient setting in the United States, the initial treatment regimen often
consists of 1% or 1.2% anthralin applied for 5 to 10 minutes per day. Subsequently, the application
time is titrated up to 20 to 30 minutes as tolerated.
Benefit from anthralin therapy is often evident within the first few weeks of therapy. When
administered by patients in the outpatient setting, anthralin is less effective than topical vitamin D or
potent topical corticosteroid therapy [25,63,64].
ULTRAVIOLET LIGHT
Ultraviolet (UV) irradiation has long been recognized as beneficial for the control of psoriatic skin
lesions. UV radiation may act via antiproliferative effects (slowing keratinization) and anti-
inflammatory effects (inducing apoptosis of pathogenic T cells in psoriatic plaques). In choosing UV
therapy, consideration must be given to the potential for UV radiation to accelerate photodamage
and increase the risk of cutaneous malignancy.
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Office-based phototherapy and photochemotherapy require the supervision of a dermatologist
trained in these treatment modalities. Despite high efficacy and safety, the use of office-based
phototherapy has declined in the United States because of administrative issues and the
development of new systemic medications [65].
The American Academy of Dermatology and the National Psoriasis Foundation have issued joint
guidelines for the treatment of psoriasis with phototherapy [66].
Conventional modalities — Therapeutic doses of UV light can be administered as narrowband

ultraviolet B (UVB) phototherapy, broadband UVB phototherapy, or oral or bath psoralen plus
ultraviolet A (PUVA) photochemotherapy. Narrowband UVB and broadband UVB involve the delivery
of 311 nm and 290 to 320 nm of UVB radiation, respectively. Photochemotherapy (PUVA) involves
treatment with a photosensitizer (either oral or bath psoralen) followed by ultraviolet A (UVA)
radiation (320 to 400 nm). (See "UVB therapy (broadband and narrowband)" and "Psoralen plus
Phototherapy is typically administered three times per week during the treatment phrase. Upon
achievement of a satisfactory response, the frequency of treatment may be tapered to the lowest
frequency required to maintain improvement. Treatment protocols for phototherapy are reviewed
separately. (See "UVB therapy (broadband and narrowband)", section on 'Dosimetry and treatment
protocols' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Treatment
protocols'.)
Selection among modalities of phototherapy is based upon consideration of efficacy, safety,

availability, and ease of therapy. Narrowband UVB is generally preferred over PUVA
photochemotherapy based upon greater ease of administration (administration of psoralens not
required) and a less severe side effect profile. Randomized trials comparing the efficacy of
narrowband UVB with PUVA have yielded inconsistent findings, though it appears that oral PUVA
may provide a faster and more sustained response [67]. There are few data on the comparative
efficacy of oral and bath PUVA for psoriasis. A small, open, randomized trial of 74 patients with
moderate to severe psoriasis did not find a significant difference in efficacy between the two
treatments [68]. (See "UVB therapy (broadband and narrowband)", section on 'Short- and long-term
adverse effects' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse
effects'.)
Narrowband UVB is generally considered more effective than broadband UVB phototherapy,
contributing to acceptance of narrowband UVB as the preferred form of UVB phototherapy for
psoriasis, provided it is available [66]. Although greater efficacy of narrowband UVB over broadband
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UVB for plaque psoriasis is supported by some studies [69,70], this has not been confirmed in high-
quality, randomized trials [67].
Home phototherapy — An alternative to office-based phototherapy is the use of a home UVB

phototherapy unit prescribed by the treating clinician [71]. This option may be preferred by patients
who are not in close proximity to an office-based phototherapy center, whose schedules do not
permit frequent office visits, or for whom the costs of in-office treatment exceed those of a home
phototherapy unit. Home units cost about $3000, but may prove cost-effective in the long term,
particularly when compared with biologic therapies. Insurance coverage of these units varies.
For some dermatologists, uncertainty regarding the safety of home units has led to a reluctance to
prescribe them. Some have expressed concern for the potential for improper or excessive usage of
these devices [72]. In contrast, a randomized trial of 196 subjects found that narrowband UVB
administered via home units was as safe and effective as office-based treatments [72]. Home
phototherapy units that are equipped with electronic controls that allow only a prescribed number of
treatments are available and may help to mitigate clinician concerns.
Commercial tanning beds can improve psoriasis and are occasionally used for patients without
access to medical phototherapy [73,74]. However, data are limited on this mode of treatment, and
clinicians and patients should be cognizant that there is significant variability in the UV output of
tanning beds [75].
Excimer laser — The excimer laser, a laser that emits UVB light, is an alternative for the treatment of
localized areas of psoriasis. The 308 nm excimer laser allows treatment of only involved skin; thus,
considerably higher doses of UVB can be administered to psoriatic plaques at each treatment
session when compared with traditional phototherapy. (See "Targeted phototherapy".)
Uncontrolled trials suggest that laser therapy results in faster responses than conventional
phototherapy [76,77]. As an example, one study of excimer laser therapy involved 124 patients with
stable mild to moderate plaque psoriasis, of whom 80 completed the entire protocol [76]. Treatments
were scheduled twice weekly. After 10 or fewer treatments, 84 and 50 percent of patients achieved
the outcomes of 75 percent or better and 90 percent or better clearing of plaques, respectively. This
number of treatments was far fewer than that typically required of phototherapy (25 or more). Side
effects of laser therapy included erythema and blistering; in contrast to whole body phototherapy
burns, the localized phototherapy burns were generally well tolerated because of the limited areas
treated, and no patient discontinued therapy because of adverse effects.
A common sequela of excimer laser therapy is the induction of UV-induced hyperpigmentation

(tanning) in treated areas, which can be cosmetically distressing for some patients.
Hyperpigmentation slowly resolves after the discontinuation of treatment.
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Like 311 nm UVB, the excimer laser represents a therapeutic advance toward specific wavelength
therapies for psoriasis. While both the excimer laser and narrowband UVB are approved for use in
psoriasis, inconsistencies in third party coverage for these treatments limit their utilization.
Cancer risk — A concern with PUVA is an increased risk of nonmelanoma skin cancer and
melanoma. Ongoing monitoring is indicated in patients who have received prolonged courses of
PUVA. In general, phototherapy is contraindicated in patients with a history of melanoma or
extensive nonmelanoma skin cancer. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy",
section on 'Skin cancer'.)
Folate deficiency — Folate deficiency has been associated with health disorders such as neural tube
defects in fetuses of affected pregnant women, anemia, and hyperhomocysteinemia (a risk factor for
cardiovascular disease). In an in vitro study, exposure of plasma to UVA led to a 30 to 50 percent
decrease in the serum folate level within 60 minutes [78]. However, folate deficiency secondary to
UVA exposure has not been proven to occur in vivo. In a small randomized trial of healthy subjects,
no difference in serum folate levels was identified between subjects irradiated with UVA for six
sessions and untreated subjects [79]. In addition, an observational study of 35 psoriasis patients
found that narrowband UVB had no effect on serum folate levels after 18 treatment sessions [80].
Saltwater baths — Exposure to natural sunlight improves psoriasis. Bathing in sea water in
combination with sun exposure (climatotherapy) has also been used as a therapy for psoriasis, as
has the use of salt water baths with artificial UV exposure (balneophototherapy). (See 'Ultraviolet
light' above.)
In a large, open, randomized trial, treatment with UVB after a saltwater bath had greater efficacy than
UVB after a tap-water bath, and similar efficacy to bath PUVA [81]. Although the raters of disease
severity were intended to be blinded, raters knew treatment assignment in nearly 60 percent of
cases. Additionally, less than half the patients were considered to have met the study's prespecified
criteria for having been eligible and treated per protocol. In per-protocol analyses, no difference was
found between saltwater and tap-water baths, and bath PUVA was superior to UVB after a saltwater
bath.
Additional studies are required to demonstrate that combining saltwater baths with phototherapy is
superior to tap-water baths plus phototherapy or to phototherapy alone.
SYSTEMIC THERAPIES
A variety of systemic medications are used for the treatment of psoriasis [82-84], particularly for
patients with more than 5 percent body surface area involvement or less extensive, but debilitating,
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disease. In 2008 and 2009, the American Academy of Dermatology published guidelines for the
management of psoriasis with systemic therapies [82,83]. In addition, European S3-Guidelines on the
systemic treatment of psoriasis have been published [85,86]. The British Association of
Dermatologists has also published guidelines for the use of systemic biologic therapies [87]. (See
'Society guideline links' below.)
Options for systemic therapy include immunosuppressive or immunomodulatory drugs such as

methotrexate, cyclosporine, apremilast and biologic agents. Systemic retinoids, which improve
psoriasis through effects on epidermal proliferation and differentiation as well as
immunomodulation, are also used for the treatment of this condition [82].
Biologic agents are the most effective therapies for moderate to severe psoriasis. Network meta-
analyses support their efficacy [88,89]. One network meta-analysis of randomized trials compared
the efficacy of older oral agents (acitretin, cyclosporine, fumaric acid esters, methotrexate), newer
small molecules (apremilast, tofacitinib, ponesimod), anti-tumor necrosis factor (TNF)-alpha drugs
(etanercept, infliximab, adalimumab, certolizumab), the anti-interleukin (IL)-12/IL-23 agent
ustekinumab, IL-17 blocking drugs (secukinumab, ixekizumab, brodalumab), anti-IL-23/IL-39 drugs
(guselkumab, tildrakizumab), alefacept, and itolizumab for moderate to severe psoriasis [88]. The
agents most likely to lead to at least 90 percent improvement in the Psoriasis Area and Severity
Index score (PASI 90) within 12 to 16 weeks were the biologic agents ixekizumab, secukinumab,
brodalumab, guselkumab, certolizumab, and ustekinumab. In addition, the anti-IL-17, anti-IL-12/IL-23,
anti-IL-23/IL-39, and anti-TNF-alpha biologic agents were more effective than oral/small molecule
agents.
Although knowledge of the relative efficacies of systemic treatments for psoriasis is useful,
consideration of factors such as drug side effects, patient preference, drug availability, and treatment
cost (eg, the high cost of biologic agents compared with conventional therapies) also play an
important role in treatment selection.
Impact of COVID-19 pandemic — The 2020 COVID-19 pandemic has led organizations, including the
American Academy of Dermatology, to issue guidance regarding the use of biologic agents or other
systemic immunomodulatory drugs during the pandemic [90]. Use of systemic immunomodulatory
therapies during this period is reviewed separately. (See "Coronavirus disease 2019 (COVID-19):
Epidemiology, virology, clinical features, diagnosis, and prevention".)
Methotrexate — The folic acid antagonist methotrexate has been used successfully in the treatment
of psoriasis for over 50 years [91]. It is also effective for the treatment of psoriatic arthritis and
psoriatic nail disease. Initial thoughts on the mechanism of action centered around the
antiproliferative effects of methotrexate on DNA synthesis in epidermal cells; subsequent evidence
1290
supports the concept that it is the immunosuppressive effects of methotrexate on activated T cells
that controls psoriasis [92]. (See "Treatment of psoriatic arthritis", section on 'Methotrexate'.)
Methotrexate appears to be less effective than at least some of the biologic agents (see 'Biologic
agents' below). In one trial, 271 patients with moderate to severe plaque psoriasis were randomized
to receive oral methotrexate (7.5 to 25 mg per week), adalimumab (40 mg every other week), or
placebo [93]. After 16 weeks, the proportion of patients achieving a 75 percent improvement in the
PASI score with methotrexate was more than that with placebo but less than with adalimumab (36,
19, and 80 percent, respectively). A placebo-controlled randomized trial evaluating subcutaneous
methotrexate (17.5 to 22.5 mg per week) in patients with moderate to severe plaque psoriasis found
a similar efficacy rate. After 16 weeks, 37 of 91 patients (41 percent) in the methotrexate group
achieved 75 percent improvement in the PASI score compared with 3 of 29 patients (10 percent) in
the placebo group [91].
Methotrexate is usually administered in an intermittent low-dose regimen such as once weekly.

Similar regimens are in use in patients with rheumatoid arthritis. Administration can be oral,
intravenous, intramuscular, or subcutaneous; the usual dose range is between 7.5 and 25 mg per
week. Treatment is usually started at 10 to 15 mg weekly. Older patients who can be expected to
have impaired renal function can be given a single test dose of 5 mg with blood work one week later,
followed by upward titration and close monitoring for toxicity. Dose can then be escalated every four
to eight weeks depending on tolerance, efficacy, and toxicity. Subcutaneous methotrexate can be
used and may be helpful when doses higher than 15 mg/week are needed, as hepatic metabolism
may limit the bioavailability of higher methotrexate doses. Unlike cyclosporine, which is generally
used for only a limited duration of treatment because of cumulative renal toxicity, methotrexate can
be used for long-term therapy. (See "Use of methotrexate in the treatment of rheumatoid arthritis"
and 'Systemic calcineurin inhibitors' below.)
Folic acid, 1 mg daily, protects against some of the common side effects seen with low-dose
methotrexate such as stomatitis [94]. Folate does not appear to protect against pulmonary toxicity,
and it is uncertain whether it protects against hepatic toxicity; monitoring for bone marrow
suppression and hepatotoxicity are necessary during therapy. Concurrent use of other medications
that interfere with folic acid metabolism, such as sulfa antibiotics, can increase the toxicity of
methotrexate. (See "Major side effects of low-dose methotrexate".)
For patients with one or more risk factors for hepatotoxicity from methotrexate, use of a different
systemic drug should be considered. (See 'Hepatotoxicity and liver biopsy' below.)
Hepatotoxicity and liver biopsy — In the past, the American Academy of Dermatology
recommended that all patients with psoriasis undergo liver biopsy to evaluate for hepatotoxicity after
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every 1 to 1.5 g of cumulative methotrexate [95]. In 2009, the American Academy of Dermatology and
the National Psoriasis Foundation updated this recommendation with monitoring guidelines that are
dependent upon the presence or absence of risk factors for hepatotoxicity [82,96].
Risk factors for hepatotoxicity from methotrexate include [96]:
● History of more than moderate alcohol consumption

● Persistent abnormal liver chemistry studies
● History of liver disease, such as chronic hepatitis B or C
● Family history of inherited liver disease (eg, hemochromatosis)
● Diabetes mellitus
● Obesity
● History of significant exposure to hepatotoxic drugs (other than methotrexate) or chemicals
● Absence of folate supplementation during methotrexate therapy
● Hyperlipidemia
Patients without risk factors for hepatotoxicity should have liver chemistries drawn every one to
three months. If five out of nine serum AST levels are elevated over the course of 12 months, or if the
serum albumin level is decreased in the context of normal nutritional status and well-controlled
psoriasis, a liver biopsy should be performed.
Liver biopsy should also be considered after a cumulative dose of 3.5 to 4 g of methotrexate has
been administered. Once patients have reached this dose, options include proceeding with a liver
biopsy, continuing to monitor without a liver biopsy, or discontinuing methotrexate therapy.
In patients with risk factors for hepatotoxicity for whom the decision is made to proceed with
methotrexate, liver biopsies are considered earlier in the course of therapy. Since a fair number of
patients will discontinue therapy within the first two to six months, it is reasonable to perform the
biopsy after this time period. For patients who continue methotrexate, liver biopsies should be
considered after every 1 to 1.5 g of cumulative methotrexate. Once patients have reached this dose,
options include proceeding with a liver biopsy, discontinuing methotrexate, or consulting with a
hepatologist for further evaluation.
Less invasive tests for hepatic fibrosis in patients on methotrexate are being tested; definitive
assessment of their usefulness is not available [97].
Retinoids — Systemic retinoids (derivatives of vitamin A) are utilized for patients with severe
psoriasis, including pustular and erythrodermic forms, and in patients with HIV-associated psoriasis.
The retinoid of choice in psoriasis is acitretin. In a pilot study, 6 of 11 patients with psoriasis and HIV
infection achieved good to excellent results with acitretin therapy, with four achieving complete
1292
clearing of their skin disease [98]. The usual dose range of acitretin is 25 mg every other day to 50
mg daily.
Acitretin can be used in combination with UVB or PUVA therapy. Used in this way, patients have
higher response rates with better tolerance and less UV exposure [99,100].
Monitoring for hypertriglyceridemia and hepatotoxicity are required with retinoid therapy. Common
side effects include cheilitis and alopecia. Acitretin is teratogenic; it is only indicated in men and in
women of nonreproductive potential. Pregnancy is contraindicated for three years after
discontinuing the drug [101].
Systemic calcineurin inhibitors — The T cell suppressor cyclosporine is effective in patients with
severe psoriasis [102,103]. Usual doses are in the range of 3 to 5 mg/kg per day orally. Improvement
is generally observed within four weeks.
The use of cyclosporine in psoriasis is based upon multiple studies supporting its status as a highly
and rapidly effective treatment [82,104-106]. In a placebo-controlled randomized trial, after eight
weeks of treatment with 3, 5, or 7.5 mg/kg of cyclosporine per day, 36, 65, and 80 percent of patients,
respectively, were rated as clear or almost clear of psoriasis [104]. All three regimens were superior
to placebo, and patients who received the 5 mg dose were least likely to require dose alterations due
to side effects or lack of efficacy.
A few randomized trials have compared the efficacy of cyclosporine and methotrexate, utilizing
varying treatment regimens and providing different results. Although a 16-week randomized trial in
88 patients failed to find a significant difference in the effects of cyclosporine (3 to 5 mg/kg per day)
and methotrexate (15 to 22.5 mg per week) on moderate to severe plaque psoriasis [107], a
subsequent 12-week randomized trial of 84 patients with moderate to severe plaque psoriasis found
greater efficacy with cyclosporine (3 to 5 mg/kg per day) over methotrexate (7.5 to 15 mg per week)
[108]. A smaller trial of patients with severe psoriasis found superior efficacy of methotrexate over
cyclosporine (3 to 4 mg/kg per day), but utilized much higher doses of methotrexate than are
typically prescribed in clinical practice (0.5 mg/kg per week) [109].
Close monitoring is required since renal toxicity and hypertension are common and often limit the
long-term use of cyclosporine in patients with psoriasis. (See "Cyclosporine and tacrolimus
nephrotoxicity".)
An investigational oral calcineurin inhibitor, ISA247, was efficacious in randomized trials in patients
with moderate to severe plaque psoriasis, and may have less nephrotoxicity than cyclosporine [110].
Apremilast — Apremilast, a phosphodiesterase 4 inhibitor, is another oral agent for the treatment of
moderate to severe plaque psoriasis [111-114]. Phosphodiesterase 4 inhibition reduces production
1293
of multiple cytokines involved in the pathogenesis of psoriasis. Apremilast is costly, priced closer to
biologics than to methotrexate. The drug can also be effective for psoriatic arthritis. (See "Treatment
of psoriatic arthritis", section on 'Apremilast'.)
Apremilast is indicated for the treatment of moderate to severe plaque psoriasis in patients who are
candidates for phototherapy or systemic therapy. The approval was supported by the findings of two
16-week multicenter randomized trials in which a total of 1257 adults with moderate to severe
psoriasis were randomly assigned to receive 30 mg of apremilast twice daily or placebo [115]. In the
first trial, 33 percent of 562 patients treated with apremilast achieved 75 percent improvement in the
Psoriasis Area and Severity Index (PASI 75), compared with only 5 percent of 282 patients in the
placebo group. Results of the second trial were similar; 29 percent of 274 adults treated with
apremilast achieved PASI 75, compared with 6 percent of 137 patients in the placebo group.
Although apremilast represents an alternative systemic agent for the treatment of psoriasis, reported
treatment success rates with apremilast are lower than those frequently reported for biologic agents
[116].
The use of a 30 mg twice daily dose of apremilast is further supported by a phase II randomized trial
of 352 adults with moderate to severe plaque psoriasis that found lower efficacy with reduced doses.
Among patients treated with 30 mg twice daily, 20 mg twice daily, 10 mg twice daily, and placebo,
PASI 75 was achieved by 41, 29, 11, and 6 percent of patients, respectively [113].
Apremilast is associated with a short-term risk of diarrhea, especially when treatment is started,
occurring in roughly 15 to 20 percent of patients. Tolerability of apremilast is improved by slowly
ramping up the dose when treatment is initiated. The recommended dose titration schedule for
adults is as follows:
● Day 1 – 10 mg in morning
● Day 2 – 10 mg in morning and 10 mg in evening
● Day 6 and thereafter – 30 mg twice daily
In adult patients with severe renal impairment, the recommended final dose is 30 mg once daily. At
the start of therapy, only the morning dose of the above titration schedule is given.
Examples of other reported side effects of apremilast include nausea, upper respiratory infection,
headache, and weight loss. Periodic monitoring of weight is recommended [115]. Advising patients,
their caregivers, and families to be alert for worsening depression, suicidal thoughts, or other mood
1294
changes during treatment also is suggested based upon the possibility of a slight increase in risk for
depression [115].
Biologic agents — Biologic agents are important treatment options for moderate to severe plaque
type psoriasis [87,88,117-119]. The available biologics for psoriasis have excellent short-term and
long-term efficacy and favorable tolerability. Examples of biologic therapies include etanercept,
infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab,
tildrakizumab, and certolizumab pegol.
Alefacept, another biologic agent, is no longer marketed. Itolizumab, a biologic agent marketed in
India, is not available in the United States.
There is a concern that all TNF-alpha inhibitors have the potential to activate latent infections such
as tuberculosis, and increased rates of infection have been seen in patients with rheumatoid arthritis
treated with etanercept, infliximab, and adalimumab. In addition, risk for herpes zoster may be
increased in patients receiving biologic therapy in combination with methotrexate [120]. Anti-IL-17
biologic drugs (eg, ixekizumab, secukinumab, brodalumab) have been associated with a slight
increase in risk for candidal infections [121].
An analysis of data from adults with psoriasis in a large registry of patients eligible to receive or
receiving conventional systemic or biologic therapy (Psoriasis Longitudinal Assessment and
Registry [PSOLAR]) found a higher risk of serious infections with adalimumab and infliximab
compared with nonmethotrexate and nonbiologic therapies [122]. Serious infection rates among
patients treated with infliximab, adalimumab, etanercept, and ustekinumab were 2.49, 1.97, 1.47, and
0.83 per 100 patient-years, respectively. Among patients who had never received a biologic therapy
or methotrexate and patients who had never received a biologic therapy but had received
methotrexate, rates were 1.05 and 1.28 per 100 patient-years, respectively.
Another publication from the PSOLAR registry provides some reassurance regarding the use of
biologic therapy for psoriasis [123]. Compared with treatment with nonbiologic agents, biologic
therapy did not appear to be a significant predictor of death, major adverse cardiovascular events
(MACE), or malignancy. Patients were not randomized to the different treatment arms in the PSOLAR
registry, and therefore selection bias could account for differences (or lack of differences) between
groups.
Potential side effects of TNF-alpha inhibitors are reviewed in greater detail separately. (See "Tumor
necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-
alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Risk of
malignancy" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
1295
TNF-alpha inhibitors — Biologic tumor necrosis factor (TNF)-alpha inhibitors utilized for psoriasis
include etanercept, infliximab, adalimumab, and certolizumab pegol.
Etanercept — The TNF-alpha inhibitor etanercept is of benefit in psoriasis [124-128]. It is

approved by the US Food and Drug Administration (FDA) for adults with psoriatic arthritis and for
patients age four years or older with chronic moderate to severe plaque psoriasis. Standard dosing
for etanercept for adults is subcutaneous injection of 50 mg twice weekly for the initial three months
of therapy, followed by a 50 mg injection once weekly for maintenance therapy. Standard pediatric
dosing is 0.8 mg/kg weekly, with a maximum dose of 50 mg per week. Etanercept is also an effective
treatment for psoriatic arthritis. (See "Treatment of psoriatic arthritis", section on 'Resistant to
nonbiologic DMARDs'.)
A randomized trial of etanercept in 652 adult patients with active but stable plaque psoriasis
involving at least 10 percent of the body surface area found three doses of subcutaneous etanercept
(25 mg weekly, 25 mg twice weekly, 50 mg twice weekly) significantly superior to placebo [125]. After
12 weeks, there was at least a 75 percent improvement in a psoriasis area and severity index (PASI)
score in 14, 34, 49, and 4 percent, respectively. After 24 weeks, such an improvement was seen in 25,
44, and 59 percent, respectively (no patients received placebo for more than 12 weeks). Etanercept
was well tolerated with adverse events and infections occurring at similar rates in all four groups.
A 12-week randomized trial found similar benefits with subcutaneous etanercept 50 mg twice
weekly, and that, compared with placebo, patients receiving etanercept had significant improvements
in measures of fatigue and depression [129]. In another randomized trial, etanercept was effective
for moderate to severe plaque psoriasis in children and adolescents [130]. The long-term safety of
etanercept for psoriasis is supported by a 96-week study of etanercept 50 mg twice weekly [131].
The formation of anti-etanercept antibodies has been reported to occur in 0 to 18 percent of patients
treated with the drug for psoriasis [132]. However, in contrast to antibodies against infliximab and
adalimumab in patients treated for psoriasis with those agents, the formation of anti-etanercept
antibodies does not appear to reduce treatment efficacy [132].
Etanercept-szzs (GP2015) is an etanercept biosimilar that has similar efficacy and safety in patients
with moderate to severe plaque psoriasis [133].
Infliximab — The TNF-alpha inhibitor infliximab is of benefit in patients with moderate to severe
plaque psoriasis and appears to generally be well tolerated [134-137]. In addition, the findings of a
systematic review suggest that the onset of action of infliximab is faster than several other
commercially available biologic agents [138]. Standard dosing for infliximab for adults is intravenous
infusion of 5 mg/kg at weeks 0, 2, and 6, followed by every eight weeks thereafter. Infliximab is also
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an effective treatment for psoriatic arthritis. (See "Treatment of psoriatic arthritis", section on
'Resistant to nonbiologic DMARDs'.)
Infliximab was efficacious for psoriasis in a multicenter randomized trial in 249 patients with severe
plaque psoriasis. Compared with placebo, more patients treated with infliximab 3 mg/kg or 5 mg/kg
(given intravenously at weeks zero, two, and six) achieved at least a 75 percent improvement in the
PASI score at week 10 (6 percent versus 72 and 88 percent, respectively) [136]. The duration of
response appeared to be longer with the higher dose. More patients treated with infliximab had
serious adverse events (12 versus 0), including four cases that the authors felt were reasonably
related to treatment: squamous cell carcinoma, cholecystitis, diverticulitis, and pyelonephritis with
sepsis.
The efficacy of infliximab (5 mg/kg given at weeks 0, 2, 6, 14, and 22) was compared with
methotrexate (15 to 20 mg per week) in a 26-week open-label randomized trial in patients with
moderate to severe psoriasis (RESTORE1 trial) [139]. At week 16, patients who did not achieve at
least 50 percent improvement were able to switch to the alternative therapy. The trial found that
patients treated with infliximab (n = 653) exhibited greater improvement (78 versus 42 percent
achieved 75 percent improvement in the PASI score by week 16) and were much less likely than
patients in the methotrexate group (n = 215) to require switching to the alternative therapy (1 versus
29 percent) [139]. In addition, patients who were transitioned from methotrexate to infliximab fared
better than those who switched to methotrexate from infliximab; 73 versus 11 percent achieved 75
percent improvement in the PASI score.
Maintenance therapy with infliximab also appears to be effective [137,140,141]. A randomized trial
using the dosing schedule above with infliximab 5 mg/kg through six weeks, but then adding
maintenance dosing of infliximab 5 mg/kg every eight weeks through 46 weeks found that 61
percent of patients had at least a 75 percent improvement in the PASI score at week 50 [137].
Infliximab was generally well tolerated. The use of maintenance therapy was further supported by a
50-week randomized trial; patients treated with continuous therapy (3 or 5 mg/kg infusion every
eight weeks after induction therapy at zero, two, and six weeks) maintained the response to
treatment better than patients who received intermittent "as needed" therapy (3 or 5 mg/kg infusions
separated by at least four weeks when PASI improvement fell below 75 percent) [140].
In addition to experiencing better maintenance of response, there are some data that suggest that
patients who receive continuous maintenance therapy with infliximab may be less likely to
experience serious infusion-related reactions than patients who receive intermittent maintenance
therapy. In trials comparing the two modes of maintenance therapy, slightly higher rates of infusion-
related reactions have been observed among recipients of intermittent maintenance therapy
[140,141]. A 128-week randomized trial (RESTORE2 trial) designed to compare the long-term efficacy
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of continuous maintenance therapy (5 mg/kg of infliximab every eight weeks after induction) and
intermittent maintenance therapy (reinduction with up to four 5 mg/kg infusions of infliximab over 14
weeks if more than a 50 percent loss in PASI improvement occurred) was terminated early (at week
124) due to an observation of a higher proportion of serious infusion-related reactions in the
intermittent therapy group (8 of 219 [4 percent] versus 1 of 222 patients [<1 percent]) [141]. The
reason for this observation was unclear. Whether other regimens of intermittent maintenance
therapy would be less likely to yield infusion reactions remains to be seen.
Studies in psoriasis, inflammatory bowel disease, and rheumatoid arthritis have suggested that the
production of antibodies to infliximab may contribute to the loss of response to infliximab in some
patients with these diseases [132,142-144]. Anti-infliximab antibodies have been reported to occur in
5 to 44 percent of patients who receive infliximab for psoriasis [132,145]. (See "Tumor necrosis
factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section
on 'Anti-drug antibodies'.)
Infliximab-dyyb (CT-PI3) is a biosimilar to infliximab. In a randomized trial that included patients with
various infliximab-responsive diseases, including psoriasis, switching to infliximab-dyyb was not
inferior to continued originator infliximab therapy [146].
Adalimumab — Adalimumab, a humanized monoclonal antibody with activity against TNF-

alpha, was originally used for patients with rheumatoid arthritis and is also effective for psoriatic
arthritis (see "Treatment of psoriatic arthritis"). Adalimumab is approved by the FDA for treatment of
adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic
therapy or phototherapy. Standard dosing for adalimumab for adults is an initial subcutaneous
injection of 80 mg of adalimumab followed by 40 mg given every other week, beginning one week
after the initial dose. (See "Treatment of psoriatic arthritis", section on 'Resistant to nonbiologic
DMARDs'.)
Examples of studies supporting the efficacy of adalimumab include:
● A randomized trial in 147 patients with moderate to severe plaque psoriasis compared
adalimumab by subcutaneous injection 40 mg every other week, 40 mg weekly, and placebo
[147]. After 12 weeks, more patients treated with adalimumab every other week or weekly
achieved at least a 75 percent improvement in the PASI score (53 and 80 percent, respectively),
versus 4 percent with placebo. In an open label extension of the study, improvements were
sustained for 60 weeks.
● A randomized trial in 490 patients with moderate to severe psoriasis who had achieved a 75
percent improvement in the PASI score after 32 weeks of adalimumab found that continuing
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adalimumab resulted in a higher percentage of patients maintaining their response at 52 weeks
(95 versus 72 percent) [148].
● Therapy with adalimumab was more effective than methotrexate in a randomized trial involving
271 patients with moderate to severe psoriasis [93]. (See 'Methotrexate' above.)
● A randomized trial found that adalimumab was more effective than placebo for the treatment of
moderate to severe chronic plaque psoriasis involving the hands or feet [149]. After 16 weeks,
disease was cleared or almost cleared in 15 out of 49 patients in the adalimumab group (31
percent) compared with 1 out of 23 patients in the placebo group (4 percent).
Adalimumab may be an effective alternative for patients who fail to respond to etanercept [150-152].
In a multicenter, open-label study, patients who did not improve with 50 mg of etanercept twice
weekly (n = 50) or who worsened following a dose reduction of etanercept to 50 mg once weekly (n =
35) were treated with 40 mg of adalimumab every other week [150]. After 12 weeks, psoriasis was
cleared or almost cleared in 34 percent (95% CI 20-48) of patients who had failed etanercept and 31
percent (95% CI 15-48) of patients who had disease recurrence on the lower dose of etanercept.
Treatment success rates approached 50 percent when adalimumab (40 mg weekly or every other
week) was given for an additional 12 weeks.
Formation of antibodies against adalimumab is reported to occur in 6 to 50 percent of patients

treated with adalimumab for psoriasis and may reduce the response to therapy [132,145,153]. (See
"Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune
diseases", section on 'Anti-drug antibodies'.)
Further study is necessary to determine whether assessing serum levels of adalimumab during
treatment will be useful for improving responses to therapy [154].
Drugs biosimilar to adalimumab include adalimumab-atto and adalimumab-adbm [155,156]. In a

randomized trial that compared adalimumab-atto with adalimumab in 350 adults with moderate to
severe plaque psoriasis, the two drugs had similar efficacy and safety after 16 weeks of treatment
[157].
Certolizumab pegol — Certolizumab pegol is a pegylated humanized antibody Fab fragment

with specificity for TNF-alpha. In 2018, the FDA approved the drug for the treatment of adults with
moderate to severe psoriasis who are candidates for systemic therapy or phototherapy. Standard
dosing for certolizumab is 400 mg every other week. An optional regimen for patients who weigh ≤90
kg is 400 mg at weeks 0, 2, and 4, followed by 200 mg every other week. A potential advantage of
certolizumab pegol is minimal transfer across the placenta; unlike other anti-TNF biologics,
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certolizumab pegol does not bind the neonatal Fc receptor because it lacks the IgG Fc. The drug is
also effective for psoriatic arthritis.
Support for the use of certolizumab comes from phase III randomized trials [158,159]. In the
CIMPASI-1 and CIMPASI-2 trials, adults with moderate to severe chronic plaque psoriasis (234 adults
in CIMPASI-1 and 227 adults in CIMPASI-2) were randomly assigned to 400 mg of certolizumab pegol
every two weeks, 200 mg of certolizumab pegol every two weeks (after loading dose of 400 mg at
weeks 0, 2, and 4), or placebo every two weeks [158]. Patients who achieved at least PASI 50
continued treatment through 48 weeks. At week 16, more patients in the certolizumab pegol 400 mg
and certolizumab pegol 200 mg groups achieved PASI 75 than in the placebo group. PASI 75
response rates in CIMPASI-1 were 76, 67, and 7 percent, respectively. In CIMPASI-2, response rates
were 83, 81, and 12 percent, respectively. Responses to certolizumab pegol were maintained over 48
weeks. The most common adverse effects among patients receiving certolizumab were
nasopharyngitis and upper respiratory infection. In total, serious treatment-emergent adverse effects
occurred in 18 patients who received certolizumab pegol 400 mg, 11 patients who received
certolizumab pegol 200 mg, and 1 patient in the placebo groups.
A separate phase III trial (CIMPACT) randomly assigned 559 adults with moderate to severe chronic
plaque psoriasis to certolizumab 400 mg, certolizumab 200 mg, or placebo every two weeks for 16
weeks or etanercept 50 mg twice weekly for 12 weeks [159]. The trial found both the 400 and 200 mg
dose regimens more effective than placebo, with greater response to the 400 mg dose. At 12 weeks,
certolizumab 400 mg was more effective than etanercept, and certolizumab 200 mg was noninferior
to etanercept for achieving PASI 75. As in the CIMPASI trials, nasopharyngitis and upper respiratory
infections were the most common adverse effects.
Inhibitors of the IL-17 pathway — Inhibitors of the interleukin 17 (IL-17) pathway utilized for the
treatment of psoriasis include secukinumab, ixekizumab, and brodalumab.
Secukinumab — Secukinumab, an anti-IL-17A monoclonal antibody, is an effective treatment

for moderate to severe plaque psoriasis [160-168]. Standard dosing for plaque psoriasis is 300 mg
given subcutaneously once weekly at weeks 0, 1, 2, 3, and 4 followed by 300 mg every four weeks.
Doses of 150 mg are sufficient for some patients. Secukinumab is also effective for psoriatic
arthritis. (See "Treatment of psoriatic arthritis", section on 'Secukinumab'.)
Two 52-week phase III placebo-controlled trials (ERASURE trial and FIXTURE trial) support the
efficacy of secukinumab for moderate to severe plaque psoriasis [160]. In both trials, secukinumab
was given as a 300 mg or 150 mg dose once weekly for five weeks, then once every four weeks. In
the ERASURE trial (n = 738) a 75 percent reduction in Psoriasis Area and Severity Index (PASI) score
at week 12 was achieved by 82 percent of patients in the 300 mg secukinumab group and 72 percent
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of patients in the 150 mg secukinumab group, compared with only 5 percent of patients in the
placebo group. The FIXTURE trial (n = 1306), which incorporated similar doses of secukinumab,
found that secukinumab was superior to both etanercept (50 mg twice weekly for 12 weeks, then
once weekly) and placebo. After 12 weeks, a 75 percent reduction in PASI score was detected in 77
percent of patients in the 300 mg secukinumab group, 67 percent of patients in the 150 mg
secukinumab group, 44 percent of patients in the etanercept group, and 5 percent of patients in the
placebo group. Placebo-controlled randomized trials evaluating the efficacy of secukinumab
administered with an autoinjector or prefilled syringe on moderate to severe psoriasis also support
the drug's efficacy [161,162].
Secukinumab has greater efficacy for moderate to severe plaque psoriasis than ustekinumab with a
similar degree of safety. In a prospective trial (CLEAR trial), 676 adults with moderate to severe
plaque psoriasis were randomly assigned to secukinumab (300 mg given at baseline, week 1, week 2,
and week 3, then every 4 weeks) and ustekinumab (45 mg or 90 mg given at baseline, week 4, and
then every 12 weeks) [163]. After 16 weeks, 90 percent improvement in PASI score occurred in 79
percent of patients in the secukinumab group compared with 58 percent of patients in the
ustekinumab group. The rates of adverse effects were similar in the two groups. An analysis of
additional data from the CLEAR trial revealed that with continued treatment, the greater efficacy of
secukinumab persists for at least 52 weeks [164]. At week 52, 76 percent of patients in the
secukinumab group achieved at least 90 percent improvement in the PASI score compared with 61
percent in the ustekinumab group. Safety was comparable between the two groups.
Secukinumab demonstrated less long-term efficacy than guselkumab in a randomized trial. (See
'Guselkumab' below.)
Ixekizumab — In March 2016 the FDA approved ixekizumab, a humanized monoclonal antibody
against IL-17A, for the treatment of moderate to severe plaque psoriasis in adults. Phase III trials
support the efficacy of ixekizumab [169-174]. Standard dosing for ixekizumab is 160 mg at week 0,
followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12. Subsequently, 80 mg are given every four weeks.
Ixekizumab is also effective for psoriatic arthritis. (See "Treatment of psoriatic arthritis", section on
'Ixekizumab'.)
In the UNCOVER-2 (n = 1224) and UNCOVER-3 (n = 1346) trials, patients with moderate to severe
plaque psoriasis were randomly assigned to receive 80 mg of ixekizumab every two weeks after a
160 mg starting dose, 80 mg of ixekizumab every four weeks after a 160 mg starting dose,
etanercept (50 mg twice weekly), or placebo in a 2:2:2:1 ratio [169]. At week 12, more patients treated
with ixekizumab every two weeks or ixekizumab every four weeks achieved PASI 75 than patients
treated with etanercept or placebo. In UNCOVER-2, PASI 75 rates were 90, 78, 42, and 2 percent,
respectively. PASI 75 rates in UNCOVER-3 were 87, 84, 53, and 7 percent, respectively. In a third
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phase III trial (UNCOVER-1, n = 1296) that compared the same two- and four-week dose regimens for
ixekizumab to placebo, PASI 75 rates at week 12 were 89, 83, and 4 percent, respectively [170].
The 12-week induction periods in the UNCOVER trials were followed by 48-week extension periods.
In UNCOVER-1 and UNCOVER-2, patients who responded to ixekizumab at week 12 (clear or minimal
psoriasis on static Physician Global Assessment) were randomly reassigned to receive 80 mg of
ixekizumab every four weeks, 80 mg of ixekizumab every 12 weeks, or placebo. At the week 60 time
point, 74, 39, and 7 percent of patients, respectively, still had clear or minimal psoriasis. Patients in
UNCOVER-3 continued ixekizumab at a dose of 80 mg every four weeks after the induction period at
the discretion of the investigator and patient. At week 60, clear or minimal psoriasis rates among
patients initially treated with ixekizumab every two weeks and every four weeks were 75 and 73
percent, respectively. The rates of serious adverse effects were similar in the ixekizumab and
placebo groups. Overall, neutropenia, candidal infection, and inflammatory bowel disease occurred in
12, 3, and less than 1 percent of all patients exposed to ixekizumab during weeks 0 to 60,
respectively. Neutropenia was generally transient and did not result in cessation of ixekizumab.
Brodalumab — Brodalumab, an anti-IL-17 receptor A monoclonal antibody, has high efficacy for
psoriasis. In February 2017, the FDA approved brodalumab for the treatment of moderate to severe
plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have
failed to respond or have lost response to other systemic therapies [175]. Recommended dosing is
210 mg given at weeks 0, 1, and 2 and then every two weeks. In the United States, use of the drug will
require participation in a Risk Evaluation and Mitigation Strategy program due to concerns regarding
risk for suicidal ideation and completed suicides in treated patients. However, a causal relationship
between brodalumab treatment and suicidal ideation and behavior has not been confirmed. An
analysis of data from five clinical trials did not find evidence of causality [176].
Data from phase III randomized trials support the efficacy of brodalumab for moderate to severe
plaque psoriasis [177,178]. In two identically designed trials (AMAGINE-2 [n = 1831] and AMAGINE-3
[n = 1881]), patients were assigned in a 2:2:1:1 ratio to receive brodalumab 210 mg every two weeks;
brodalumab 140 mg every two weeks; standard dosing of ustekinumab on day 1, week 4, and then
every 12 weeks (45 mg dose if body weight ≤100 kg, 90 mg dose if body weight >100 kg); or placebo.
At week 12, more patients receiving 210 mg of brodalumab or 140 mg of brodalumab achieved PASI
75 compared with patients in the placebo group (86, 67, and 8 percent, respectively [AMAGINE-2],
and 85, 69, and 6 percent, respectively [AMAGINE-3]). In addition, the rate of complete clearance of
skin disease (PASI 100) at week 12 was higher among patients given 210 mg of brodalumab
compared with patients receiving ustekinumab (44 versus 22 percent, respectively [AMAGINE-2], and
37 versus 19 percent, respectively [AMAGINE-3]). A statistically significant benefit of the 140 mg
dose of brodalumab over ustekinumab for achieving PASI 100 was evident in AMAGINE-3 at week 12
but not in AMAGINE-2. Mild to moderate Candida infections were more frequent in the brodalumab
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groups than in the ustekinumab and placebo groups, and neutropenia occurred more frequently in
the brodalumab and ustekinumab groups than in the placebo group. In addition, two suicides
occurred in patients receiving brodalumab in crossover and open-label phases of AMAGINE-2.
Inhibitors of IL-23 and related cytokines — Antipsoriatic drugs with anti-interleukin 23 (IL-23)
activity include ustekinumab, guselkumab, tildrakizumab, and risankizumab.
Ustekinumab — Ustekinumab is a human monoclonal antibody that targets IL-12 and IL-23.
Ustekinumab is indicated for the treatment of adults and children 12 years and older with moderate
to severe psoriasis who are candidates for phototherapy or systemic therapy. Dosing of ustekinumab
is weight based. Standard dosing for ustekinumab for adults ≤100 kg is 45 mg given at weeks 0, 4,
and every 12 weeks thereafter. A 90 mg dose given in the same regimen is recommended for adults
who weigh more than 100 kg. Ustekinumab can also improve psoriatic arthritis. (See "Treatment of
psoriatic arthritis", section on 'Ustekinumab'.)
Phase III trials have confirmed the efficacy of ustekinumab [179-183]. Examples of phase III trial data
on ustekinumab therapy include:
● In a randomized trial where 766 patients had moderate to severe plaque psoriasis, more patients
treated with ustekinumab 45 mg or 90 mg achieved at least a 75 percent improvement in the
PASI score (PASI 75) at week 12 than those treated with placebo (67 and 66 versus 3 percent)
[179]. Ustekinumab was administered monthly by subcutaneous injection for the first two doses
and then every 12 weeks. Responders who were kept on therapy generally maintained
improvements in psoriasis out to at least 76 weeks. Serious adverse events were seen at similar
rates in the ustekinumab and placebo arms.
● In a second similarly designed trial where 1230 patients had moderate to severe plaque
psoriasis, more patients treated with ustekinumab 45 mg or 90 mg achieved PASI 75 at week 12
than those treated with placebo (67 and 76 versus 4 percent) [180]. Patients who achieved a
partial response at week 28 were randomly assigned to continue every 12 week dosing or
escalate to every 8 week dosing. More frequent dosing did not enhance response rates at one
year in patients receiving 45 mg but did enhance 75 percent improvement rates in those
receiving 90 mg (69 versus 33 percent with continued 12 week dosing). Serious adverse events
were again seen at similar rates in the ustekinumab and placebo arms.
The utility of therapeutic drug monitoring for optimization of response to ustekinumab is under
investigation. A prospective cohort study of 491 adults treated with ustekinumab for psoriasis found
an association between higher serum ustekinumab levels measured 1 to 12 weeks after the start of
treatment and achievement of a PASI 75 response after six months of treatment (odds ratio [OR]
1.38, 95% CI 1.11-1.71) [184]. However, other outcome measures of PASI response assessed in the
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study did not demonstrate a similar correlation. Drug monitoring of ustekinumab levels is neither
required nor a standard component of ustekinumab treatment.
Trial data on the use of ustekinumab in adolescents with psoriasis are limited. A randomized trial of
110 adolescents (ages 12 to 17 years) with moderate to severe psoriasis (CADMUS) found
ustekinumab effective in this population [183]. The response to ustekinumab (0.75 mg/kg if weight
≤60 kg, 45 mg if weight >60 but ≤100 kg, and 90 mg if weight >100 kg) given at weeks 0, 4, and every
12 weeks was similar to the response observed in the adult population.
The efficacy of ustekinumab appears to persist over time. In one of the phase III randomized trials
above [179], ustekinumab maintained a high level of efficacy over three years [185]. In addition,
treatment appears to be well tolerated [186,187].
A randomized trial reported superior efficacy of ustekinumab over etanercept for the treatment of
psoriasis [188]. In this trial, 903 patients with moderate to severe psoriasis received 90 mg of
ustekinumab at weeks 0 and 4, 45 mg of ustekinumab at weeks 0 and 4, or 50 mg of etanercept twice
weekly. After 12 weeks, 75 percent improvement in the PASI score was observed in 73.8, 67.5, and
56.8 percent of patients in the 90 mg ustekinumab, 45 mg ustekinumab, and etanercept groups,
respectively. In addition, some patients who did not respond to etanercept benefited from treatment
with ustekinumab. Twelve weeks after crossover to 90 mg of ustekinumab (administered at weeks
16 and 20), 48.9 percent achieved 75 percent improvement in the PASI score. The incidence of
serious adverse effects was similar between treatment groups.
Data are limited on the best methods for transitioning patients from other therapies to ustekinumab.
In a randomized trial (TRANSIT trial) performed in 490 patients with moderate to severe plaque
psoriasis who had insufficient responses to methotrexate, measures of the efficacy and safety of
ustekinumab after 12 weeks were similar among patients who immediately discontinued
methotrexate at the start of ustekinumab therapy and patients who gradually withdrew methotrexate
during the first four weeks after starting ustekinumab [189]. Standard doses of ustekinumab were
given; patients weighing 100 kg or less and patients weighing more than 100 kg were assigned to 45
and 90 mg doses, respectively. The findings of this study suggest that tapering of methotrexate
during the transition to ustekinumab treatment may not be necessary. While there are not extensive
data on the use of ustekinumab with methotrexate in patients with psoriasis, ustekinumab is FDA
approved as a treatment with or without concomitant methotrexate in patients with psoriatic
arthritis. (See "Treatment of psoriatic arthritis".)
Because of its immunomodulatory mechanism of action, there is concern that ustekinumab may
increase the risk for infections and malignancy. However, five-year safety data showed no dose-
related or cumulative sign of increased risk of severe infection or malignancy [186]. Uncommon
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adverse effects that may or may not be drug-related, such as reversible posterior
leukoencephalopathy syndrome and a lymphomatoid drug eruption, have occurred in two separate
patients [190,191]. The development of noninfectious pneumonia (eg, interstitial pneumonia,
eosinophilic pneumonia, organizing pneumonia, hypersensitivity pneumonitis) has also been
infrequently reported in the setting of ustekinumab therapy [192].
Although ustekinumab was effective for psoriatic arthritis in randomized trials, concern has been
raised about whether psoriatic arthritis may worsen in certain patients during ustekinumab therapy.
A case series documents four patients with psoriasis in whom psoriatic arthritis flared during
ustekinumab therapy [193]. (See "Treatment of psoriatic arthritis".)
Reports of major adverse cardiovascular events (MACE) during phase II and III studies for
ustekinumab and briakinumab, another anti-IL-12/23 agent, led to the performance of a meta-
analysis of placebo-controlled randomized trials evaluating the relationship between anti-IL-12/23
therapy and major adverse cardiovascular events in patients with chronic plaque psoriasis [194]. The
meta-analysis found that more major adverse cardiovascular events were reported in patients who
received active treatment with ustekinumab or briakinumab than in those who received placebo (10
out of 3179 patients versus 0 out of 1474 patients). Although the difference in events was not
statistically significant, the trial lengths were short (12 to 20 weeks), and the meta-analysis may have
been underpowered to detect a significant difference.
A review of pooled data from phase II and phase III trials with up to five years follow-up did not reveal
an increased risk for major adverse cardiovascular events [186]. In addition, analysis of data from a
large observational study of patients receiving or eligible to receive systemic therapy for psoriasis
(PSOLAR) did not find an association between ustekinumab therapy and major adverse
cardiovascular events [123].
Anti-ustekinumab antibodies have been reported to occur in 4 to 6 percent of patients treated with
ustekinumab for psoriasis; however, an effect of anti-ustekinumab antibody formation on treatment
efficacy remains to be confirmed [132].
Guselkumab — Guselkumab is a human immunoglobulin G1 (IgG1) lambda monoclonal

antibody that binds to the p19 subunit of IL-23. IL-39 also contains this p19 subunit. The mechanism
of action in psoriasis is thought to involve inhibition of IL-23 signaling. Recommended dosing for
guselkumab is 100 mg at weeks 0, 4, and then every eight weeks. Guselkumab appears to have
efficacy for psoriatic arthritis and is being evaluated for this indication.
Guselkumab was effective for psoriasis in phase III randomized trials [195-197]. In the 48-week
VOYAGE 1 trial, 837 adults with moderate to severe plaque psoriasis were randomly assigned in a
2:1:2 ratio to guselkumab (100 mg at weeks 0, 4, then every 8 weeks), placebo (given at weeks 0, 4,
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and 12) followed by guselkumab (100 mg at weeks 16 and 20, then every 8 weeks), or adalimumab
(80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks) [196]. At week 16, more patients
treated with guselkumab achieved at least 90 percent improvement in the PASI score (PASI 90) than
patients in the adalimumab or placebo groups (73, 50, and 3 percent, respectively). Guselkumab
remained more effective than adalimumab after 48 weeks. Adverse effects were comparable among
the treatment groups.
The initial 24 weeks of the 48-week phase III VOYAGE 2 trial (n = 992) involved random assignment
of adults with moderate to severe plaque psoriasis in a 2:1:1 ratio to guselkumab, placebo followed
by guselkumab, or adalimumab groups, with dosing regimens similar to those in VOYAGE 1 [197]. As
in VOYAGE 1, guselkumab was more effective than adalimumab and placebo at week 16. At week 28,
patients either continued (or started) guselkumab or transitioned to placebo followed by guselkumab
upon loss of response. Guselkumab-treated patients who had achieved at least PASI 90 were
rerandomized to one of these groups. Among the rerandomized patients, continued therapy was
associated with greater maintenance of response than withdrawal; 89 versus 37 percent maintained
PASI 90 through week 48 in the continued therapy and withdrawal groups, respectively.
In another phase III trial (the NAVIGATE trial), guselkumab was effective in patients with moderate to
severe plaque psoriasis who had inadequate responses to ustekinumab [195].
Guselkumab showed greater long-term efficacy than secukinumab in a phase 3 trial (ECLIPSE trial)
in which 1048 adults with moderate to severe plaque psoriasis were randomly assigned to either
guselkumab (100 mg at weeks 0 and 4, then every 8 weeks) or secukinumab (300 mg at weeks 0, 1,
2, 3, and 4, then every 4 weeks) [198]. In the trial, 84 percent of patients in the guselkumab group
achieved the primary trial endpoint of a PASI 90 response at week 48 compared with 70 percent of
patients in the secukinumab group, despite a more rapid initial response in the secukinumab group.
Although both treatments were generally well tolerated and had similar numbers of adverse events,
there were three occurrences of Crohn disease in the secukinumab group compared with none in the
guselkumab group and six diagnoses of nonmelanoma skin cancer in the guselkumab group
compared with two in the secukinumab group. The findings of this trial support the selection of
guselkumab over secukinumab when a high likelihood of greater long-term control of psoriasis is
desired. However, factors such as tolerance of treatment risks, cost, and drug availability also
influence the selection of a biologic therapy for psoriasis.
Upper respiratory tract infections, tinea and herpes simplex virus infections, arthralgia, diarrhea, and
gastroenteritis are the most common adverse effects of guselkumab.
Tildrakizumab — Tildrakizumab is a human immunoglobulin G1 (IgG1) kappa monoclonal

antibody that binds to the p19 subunit of IL-23. In 2018, the FDA approved tildrakizumab for the
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treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic
therapy or phototherapy. Recommended dosing is 100 mg given subcutaneously at weeks 0 and 4
and then every 12 weeks.
Phase III trials (reSURFACE 1, reSURFACE 2) support superiority of tildrakizumab compared with
placebo and etanercept [199]. In reSURFACE 1, 772 adults with moderate to severe plaque psoriasis
were randomly assigned to receive tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo at weeks
0 and 4 and then every 12 weeks. After 12 weeks, 62, 64, and 6 percent of patients in the 200 mg, 100
mg, and placebo groups, respectively, achieved PASI 75. The reSURFACE trial randomly assigned
1090 patients to similar groups plus an etanercept group. After 12 weeks, 66, 61, 6, and 48 percent of
patients in the tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, and etanercept groups,
respectively, achieved PASI 75. Rates of serious adverse effects were similar among the groups in
both reSURFACE1 and reSURACE2. One patient in the tildrakizumab 100 mg group died of an unclear
cause during reSURFACE 2.
Risankizumab — Risankizumab is a humanized monoclonal antibody directed against the p19

subunit of IL-23 and IL-39 [200]. In 2019, the FDA approved risankizumab for the treatment of
moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or
phototherapy. Recommended dosing for risankizumab is 150 mg at week 0 and week 4, then every
12 weeks.
Risankizumab had greater efficacy than ustekinumab and placebo in phase III trials. In the 16-week
blinded phase of the 52-week UltIMMA-1 (n = 506) and UltIMMa-2 (n = 491) trials, patients with
moderate to severe plaque psoriasis were randomly assigned to risankizumab (150 mg),
ustekinumab (45 or 90 mg based upon weight), or placebo in a 3:1:1 ratio [201]. Doses in this phase
were given at zero and four weeks. In UltIMMa-1, 75, 42, and 5 percent of patients, respectively,
achieved 90 percent improvement in the PASI score at 16 weeks. In UltIMMa-2, 75, 48, and 2 percent
achieved this endpoint, respectively. Overall, the proportion of adverse effects was similar among the
three groups; however, infections were more frequent in the risankizumab and ustekinumab groups
than in the placebo group.
Risankizumab was more effective for plaque psoriasis than adalimumab in a randomized trial. In a
phase III trial (IMMvent trial) in which 605 adults with moderate to severe chronic plaque psoriasis
were randomly assigned to either risankizumab (150 mg at weeks 0 and 4, then every 12 weeks) or
adalimumab (80 mg at week 0, then 40 mg at week 1 and every other subsequent week), 72 percent
of patients in the risankizumab group achieved 90 percent improvement in the PASI score (PASI 90)
by week 16, compared with 47 percent of patients given adalimumab [202]. Risankizumab was also
more effective than adalimumab in a second phase in which 109 intermediate responders to
adalimumab were rerandomized to either risankizumab or continuation of adalimumab (66 versus 21
1307
percent achievement of PASI 90 at week 44, respectively). Adverse effect rates were similar between
risankizumab and adalimumab groups.
Other — Itolizumab, a monoclonal antibody against the T cell costimulator CD6, is a biologic agent
that is available for the treatment of psoriasis in India. Itolizumab is not available in the United
States.
The findings of a phase III trial support the superiority of itolizumab compared with placebo for the
treatment of moderate to severe plaque psoriasis [203]. However, response rates in the phase III trial
were lower than those reported in phase III trials of infliximab, adalimumab, and ustekinumab
therapy [137,148,179,180]. The efficacy of itolizumab has not been directly compared with other
biologic agents.
Other immunosuppressive agents — Other immunosuppressive agents are sometimes used in

selected cases of severe psoriasis [103]. These drugs include hydroxyurea, 6-thioguanine, and
azathioprine, which have a place in the treatment of psoriasis when other systemic modalities
cannot be used, and tacrolimus, which is similar to cyclosporine and requires larger studies before it
can be considered an accepted alternative [82]. Daclizumab, which is used for prevention of renal
transplant rejection, and the cancer chemotherapeutic drug paclitaxel are also under investigation
for use in severe psoriasis [204,205]. Abatacept, a drug used for psoriatic arthritis, has modest
benefit in psoriasis [206].
Fumaric acid esters — Fumaric acid esters (fumarates) have been used to treat psoriasis in Northern
Europe [207]. A systematic review of randomized trials found evidence to support superior efficacy
of fumaric acid esters compared with placebo for psoriasis; however, the quality of the evidence was
low overall [208]. In a randomized trial of 60 patients with moderate to severe psoriasis, reductions in
disease severity after treatment with fumaric acid esters were similar to those observed with
methotrexate therapy [209]. Additional trials of fumarates are being performed.
Lymphopenia is an occasional side effect of treatment with fumaric acid esters. In 2013, two cases
of progressive multifocal leukoencephalopathy (PML) were reported in patients who continued to
receive long-term fumaric acid ester therapy despite the development of severe lymphopenia
[210,211]. These patients did not have other known causes of immunodeficiency. PML in the setting
of fumaric acid therapy for psoriasis has also been reported in a patients without severe
lymphocytopenia [212,213].
TONSILLECTOMY
1308
An association between psoriasis (especially guttate psoriasis) and streptococcal infection has
contributed to investigations of the role of tonsillectomy for the treatment of psoriasis. (See "Guttate
psoriasis", section on 'Pathogenesis'.)
A systematic review that evaluated data on tonsillectomy for guttate or plaque psoriasis from
controlled and observational studies (including case reports and case series) found that the majority
of reported patients experienced improvement in psoriasis after tonsillectomy (290 of 410 patients)
[214]. Lengthening of psoriasis remissions and improvement in response to treatments for psoriasis
were also documented. However, data were insufficient to recommend the routine use of
tonsillectomy for psoriasis because most of the patient data were derived from case reports and
case series and publication bias may have contributed to the favorable results. Further study is
necessary to confirm the effects of tonsillectomy on psoriasis.
Given the limitations of the available data, tonsillectomy should be reserved for select patients with
recalcitrant psoriasis that clearly exhibits exacerbations related to episodes of tonsillitis [214].
Tonsillectomy is not a benign procedure; infection, hemorrhage, laryngospasm, bronchospasm,
temporomandibular joint dysfunction, vocal changes, and rarely airway compromise are potential
adverse effects [214]. Relapse after tonsillectomy is also possible.
Because of the potential morbidity associated with tonsillectomy, a method to determine which
patients are most likely to benefit from the procedure would be of value. Homozygous HLA-Cw*0602
carriage appeared to correlate with greater benefit from tonsillectomy in a prospective cohort study
of 28 patients with moderate to severe chronic plaque psoriasis and a history of psoriasis
exacerbations in association with sore throat and/or streptococcal throat infections [215]. Among
the 4 HLA-Cw*0602 homozygotes, 17 HLA-Cw*0602 heterozygotes, and 7 HLA-Cw*0602 negative
patients, the Psoriasis Area and Severity Index scores fell by 82, 42, and 31 percent, respectively,
during the 24-month follow-up period. Additional study is necessary to determine whether HLA-
Cw6*0602 carriage is a reliable predictor of the response to tonsillectomy.
DIET
There has been uncertainty regarding the role of dietary interventions in the treatment of psoriasis. In
2018, based upon a systematic review of the literature, the Medical Board of the National Psoriasis
Foundation released dietary recommendations for adults with psoriasis [216]. The authors found
high-quality evidence to support weight reduction with a hypocaloric diet as an adjunct to standard
medical therapy for overweight or obese adults (body mass index [BMI] ≥25) with psoriasis as well
as a gluten-free diet in individuals with psoriasis and confirmed celiac disease. In addition, the board
suggested a three-month trial of a gluten-free diet as an adjunct to standard medical therapy in
1309
adults with psoriasis who test positive for serologic markers of gluten sensitivity. Of note, universal
screening of individuals with psoriasis for gluten sensitivity was discouraged in favor of limiting
screening to individuals with a first-degree relative with celiac disease or active gastrointestinal
symptoms. There was insufficient evidence of efficacy to recommend supplements, including fish
oil, vitamin D, selenium, and vitamin B12, for psoriasis.
Additional study is also necessary to explore the effects of specific dietary patterns on psoriasis
[216]. A French web-based questionnaire cohort study found an inverse association between
psoriasis severity and the degree of adherence to the Mediterranean diet (a diet high in fruits,
vegetables, legumes, cereals, bread, fish, fruit, nuts, and extra-virgin olive oil) [217]. However, data are
insufficient to confirm a beneficial effect of this diet. (See "Healthy diet in adults", section on
'Mediterranean diet'.)
EMERGING THERAPIES
There are multiple therapies under investigation for the treatment of psoriasis. These therapies are
designed to mediate psoriasis through a variety of mechanisms.
● Therapies targeting the Th17 pathway – Interleukins (ILs) in the Th17 pathway (IL-23 and IL-17)
play a pivotal role in the pathogenesis of psoriasis and have become targets for drug
development. Drugs targeting the Th17 pathway, such as bimekizumab (a humanized
monoclonal antibody targeting IL-17A and IL-17F), are under investigation for psoriasis [218].
● Small molecules – Other potential therapies include various small molecules that target the
interruption of cellular signaling; such signaling is critical to propagation of the inflammatory
response. Examples of small molecules that are being studied for the treatment of psoriasis
include molecules that block Janus kinases (JAKs) [219-222], lipids [223], a protein kinase C
inhibitor [224], a selective tyrosine kinase 2 (TYK2) inhibitor [225], and crisaborole, a topical
phosphodiesterase 4 inhibitor.
• Oral tofacitinib, a small molecule JAK inhibitor approved and marketed for the treatment of
rheumatoid arthritis, was effective for moderate to severe plaque psoriasis in randomized
trials [220,221,226-228]. In a phase III trial that randomly assigned 1106 adults with
moderate to severe plaque psoriasis to treatment with tofacitinib 10 mg twice daily,
tofacitinib 5 mg twice daily, etanercept (50 mg twice weekly), or placebo, tofacitinib 10 mg
twice daily was superior to placebo and noninferior to etanercept for achieving 75 percent
improvement in PASI score [226]. By week 12, 64, 40, 59, and 6 percent of patients treated
with tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, etanercept, and placebo
achieved this endpoint, respectively. Tofacitinib 10 mg twice daily and tofacitinib 5 mg twice
1310
daily were effective for chronic plaque psoriasis in other phase III trials [227]. The best
results are achieved with 10 mg twice-daily dosing.
The onset of effect of tofacitinib can be fairly rapid, with responses evident by week 4, and
there are data to support the efficacy of tofacitinib through two years [228]. Treatment is
generally well tolerated [229]. Tofacitinib may increase risk for infection. Elevations of
cholesterol and creatine phosphokinase levels also may occur during therapy [226,227].
In addition, a phase II randomized trial found that a topical formulation of tofacitinib was
more effective for plaque psoriasis than vehicle [220].
• Baricitinib, another oral reversible inhibitor of JAK1/JAK2 tyrosine kinases, has been
evaluated for the treatment of moderate to severe psoriasis in a phase II, dose ranging,
randomized trial [230]. In this study, 271 patients were randomly assigned to treatment with
daily doses of baricitinib 2, 4, 8, or 10 mg, or placebo. At 12 weeks, more patients in the
baricitinib 8 and 10 mg groups than those in the placebo group achieved a 75 percent
improvement in the PASI score from baseline (43, 54, and 17 percent, respectively). Adverse
effects were more common among patients receiving the highest baricitinib doses and
included infections, lymphopenia, neutropenia, anemia, and elevation of creatine
phosphokinase.
• In a phase II trial (n = 268), selective inhibition of TYK2, an intracellular signaling enzyme

involved in the pathogenesis of psoriasis, with the experimental agent BMS-986165 was
associated with clinical improvement in adults with moderate to severe psoriasis [225].
Participants were randomly assigned to one of five dose regimens for BMS-986165 or
placebo. After 12 weeks, more patients receiving 3 mg daily, 3 mg twice daily, 6 mg twice
daily, or 12 mg daily of BMS-986165 achieved 75 percent improvement in the PASI score
than patients in the placebo group (39, 69, 67, 75, and 7 percent, respectively). A dose of 3
mg every other day was not superior to placebo. Adverse effects were more common in the
active treatment groups. The most common adverse effects were nasopharyngitis,
headache, diarrhea, nausea, and upper respiratory infection. In addition, mild to moderate
acne was more frequent in the active treatment groups, and one diagnosis of melanoma
occurred in the 3 mg daily group.
• Targeting of the sphingosine 1-phosphate receptor 1 (S1PR1), a receptor involved in the

movement of lymphocytes from secondary lymphoid tissues into the circulation, may be an
additional effective method to treat psoriasis. Ponesimod, a selective modulator of S1PR1
also studied for the treatment of multiple sclerosis, induces internalization of S1PR1,
thereby inhibiting sphingosine 1-phosphate (S1P)-induced egress of lymphocytes. In a
1311
phase II randomized trial that evaluated ponesimod in 326 patients with moderate to severe
chronic plaque psoriasis, patients treated with ponesimod were significantly more likely
than patients treated with placebo to achieve a 75 percent reduction in PASI score after 16
weeks [231].
• In small, uncontrolled studies, treatment with a glucagon-like peptide 1 (GLP-1) analog

(exenatide or liraglutide) seemed to promote modest improvement in psoriasis in patients
with both psoriasis and type 2 diabetes [232,233]. However, a placebo-controlled
randomized trial (n = 20) found liraglutide ineffective for plaque psoriasis [234].
• In case reports, treatment with crisaborole, a topical phosphodiesterase 4 inhibitor, has

been associated with improvement in facial psoriasis, intertriginous psoriasis, and
palmoplantar psoriasis manifesting as erythematous plaques, papules, and deep-seated
pustules on the palms and soles [235,236].
● Topical calcineurin inhibitor – Historically, poor efficacy of topical cyclosporine for plaque
psoriasis has been attributed to poor topical absorption. In a small randomized trial, a novel
formulation of topical cyclosporine using liposomal carriers to improve penetration of the
stratum corneum was effective for limited chronic plaque psoriasis [237].
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
1312
● Basics topics (see "Patient education: Psoriasis (The Basics)" and "Patient education: Topical
corticosteroid medicines (The Basics)")
● Beyond the Basics topics (see "Patient education: Psoriasis (Beyond the Basics)")
The National Psoriasis Foundation is a nonprofit organization that provides useful information to
patients with psoriasis and their clinicians. Membership includes access to a newsletter that
provides information on current areas of research and new treatments. Brochures on various forms
of psoriasis treatment (topical, phototherapy, systemic agents) and specific fact sheets on each
biologic treatment are available from the Foundation and its website.
National Psoriasis Foundation
6600 SW 92nd Ave., Suite 300
Portland, OR 97223-7195
1-800-723-9166
www.psoriasis.org
Numerous topical and systemic therapies are available for the treatment of psoriasis. Treatment
modalities are chosen on the basis of disease severity, relevant comorbidities, patient preference
(including cost and convenience), efficacy, and evaluation of individual patient response. (See
'Approach' above.)
● Psoriasis can have negative psychosocial effects. Clinicians should address the psychosocial
needs of patients with psoriasis. The National Psoriasis Foundation provides extensive
resources to help patients with psychosocial problems and to educate patients on their
treatment options. (See 'Psychosocial aspects' above.)
● We suggest that patients with limited plaque psoriasis be initially treated with topical
corticosteroids and emollients (Grade 2B). (See 'Limited disease' above.)
Alternatives include tar, topical retinoids (tazarotene), topical vitamin D, and anthralin. For facial
or intertriginous areas, topical tacrolimus or pimecrolimus may be used as alternatives or as
corticosteroid sparing agents. Improvement can be anticipated within one or two months.
Combination regimens may be required, including localized phototherapy. Patient adherence
may be the largest barrier to treatment success with topical therapies; early follow-up (one week
1313
after starting treatment) may improve compliance. (See 'Topical therapies' above and 'Ultraviolet
light' above.)
● We suggest that most patients with moderate to severe plaque psoriasis be initially treated with
phototherapy if feasible and practical (Grade 2B). (See 'Moderate to severe disease' above.)
The topical therapies discussed above are generally also required as adjuvant therapy and for
symptomatic relief (see 'Topical therapies' above). In patients with contraindications to
phototherapy or who have failed phototherapy, we suggest treatment with a systemic agent
(Grade 2B).
Financial considerations or time constraints may also make systemic therapy preferable to
phototherapy for some patients. Systemic agents include retinoids, methotrexate, cyclosporine,
apremilast, and biologic immune modifying agents such as etanercept, adalimumab, infliximab,
certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, guselkumab,
tildrakizumab, and risankizumab. Treatment of psoriatic arthritis is discussed in detail
separately. (See "Treatment of psoriatic arthritis".)
Improvement should be observed within weeks. Patients with moderate to severe psoriasis on
systemic treatment will generally require care by a dermatologist. (See 'Moderate to severe
disease' above.)
For patients receiving methotrexate for the management of psoriasis, the decision to perform a
liver biopsy should be individualized based upon a patient's risk factors, liver chemistry results,
and cumulative methotrexate dose, in accord with updated guidelines from the American
Academy of Dermatology. (See 'Hepatotoxicity and liver biopsy' above.)
1314
GRAPHICS
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2) ¶
Betamethasone Ointment Diprosone 0.05
dipropionate
formulation (AF)
Gel Topicort 0.05

¶
Fluocinonide Cream, gel, ointment, Lidex 0.05
solution

¶ ¶
High potency Amcinonide Cream Cyclocort , Amcort 0.1
(group 3) ¶
Lotion Amcort 0.1

Foam Luxiq 0.12

¶
Diflorasone diacetate Cream Florone 0.05

States)
¶
1315
emollient

Kenalog ¶, Triderm


solution

¶
Ointment Kenalog 0.1

spray


¶
Desonide Ointment DesOwen, Tridesilon 0.05
Gel Desonate 0.05

solution Lipocream

probutate

ointment

¶
Ointment Kenalog 0.025


¶
Desonide Cream DesOwen, Tridesilon 0.05
Foam Verdeso 0.05

¶
Fluocinolone acetonide Cream, solution Synalar 0.01
Shampoo Capex 0.01
Δ
1316
Body, Derma-
Smoothe/FS Scalp

¶
Least potent Hydrocortisone (base, Cream, ointment Hytone, Nutracort 2.5
(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1317
Erythrodermic psoriasis in adults

Authors: Jason E Hawkes, MD, MS, FAAD, Kristina Callis Duffin, MD
Section Editor: Jeffrey Callen, MD, FACP, FAAD
INTRODUCTION
Erythrodermic psoriasis is an uncommon, severe variant of psoriasis that is characterized by widespread

erythema of the skin. Patients with this psoriasis subtype typically present with erythema involving more than
75 percent of the body surface area and associated scale, pustules, or exfoliation of the skin (picture 1A-C).
Recognition of this potentially life-threatening form of psoriasis is imperative. A detailed history and thorough
evaluation of the patient are necessary to establish a diagnosis and rule out conditions that closely mimic
erythrodermic psoriasis. (See "Erythroderma in adults" and "Neonatal and infantile erythroderma".)
The clinical manifestations, diagnosis, and management of erythrodermic psoriasis will be discussed here.
Other variants of psoriasis are reviewed separately.
● (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

● (See "Treatment of psoriasis in adults".)
EPIDEMIOLOGY
Psoriasis is estimated to affect approximately 3 percent of the adult population in the United States [1]. There
are several psoriasis subtypes, including chronic plaque, psoriatic arthritis, inverse, guttate, pustular, and
erythrodermic variants. Erythrodermic psoriasis is the least common psoriasis subtype and occurs in less
than 3 percent of patients [2]. Some experts have suggested that the distinction between pustular and
erythrodermic psoriasis is arbitrary given their frequent co-occurrence and overlapping clinical features. (See
1318
"Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis" and 'Clinical manifestations'
below.)
The age of onset of erythroderma is highly variable. In a series of 50 patients with erythrodermic psoriasis,
the average age of onset was 48 years [3]. There appears to be a slight predilection for males in adulthood
[3]; however, detailed epidemiologic data for this condition are limited due to its rarity.
PATHOGENESIS
Similar to other psoriasis variants, erythrodermic psoriasis is the result of a complex interaction between the
skin, environmental and genetic factors, and the immune system. Few studies have examined the molecular
mechanisms driving the development of this disease variant, and the immunopathogenesis is not fully
understood. (See "Pathophysiology of plaque psoriasis".)
A study evaluating the gene expression profiles of involved skin from patients with chronic plaque, inverse,
and erythrodermic variants of psoriasis found similarities among these variants, suggesting a shared
pathway for disease development [4]. More than 95 percent of the differentially expressed genes in
erythrodermic psoriasis were also differentially expressed in plaque psoriasis. Differential expression of
genes relating to the interleukin-17A signaling pathway accounted for the greatest amount of similarity
between plaque and erythrodermic psoriasis. However, differences in the T helper cell (Th) populations and
inflammatory cytokines isolated from the blood of patients with erythrodermic psoriasis compared with
plaque psoriasis have also been described [5,6].
A shared pathway for erythroderma is suggested based upon a study that compared the immunophenotypic
features of psoriasis and atopic dermatitis. Although the study found significant differences in the Th1:Th2
ratio between chronic psoriasis and chronic atopic dermatitis, no differences in the Th1, Th2, Th17, and Th22
cell populations were observed between erythrodermic psoriasis and erythrodermic atopic dermatitis [7].
RISK FACTORS
The major risk factors for erythrodermic psoriasis are a personal or family history of psoriasis, medication
exposure (particularly systemic glucocorticoids), and medical illness.
● History of psoriasis – The majority of patients with erythrodermic psoriasis have a known personal or
family history of psoriasis [3]. Importantly, erythrodermic psoriasis may be the initial presentation of
psoriasis.
● Medications – The most important medication-associated trigger of erythrodermic psoriasis is

treatment with systemic glucocorticoids or the abrupt withdrawal of systemic antipsoriatic medications
such as methotrexate and cyclosporine [3,8]. Erythrodermic psoriasis can also be triggered by an
administration of antipsoriatic medications, such as oral and topical retinoids (eg, acitretin and
tazarotene), methotrexate, cyclosporine, and overuse of topical corticosteroids (ie, use of more than 60 g
1319
per week of a high-potency topical corticosteroid) [3]. Other medications associated with the
development of erythrodermic psoriasis include tumor necrosis factor (TNF)-alpha inhibitors [9,10],
trimethoprim-sulfamethoxazole [11], bupropion [12], and pegylated interferon-alpha with ribavirin [13].
● Infection – Infections have been proposed as triggers for erythrodermic psoriasis. In particular, patients
with human immunodeficiency virus (HIV) infection have increased risk for erythrodermic psoriasis. The
severity of psoriasis in HIV-infected patients positively correlates with the level of immunosuppression
[14].
Other factors that have been reported to trigger erythrodermic psoriasis include burns from phototherapy or
photochemotherapy treatments [3], stress [3,15], alcohol consumption [3], and application of topical irritants
(eg, coal tar, dithranol, and thiuram-containing rubber gloves ) [3,16,17]. Case reports suggest that
hypocalcemia can trigger erythrodermic [18] or pustular forms of psoriasis [19,20]. However, the relationship
between psoriasis and serum calcium levels is unclear.
The hallmark of erythrodermic psoriasis is the development of widespread, confluent erythema of the skin
(picture 1A-C). Erythema may develop rapidly (eg, over several days) or in a more gradual manner (eg, over
several weeks). The percentage of body surface area involvement required for a patient to be considered
erythrodermic is ambiguous; definitions range from 75 to more than 90 percent [3,21]. Scaling and exfoliation
of the skin is common and usually develops several days after the onset of erythroderma (picture 2A-D).
There may be associated palmoplantar keratoderma.
The skin is often painful and/or pruritic, particularly in areas with prominent scaling [22]. Photosensitivity
also may be present. Associated extracutaneous findings may include fever, chills, malaise, tachycardia,
arthralgias, and lymphadenopathy [3]. Laboratory abnormalities may include leukocytosis, eosinophilia, and
anemia [3].
Erythrodermic psoriasis often exhibits pustules, similar to those occurring in pustular psoriasis (picture 3A-
B). The pustules commonly involve the extremities. In a series of 50 patients with erythrodermic psoriasis, 14
patients (28 percent) had pustules [3]. Generalized pustular involvement has been reported and is
representative of the overlap between erythrodermic psoriasis and generalized pustular psoriasis. There are
no clinical features that reliably distinguish erythrodermic psoriasis with pustules from generalized pustular
psoriasis. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)
Associated nail disorders are common and range from pitting of the nail plate to more prominent nail
dystrophy and/or separation of the nail from the nail bed (onycholysis). In a series of 50 patients with
erythrodermic psoriasis, 39 (78 percent) had nail disease [3]. (See "Overview of nail disorders", section on
'Surface texture abnormalities' and "Overview of nail disorders", section on 'Defects of nail plate
attachment/nail shedding'.)
1320
DIAGNOSIS
A diagnosis of erythrodermic psoriasis should be considered in all patients presenting with erythroderma (ie,
erythema involving at least 75 percent of the body surface area). The diagnosis is made based upon the
recognition of features of psoriasis in the patient history, physical examination, and/or skin biopsy and the
absence of features indicative of other causes of erythroderma. (See "Erythroderma in adults", section on
'Determination of underlying cause'.)
History and physical examination — A detailed history and full skin examination should be performed with
particular attention to the following features:
● Personal or family history of psoriasis
● History of exposure to potential disease triggers (eg, recent systemic glucocorticoid therapy, abrupt
withdrawal of antipsoriatic medications, or infection)
● Coexistence of other physical features of psoriasis (psoriatic plaques, arthralgias, or psoriatic nail
disease)
When present, these features support a diagnosis of erythrodermic psoriasis; however, their absence does
not exclude the diagnosis. Scale and exfoliation are common associated physical features. Pustules may or
may not be present.
Features that suggest other causes of erythroderma are reviewed in detail separately. (See "Erythroderma in
adults", section on 'Physical examination'.)
Skin biopsy — Performance of a skin biopsy is generally indicated. Skin biopsies can aid in excluding other
causes of erythroderma and are often helpful in establishing a diagnosis of erythrodermic psoriasis in
challenging cases. Features characteristic of psoriasis often are present.
In a retrospective review of biopsies obtained from 45 patients diagnosed with erythrodermic psoriasis,
biopsies from 40 patients (88 percent) had histologic features consistent with psoriasis [23]. Histologic
features of early psoriasis (eg, slight epidermal hyperplasia with a reduced or absent granular layer, focal
parakeratosis, and mild spongiosis) were observed in more than half of patients from this study, whereas the
remaining patients had features of a fully developed (eg, marked epidermal hyperplasia, total loss of the
granular layer, and confluent parakeratosis) or regressing (eg, slight epidermal hyperplasia and a normal or
thickened granular layer) psoriasis plaque. The most common histologic feature observed in this study was
marked dilation and coiling of vessels within the papillary dermis [23]. (See "Erythroderma in adults", section
on 'Skin biopsy and histopathologic examination'.)
Laboratory tests — While no serologic tests confirm the diagnosis of erythrodermic psoriasis, specific
laboratory testing is frequently necessary to guide therapeutic management and exclude other causes of
erythroderma. (See 'Differential diagnosis' below and "Erythroderma in adults", section on 'Laboratory and
imaging tests'.)
1321
Distinguishing erythrodermic psoriasis from other causes of erythroderma is necessary but often
challenging. The patient history, physical findings, and biopsy results aid in narrowing the differential
diagnosis (table 1A-B). (See "Erythroderma in adults", section on 'Etiology' and "Erythroderma in adults",
section on 'Determination of underlying cause'.)
The exacerbation of a preexisting skin disease is the most common etiology of erythroderma, accounting for
more than half of all cases [24,25]. Psoriasis, atopic dermatitis, and seborrheic dermatitis are the most
common associated cutaneous diseases. Knowledge of the clinical features prior to the onset of
erythroderma is often helpful for diagnosis. Features suggestive of atopic dermatitis include an early age of
onset, strong association with allergic rhinitis and asthma, prominent involvement of flexural surfaces, and
disease worsening triggered by xerosis. Seborrheic dermatitis is typically characterized by dry or greasy
flakes of skin, which involve the scalp, eyebrows, glabella, or external ear. (See "Atopic dermatitis (eczema):
Pathogenesis, clinical manifestations, and diagnosis" and "Seborrheic dermatitis in adolescents and adults".)
Adverse drug reactions are another common cause of erythroderma, accounting for approximately 20
percent of patients presenting with erythroderma (table 2) [25]. Examples of other causes of erythroderma in
the differential diagnosis of erythrodermic psoriasis include pityriasis rubra pilaris, cutaneous T cell
lymphoma, paraneoplastic syndrome, graft-versus-host disease in patients with a history of allogenic bone
marrow transplantation, immunobullous disorders, and infections. Erythroderma may also be idiopathic.
A list of causes of erythroderma is provided in a table (table 1A). The approach to determining the underlying
cause of erythroderma is reviewed in detail separately. (See "Erythroderma in adults", section on
'Determination of underlying cause'.)
COMPLICATIONS
Potential complications of erythrodermic psoriasis include hemodynamic, thermoregulatory, and metabolic

disturbances; electrolyte imbalances; infection; and acute respiratory distress syndrome.
● Hemodynamic, metabolic, and thermoregulatory disturbances — Erythroderma is the result of increased

blood flow to the skin and cutaneous vasodilation, which account for the red appearance and warmth of
the skin, respectively. This shunting of blood to the skin results in increased cardiac output and may lead
to complications, such as peripheral edema, high-output cardiac failure, shock, or acute renal failure
[26,27]. In addition, vasodilation and increased skin perfusion lead to fluid loss and subsequent
electrolyte imbalances. Increased protein loss due to exfoliation of the skin has also been described [28],
which may lead to hypoalbuminemia and contribute to the development of peripheral edema.
Patients with erythrodermic psoriasis also exhibit impaired thermoregulation and increased metabolic
demands due to the rapid proliferation of epidermal cells [29]. The inability to properly regulate the
body's temperature results in increased water loss and may lead to electrolyte abnormalities.
1322
● Infection — Due to its exfoliative effect on large amounts of skin, erythrodermic psoriasis is associated
with a defective skin barrier and increased portals for infection. Erythrodermic psoriasis patients are
highly susceptible to skin infections, particularly staphylococcal septicemia [30].
● Acute respiratory distress syndrome (ARDS) — Several reports suggest that erythrodermic psoriasis can
be complicated by ARDS [27,31,32]. The exact etiology of this complication is not known.
MANAGEMENT
Due to a paucity of high-quality studies, there is no consensus on the best treatment algorithm for
erythrodermic psoriasis. Recommendations for management are primarily based upon small uncontrolled
studies, case series, case reports, and the recommendations of psoriasis experts [8,21]. In general,
management should involve:
● A pretreatment evaluation for disease complications and triggers

● Supportive care
● Prompt initiation of systemic antipsoriasis therapy
Pretreatment evaluation — The pretreatment evaluation should include:
● Vital signs, complete skin examination, and physical examination (to assess for signs of hemodynamic
instability or infection)
● Complete blood count with differential
● Comprehensive metabolic panel (to assess fluid and electrolyte status and assess liver and kidney
function)
● Microbiologic studies of cutaneous sites suggestive of infection
The need for additional testing is determined based upon these clinical and laboratory findings and any
baseline laboratory tests required for the selected psoriasis therapy.
The pretreatment evaluation should also include an assessment for potential causative drugs (see 'Risk
factors' above). Triggering drugs should be discontinued whenever feasible. In particular, discontinuation of
systemic glucocorticoids can be challenging, as both the administration and withdrawal of systemic
glucocorticoids can trigger erythrodermic psoriasis. A common approach is a very slow taper of the systemic
glucocorticoid while the patient is receiving systemic psoriasis therapy. (See 'Systemic psoriasis therapy'
below.)
Supportive care — Most patients with erythrodermic psoriasis require hospitalization for close clinical
monitoring, replacement of fluids and electrolytes, and assistance with skin care. The decision to hospitalize
is based upon disease severity and the presence of complications. Hemodynamically stable patients without
rapidly progressing skin disease, significant fluid and electrolyte abnormalities, or concomitant infection are
1323
candidates for outpatient therapy provided they have adequate support at home for skin care, can return for
frequent follow-up, and are in close proximity to a medical facility capable of managing erythrodermic
patients. Patients with severe disease may require admission to the intensive care unit and often benefit from
burn unit care where available.
Supportive measures useful for the management of these patients include:
● Monitoring of body temperature and hemodynamic status

● Fluid and electrolyte replacement as needed
● Nutritional support
● Treatment of associated infections
Skin-directed interventions that may improve skin discomfort and pruritus include [8]:
● Wet dressings
● Skin moisturization
● Oatmeal baths
● Topical corticosteroids (medium-potency topical corticosteroids for trunk and extremities, low-potency
topical corticosteroids for facial and intertriginous areas)
Systemic psoriasis therapy — Initiation of a systemic antipsoriatic drug is essential for attaining disease
control.
Overview — Antipsoriasis therapy should be initiated promptly. The most common drugs prescribed are
cyclosporine, infliximab, acitretin, and methotrexate. Data on the comparative efficacy of these agents are
lacking; therefore, factors such as the severity of disease, patient comorbidities, and drug availability
influence the selection of treatment.
Cyclosporine is widely accepted as the treatment of choice for acute erythrodermic psoriasis based upon
high efficacy, rapid onset of action, wide availability, and ease of administration. Patients with preexisting
renal disease or hypertension are less favorable candidates for cyclosporine therapy given the potential for
cyclosporine-induced nephrotoxicity and hypertension. (See 'Cyclosporine' below.)
Infliximab also has a rapid onset of action and is an accepted alternative to cyclosporine for acute
erythrodermic psoriasis. Downsides of infliximab include the requirement for intravenous infusion and the
high cost of this therapy. (See 'Infliximab' below.)
Acitretin and methotrexate can be effective for erythrodermic psoriasis but are less frequently used as initial
therapy because of a slower onset of action compared with cyclosporine and infliximab. Initial treatment with
these agents is primarily reserved for patients with contraindications to cyclosporine and infliximab or with
subacute disease presentations [8]. (See 'Acitretin' below and 'Methotrexate' below.)
1324
Once disease control is achieved, patients treated with cyclosporine or infliximab are generally transitioned to
other therapies, such as acitretin, methotrexate, or subcutaneously administered biologic therapies. Of note,
limiting the duration of cyclosporine therapy to less than one year is recommended because of risk for
cyclosporine-induced nephrotoxicity. Patients who initially received acitretin or methotrexate and achieved
remission with these drugs can have the dose tapered to the lowest dose necessary to maintain
improvement.
First-line therapies — Cyclosporine and infliximab are the preferred first-line therapies for erythrodermic
psoriasis. However, data on the efficacy of these therapies are limited.
Cyclosporine — Oral cyclosporine may lead to significant improvement within the first few weeks of
treatment.
● Efficacy – In an uncontrolled study of 33 adults with erythrodermic psoriasis given cyclosporine

(maximum initial dose of 5 mg/kg per day), complete remission (total disappearance of erythema and
desquamation) occurred within one year in 22 patients (67 percent), with a median time to remission of
two to four months [33]. An additional 27 percent of patients achieved marked improvement, with at least
a 70 percent reduction in the involved skin area compared with baseline.
● Administration – Cyclosporine is given orally in doses of 3 to 5 mg/kg per day. For patients with severe
disease, 5 mg/kg per day typically is given as initial treatment. Significant improvement often occurs
within the first month [33]. Once remission is achieved, the dose is tapered as tolerated over a few
months.
Risk for cyclosporine-induced nephrotoxicity limits the duration of treatment. Treatment with
cyclosporine should not exceed one year and should be discontinued after three to four months in
patients unresponsive to a dose of 5 mg/kg per day [8,34].
In addition to nephrotoxicity, important adverse effects of cyclosporine include drug interactions,

uncontrolled hypertension, and increased risk for infections and malignancy. Use of cyclosporine in
patients with preexisting renal disease or hypertension should be considered carefully. Such patients
may benefit from alternative therapies. Adverse effects of cyclosporine are reviewed in detail separately.
(See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects' and "Cyclosporine and
tacrolimus nephrotoxicity".)
Baseline and periodic monitoring of blood pressure and laboratory tests is indicated for cyclosporine
therapy. For additional information, refer to the Lexicomp drug information monograph included within
UpToDate.
Infliximab — Infliximab is a common alternative to cyclosporine for acute erythrodermic psoriasis

[8,21]. Similar to cyclosporine, infliximab has a rapid onset of action.
● Efficacy – In a retrospective study that included 24 treatment courses of infliximab in 20 patients with
erythrodermic psoriasis, 50 percent of patients given infliximab achieved at least a 50 percent
1325
improvement in either the Psoriasis Area and Severity Index score or body surface area involvement by
four weeks [35]. Good responses to infliximab have also been documented in a small uncontrolled study
and case reports [36-39].
● Administration – Infliximab is given as the standard regimen recommended for psoriasis (5 mg/kg at
zero, two, and six weeks, followed by 5 mg/kg every eight weeks). Marked improvement can occur within
the first several weeks of treatment. If there is no treatment response observed within four to six weeks,
significant benefit may be less likely to occur. In this scenario, we would transition the patient to
cyclosporine or another treatment.
Potential serious side effects of infliximab include infusion reactions, increased risk for infection,
exacerbations of heart failure, demyelinating disease, and malignancy. Infliximab is contraindicated in
patients with active infections and should be used cautiously in patients with neurologic disorders (eg,
multiple sclerosis), heart failure, or a history of malignancy. Screening for tuberculosis is recommended
prior to infliximab treatment. The adverse effects of infliximab are reviewed in detail separately. (See
"Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
Alternative first-line therapies — Acitretin and methotrexate may be effective for erythrodermic psoriasis
but exhibit a slower onset of action compared with cyclosporine and infliximab. Thus, initial treatment with
these agents is typically reserved for patients who cannot be treated with cyclosporine or infliximab or who
have subacute disease presentations.
Acitretin — Acitretin for erythrodermic psoriasis is typically given in doses of 25 to 50 mg per day. The
maximal effect of acitretin often is not evident for three to six months [34]. If at least partial improvement
does not occur within three months, we discontinue treatment.
Although acitretin is a common treatment for psoriasis, data on efficacy for the erythrodermic variant are
limited. In a 1988 review of data from 12 open or double-blind clinical studies evaluating acitretin for
psoriasis, improvement assessed as at least marked or good occurred in five of the six erythrodermic
patients treated with acitretin [40].
Acitretin can cause hyperlipidemia and hepatotoxicity, and some patients are unable to tolerate the drug due
to side effects such as paresthesias, arthralgias, cheilitis, and xerostomia. Acitretin is teratogenic and should
be avoided in pregnant women and females of child-bearing potential who intend to become pregnant within
three years after discontinuation of treatment. For additional information on side effects and monitoring, refer
to the Lexicomp drug information monograph included within UpToDate.
Methotrexate — Methotrexate is typically given on a weekly basis; adults with erythrodermic psoriasis
are typically treated with a single weekly dose of 7.5 to 25 mg per day. Folic acid supplementation (1 mg per
day) should be given in conjunction with methotrexate therapy.
Initial signs of therapeutic benefit are often evident within the first four weeks of treatment. If there are no
signs of response within four to six weeks, we discontinue methotrexate treatment.
1326
Similar to acitretin, efficacy data for erythrodermic psoriasis are limited. In a retrospective review of 157
psoriasis patients treated with methotrexate, a response rated as a "moderate" or "good" clinical response
was observed in 34 of 36 erythrodermic patients [41].
Gastrointestinal distress is a common side effect of methotrexate. Potential serious adverse effects of
methotrexate include hepatotoxicity, myelosuppression, and pulmonary toxicity. Methotrexate is teratogenic
and is contraindicated during pregnancy. The drug is also contraindicated in patients with active infections,
malignancy, bone marrow suppression, or preexisting kidney or liver disease. Close monitoring for
hematologic and hepatic side effects is essential during methotrexate therapy. For additional information on
side effects and monitoring, refer to the Lexicomp drug information monograph included within UpToDate.
Other therapies — Limited data suggest that etanercept, adalimumab, and other biologic therapies can
be effective for erythrodermic psoriasis. In a multicenter, retrospective review of 24 erythrodermic psoriasis
patients treated with various tumor necrosis factor (TNF)-alpha inhibitors, the efficacy of etanercept and
adalimumab was comparable with infliximab [35]. However, the onset of action of these agents is slower than
for cyclosporine or infliximab [21,42], making them less preferable therapies for erythrodermic psoriasis.
Small studies and case reports provide preliminary support for the use of newer biologic medications for the
treatment of erythrodermic psoriasis, including ustekinumab [43], ixekizumab [44], secukinumab [45], and
golimumab [46]. While these novel therapies represent a group of medications likely to be effective in the
treatment of erythrodermic psoriasis, subsequent larger studies are necessary prior to a recommendation for
the routine use of these therapies.
Severe, refractory disease — Combinations of systemic therapies may be appropriate in severe or

refractory cases of erythrodermic psoriasis (eg, infliximab with methotrexate or acitretin). However, evidence
for this approach is based largely on case reports or small case series [38,47].
The potential benefit of wet dressings with mid-potency topical corticosteroids (eg, triamcinolone 0.1%
cream) should not be discounted in patients with severe disease. Use in combination with systemic
treatments aids in the management of patient symptoms and may promote disease resolution. (See
'Supportive care' above.)
Contraindicated therapies — The use of systemic glucocorticoids for erythrodermic psoriasis is strongly
discouraged due to the ability of systemic glucocorticoids to trigger severe psoriasis flares. Phototherapy is
also generally avoided in erythrodermic patients given the photosensitivity of these patients, though this
recommendation is not absolute. (See 'HIV-infected patients' below.)
Special population — The approach to the treatment of erythrodermic psoriasis differs in human
immunodeficiency virus (HIV)-infected individuals.
HIV-infected patients — Patients infected with HIV are at increased risk for psoriasis, including less
common variants like erythrodermic psoriasis [48]. HIV-associated psoriasis tends to follow a more severe
disease course and is also frequently refractory to conventional antipsoriatic therapies, which primarily target
the T cell-mediated immune response. Therefore, the management of erythrodermic psoriasis in HIV-infected
1327
patients represents a challenging clinical scenario based on their relative immunosuppression, susceptibility
for infections, and severity of symptoms.
We agree with the Medical Board of the National Psoriasis Foundation, which recommends antiretroviral
therapy or ultraviolet (UV) phototherapy as first-line treatments for erythrodermic psoriasis in HIV-positive
patients [49]. The potential benefit of antiretroviral therapy for the treatment of erythrodermic psoriasis is
highlighted in a report of a patient who experienced rapid clearing of his clinical symptoms within two weeks
of initiating antiretroviral therapy despite previous failure to respond to cyclosporine, acitretin, systemic
glucocorticoids, and TNF-alpha inhibitors [50].
Acitretin is recommended as second-line treatment. The use of other conventional psoriasis medications,
such as cyclosporine, methotrexate, and TNF-alpha inhibitors, is based on limited clinical evidence, and they
should be used with caution due to the increased risk of opportunistic infections and bone marrow toxicity
[51,52]. (See 'Acitretin' above and "Treatment selection for moderate to severe plaque psoriasis in special
populations", section on 'HIV infection'.)
PROGNOSIS
Overall, the majority of erythrodermic psoriasis patients respond to one or more available treatment options.
However, prognostic data for this condition are deficient and highly variable, with mortality rates ranging
anywhere from 9 to 64 percent [3,22]. The majority of deaths associated with erythrodermic psoriasis are
attributed to bacterial infections, such as pneumonia or staphylococcal septicemia [30].
● Erythrodermic psoriasis is a potentially life-threatening, rare subtype of psoriasis characterized by

erythema involving more than 75 percent of the body surface area and the presence of scaling,
exfoliation/desquamation, and/or pustules of the skin (picture 1A-C). Systemic signs and symptoms,
including fever, chills, malaise, tachycardia, arthralgias, eosinophilia, anemia, lymphadenopathy, and
photosensitivity, are commonly associated with erythrodermic psoriasis. (See 'Clinical manifestations'
above.)
● More than half of all cases of erythrodermic psoriasis are attributed to the exacerbation of preexisting
psoriasis. Important triggers include medications (eg, the withdrawal of oral or topical corticosteroids
and the discontinuation or abrupt withdrawal of antipsoriatic therapies), infections, alcohol consumption,
and stress. (See 'Risk factors' above.)
● Differentiating erythrodermic psoriasis from other causes of erythroderma is essential but frequently
challenging. The diagnosis is made based upon the recognition of features of psoriasis in the patient
history, physical examination, and/or skin biopsy and the absence of features indicative of other causes
of erythroderma. (See 'Diagnosis' above.)
1328
● Complications of erythrodermic psoriasis include hemodynamic and metabolic disturbances, increased
metabolic requirements, a defective skin barrier, impaired thermoregulation, acute respiratory distress
syndrome (ARDS), and susceptibility to skin infections, specifically staphylococcal septicemia. (See
'Complications' above.)
● Inpatient hospitalization may be necessary for close clinical evaluation, including hemodynamic
monitoring, replacement of fluids and electrolytes, and assistance with the application of wet dressings.
Patients with severe disease may require admission to the intensive care unit and often benefit from
burn unit care where available. (See 'Supportive care' above.)
● Treatment guidelines for erythrodermic psoriasis are based on small uncontrolled studies, case series,
case reports, and expert opinion. Factors such as severity of disease, patient comorbidities, and drug
availability influence the selection of treatment. (See 'Systemic psoriasis therapy' above.)
● We suggest cyclosporine or infliximab as first-line therapy for erythrodermic psoriasis based upon the
rapid onset of action of these therapies (Grade 2C). Acitretin and methotrexate are also first-line
treatment options, though a slower onset of action makes them less preferable agents. (See 'Systemic
psoriasis therapy' above.)
● Additional treatments that may be effective include other tumor necrosis factor-alpha inhibitors (eg,
etanercept and adalimumab) and novel biologic medications (eg, ustekinumab, interleukin-17A
inhibitors) used in the treatment of other psoriasis subtypes. (See 'Other therapies' above.)
1329
GRAPHICS
Confluent, generalized erythema with prominent scale.
Courtesy of Kristina Callis Duffin, MD.
1330
Confluent generalized erythema with prominent scale.
1331
Generalized erythema with scattered areas of exfoliation.
Courtesy of Jason E. Hawkes, MD.
1332
Large patches of erythema with areas of exfoliation.
1333
Macules and patches of erythema with areas of exfoliation.
Courtesy of Jason E Hawkes, MD.
1334
Generalized erythema with overlying white scale on the trunk and upper extremities.
1335
Confluent erythema with thick scale on the bilateral lower extremities.
1336
Generalized pustules arranged in clusters on erythematous skin.
1337
Superficial pustules that coalesce to form "lakes of pus" on erythematous skin.
1338
Causes of erythroderma (exfoliative dermatitis)
Idiopathic erythroderma
Inflammatory dermatoses
Psoriasis
Atopic dermatitis
Dermatitis (other than atopic)
Pityriasis rubra pilaris
Lichen planus
Chronic actinic dermatitis
Papuloerythroderma of Ofuji
Sarcoidosis
Drug reactions
Malignancies: hematologic
Cutaneous T cell lymphoma, Sezary syndrome
Other lymphomas (Hodgkin's, non-Hodgkin's)
Leukemias
Malignancies: solid organ

Renal cell carcinoma
Hepatocellular carcinoma
Lung
Colon
Immunobullous disease
Pemphigus foliaceus, vulgaris
Bullous pemphigoid
Connective tissue disease

Dermatomyositis
Subacute lupus erythematosus
Infections
Scabies
Dermatophytosis
Congenital cutaneous candidiasis
Staphylococcus scalded skin syndrome
Beta-hemolytic streptococcal erythroderma syndrome
Blood disorders
Hypereosinophilic syndrome
Mastocytosis
Graft-versus-host disease (GVHD)
1339
Histopathologic features of erythroderma
Causes of erythroderma Key histopathologic features
Idiopathic erythroderma Nonspecific features including hyperkeratosis, parakeratosis, acanthosis,

and inflammatory infiltrate
Inflammatory dermatoses
Psoriasis Epidermal acanthosis, parakeratosis, Munro microabscesses, dilated

tortuous papillary blood vessels
Atopic dermatitis Acanthosis, hyperkeratosis, spongiosis
Dermatitis (other than atopic) Acanthosis, hyperkeratosis, spongiosis
Pityriasis rubra pilaris Acanthosis, hyperkeratosis, alternating ortho- and parakeratosis

(horizontal and vertical)
Lichen planus Lymphohistiocytic infiltrate with band-like distribution upper dermis;

obscures the dermoepidermal junction
Chronic actinic dermatitis Acanthosis, hyperkeratosis, spongiosis, perivascular chronic

inflammatory cell infiltrate, occasional atypical cerebriform lymphoid
cells
Papuloerythroderma of Ofuji
Sarcoidosis Noncaseating epithelial cell-like granulomas in the deep dermis
Drug reactions Histology varies according to the reaction pattern
In exanthematous type, interface dermatitis, vacuolar changes,

necrotic keratinocytes, inflammatory infiltrate with eosinophils
In Stevens Johnson syndrome/toxic epidermal necrolysis, partial to
full-thickness skin necrosis
Malignancies: hematologic
Cutaneous T cell lymphoma, Sézary syndrome Findings may be subtle and variable. Sézary cells (highly convoluted
cerebriform lymphocytes) along the basal layer, lichenoid infiltrate,
epidermotropism, Pautrier microabscesses. Absence of spongiosis.
Other lymphomas (Hodgkin's, non-Hodgkin's) Atypical lymphocytes in dermis and epidermis
Leukemias Leukemic cells in dermis and epidermis
Malignancies: solid organ Nonspecific, variable findings
Renal cell carcinoma
Hepatocellular carcinoma
Lung
Colon
Immunobullous disease
Pemphigus foliaceus, vulgaris Acantholysis
Bullous pemphigoid Subepidermal separation
Paraneoplastic pemphigus Acantholysis, lichenoid infiltrate, necrotic keratinocytes
Connective tissue disease
Dermatomyositis Interface dermatitis
Subacute lupus erythematosus Interface dermatitis
Infections
Scabies Scabies mite at junction of epidermis and stratum corneum; spongiosis,

dermal lymphocytic infiltrate
Dermatophytosis Hyphae
Congenital cutaneous candidiasis Hyphae and yeast-like forms
Staphylococcus scalded skin syndrome Vesiculation at level of granular cell layer
Beta-hemolytic streptococcal erythroderma syndrome
1340
Blood disorders
Hypereosinophilic syndrome Dermal eosinophilic infiltrates
Mastocytosis Dermal mast cell infiltrates
Graft-versus-host disease (GVHD) Interface dermatitis
Erythroderma occurring in the first year of life (congenital/neonatal/infant): additional diagnoses to be considered
Inherited ichthyoses
Epidermolytic hyperkeratosis (bullous congenital ichthyosiform Hyperkeratosis, acanthosis, superficial vacuolation, clumps of irregular
erythroderma) eosinophilic granules in the granular layer
Nonbullous congenital ichthyosiform erythroderma Acanthosis, hyperkeratosis, focal parakeratosis
Netherton syndrome Epidermal psoriasiform hyperplasia
Rare ichthyoses Hyperkeratosis
Primary immunodeficiencies Nonspecific features including hyperkeratosis, parakeratosis, acanthosis,

Severe combined immunodeficiency (SCID)
Severe combined immunodeficiency - Omenn syndrome (a form of

SCID)
X-linked ectodermal dysplasia with immunodeficiency
Ectodermal dysplasias
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Nonspecific features including hyperkeratosis, parakeratosis, acanthosis,
Miscellaneous
Menkes disease
1341
Drugs most frequently reported as cause of erythroderma
ACE inhibitors (enalapril, lisinopril)
Allopurinol
Bevacizumab
Carbamazepine
Chlorpromazine
Dapsone
Erythropoietin
Gold salts
Hydroxychloroquine
Imatinib
Isoniazid
Penicillin
Phenobarbital
Phenytoin
Piroxicam
Proton pump inhibitors (omeprazole, esomeprazole, pantoprazole)
Retinoids (acitretin, isotretinoin)
Streptomycin
Sulfasalazine
Terbinafine
Thalidomide
Trimethoprim/sulfamethoxazole
Vancomycin
ACE: angiotensin-converting enzyme.
Data from: Grant-Kels JM, Fedeles F, Rothe MJ. Exfoliative dermatitis. In: Fitzpatrick's Dermatology in General Medicine, 8th ed, Goldsmith L, Katz S, Gilchrest B, et al
(Eds), McGraw-Hill, 2012.
1342
Treatment selection for moderate to severe plaque psoriasis in

special populations
Author: April W Armstrong, MD, MPH
INTRODUCTION
Topical therapy is the primary mode of treatment for plaque psoriasis in patients with limited skin
involvement but is often insufficient for patients with moderate to severe plaque psoriasis (psoriasis
involving more than 5 to 10 percent of the body surface area). (See "Treatment of psoriasis in adults",
section on 'Choice of therapy'.)
The major treatment options for moderate to severe psoriasis include phototherapy and systemic
medications. Selection among these treatments must involve consideration of the patient's
comorbidities (table 1).
The approach to the treatment of plaque psoriasis in adult patients with hepatitis B virus infection,
hepatitis C virus infection, HIV infection, latent tuberculosis, and internal malignancy will be reviewed
here. General reviews of plaque psoriasis therapy are provided separately. (See "Treatment of
psoriasis in adults" and "Psoriasis in children: Management of chronic plaque psoriasis".)
OVERVIEW
The major categories of treatments for moderate to severe plaque psoriasis are listed below. Topical
agents are often used in conjunction with these therapies. (See "Treatment of psoriasis in adults".)
● Ultraviolet light phototherapy (see "Treatment of psoriasis in adults", section on 'Ultraviolet

light')
1343
• Narrowband ultraviolet B (UVB) phototherapy
• Broadband UVB phototherapy
• Psoralen plus ultraviolet A (PUVA) phototherapy
● Oral agents (see "Treatment of psoriasis in adults", section on 'Systemic therapies')
• Methotrexate
• Acitretin
• Apremilast (phosphodiesterase-4 inhibitor)
• Cyclosporine
● Biologic agents (see "Treatment of psoriasis in adults", section on 'Biologic agents')
• Etanercept (tumor necrosis factor [TNF]-alpha inhibitor)

• Adalimumab (TNF-alpha inhibitor)
• Infliximab (TNF-alpha inhibitor)
• Ustekinumab (interleukin [IL] 12 and IL-23 inhibitor)
• Secukinumab (IL-17A inhibitor)
• Ixekizumab (IL-17A inhibitor)
• Brodalumab (IL-17RA inhibitor)
• Guselkumab (IL-23 inhibitor)
• Tildrakizumab (IL-23 inhibitor)
• Risankizumab (IL-23 inhibitor)
These therapies have side effects that can be detrimental in patients with certain underlying
diseases. For example, the safety of a potentially hepatotoxic drug, such as methotrexate, is a
concern when treating patients with hepatitic disorders. In addition, the potential adverse effects of
immunosuppressive therapy on patients with chronic infections or malignancies must be
considered.
Selection of the optimal approach to treatment in patients with comorbidities, such as hepatitis B
virus infection, hepatitis C virus infection, HIV infection, latent tuberculosis, and malignancy, is
hampered by limited data on the safety of these treatments in the psoriasis population. Proposed
guidelines have been based upon a combination of published data from patients with psoriasis, data
from studies of similar treatment regimens for other diseases, and expert consensus (table 1) [1-7].
CHRONIC HEPATITIS B VIRUS INFECTION
Hepatitis B virus (HBV) infection is one of the most common chronic viral infections in humans [8,9].
1344
HBV infection is divided into phases that reflect the interplay between virus replication and the host
immune response (figure 1). Laboratory studies are useful for determining the phase of the disease
(table 2A-B). In patients with chronic HBV infection, hepatitis B surface antigen (HBsAg) and
immunoglobulin G (IgG) hepatitis B core antibodies (IgG anti-HBc) persist in serum. Hepatitis e
antigen (HBeAg), a marker of viral replication and infectivity that is usually associated with high
levels of HBV DNA in serum and active liver disease, also may be detected. Upon recovery from HBV
infection, HBsAg is no longer detectable in serum. However, patients with prior infection remain
positive for IgG anti-HBc and are at risk for reactivation of disease during immunosuppressive
therapy, particularly when hepatitis surface antibody (anti-HBs) negative. (See "Hepatitis B virus:
Clinical manifestations and natural history" and "Hepatitis B virus reactivation associated with
immunosuppressive therapy".)
Our approach — Overall, data on the safety of psoriasis therapies in patients with HBV infection are
limited. Consideration of two factors is necessary for selection of a therapeutic agent:
● Does the therapy have direct hepatotoxic effects that can compound the existing viral liver
disease?
● Does the therapy have immunomodulatory effects that may promote viral replication and
reactivation of HBV infection? (See "Hepatitis B virus reactivation associated with
immunosuppressive therapy".)
In patients with moderate to severe plaque psoriasis and HBV infection, we use ultraviolet B (UVB)
phototherapy (preferably narrowband UVB) supplemented with topical therapy as first-line treatment
when it is available and convenient for the patient [2]. Narrowband UVB phototherapy is effective for
psoriasis and has negligible risk for hepatotoxicity, systemic immunosuppression, or other systemic
side effects. (See 'Phototherapy' below.)
If UVB phototherapy is not feasible, we consider systemic therapy (table 1). Preferred systemic
therapies are apremilast and ustekinumab, based upon the mechanism of action of apremilast and
the availability of long-term safety data for ustekinumab (see 'Ustekinumab' below). Secukinumab,
ixekizumab, brodalumab, guselkumab, and tildrakizumab may also be well tolerated based upon their
mechanisms of action, although cautious use of these drugs is indicated because of a paucity of
safety data in this population. Selection amongst these systemic therapies is also based upon
consideration of factors such as other comorbidities, clinician familiarity with specific agents, patient
preference, treatment history, and treatment availability. (See 'Biologic agents' below and 'Oral
agents' below and "Treatment of psoriasis in adults".)
Phototherapy — UVB phototherapy is generally considered safe in patients with HBV infection (table
1). Although the immunosuppressive effects of ultraviolet light are believed to contribute to the
1345
efficacy of UVB phototherapy in psoriasis and the risk for reactivation of HBV infection due to
phototherapy has not been evaluated, the systemic effects of treatment are likely minimal [2,10]. (See
"Treatment of psoriasis in adults", section on 'Ultraviolet light'.)
The lack of need for topical or systemic administration of psoralens has led to a preference for UVB
phototherapy (particularly narrowband UVB phototherapy) as the preferred mode of phototherapy for
psoriasis. Although two one-year studies of patients without hepatitis failed to find statistically
significant histologic differences in pre-psoralen plus ultraviolet A (PUVA) and post-PUVA liver
biopsy specimens [11,12], there have been several reports of liver injury after PUVA therapy [13-17].
In addition, severe liver disease is a relative contraindication for treatment with PUVA (table 3). (See
"Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
Oral agents — Treatment with methotrexate or acitretin is generally avoided in patients with HBV
infection. Limited data suggest apremilast is well tolerated. Cyclosporine should be used with
caution (table 1).
● Methotrexate – Reactivation of HBV infection resulting in fulminant hepatic failure has been
documented in case reports of patients treated with methotrexate for rheumatologic diseases
[18-21]. This finding and the potential for methotrexate-induced hepatotoxicity raise concern
about the safety of methotrexate therapy in patients with HBV infection, particularly given the
existence of other therapeutic options. A 2012 consensus statement from the Medical Board of
the National Psoriasis Foundation advised that methotrexate should not be prescribed in this
population [1,22]. (See "Major side effects of low-dose methotrexate" and "Treatment of
psoriasis in adults", section on 'Methotrexate'.)
● Acitretin – Acitretin is not an immunosuppressant [23,24]. Therefore, despite a lack of data on

the safety of acitretin use in HBV-infected patients, acitretin is not thought to increase the risk
for reactivation of HBV infection.
However, elevation of liver enzymes is a common side effect of acitretin [25], though severe
hepatotoxic reactions are rare [24,26]. A two-year study of pretreatment and post-treatment liver
biopsies in patients treated with acitretin for psoriasis failed to find clinically significant toxic
effects on the liver, suggesting that hepatic tolerance of the drug may be good in healthy
patients [25]. However, patients with chronic HBV infection may be more susceptible to
hepatotoxic effects from acitretin; therefore, its use is not recommended. Patients treated with
acitretin should be followed closely for laboratory evidence of liver toxicity and comanaged with
a hepatologist. (See "Treatment of psoriasis in adults", section on 'Retinoids'.)
● Apremilast – There are no known direct hepatotoxic effects of apremilast. Although data on the
effect of apremilast on HBV infection are lacking, the mechanism of action of apremilast
1346
suggests risk for reactivation of HBV infection may be low. Apremilast is considered one of the
preferred treatment options in this patient population. (See "Treatment of psoriasis in adults",
section on 'Apremilast'.)
● Cyclosporine – The safety of cyclosporine in patients with psoriasis and hepatitis B has not
been specifically evaluated. Immunosuppressive properties of cyclosporine raise concern for
the possibility of reactivation of HBV infection [27,28]. Caution is indicated for use of
cyclosporine in patients with psoriasis and HBV infection. Patients should be managed in
conjunction with a hepatologist, and initiation of antiviral therapy is recommended prior to
treatment in HBsAg-positive patients. Close laboratory monitoring for signs of reactivation of
infection should be performed during treatment; liver function tests and viral load should be
routinely monitored. (See "Hepatitis B virus reactivation associated with immunosuppressive
therapy".)
Cyclosporine is generally used as a short-term treatment (eg, up to 12 weeks); long-term use is

avoided due to drug side effects. (See "Treatment of psoriasis in adults", section on 'Systemic
calcineurin inhibitors'.)
Biologic agents — The use of tumor necrosis factor (TNF)-alpha inhibitors (eg, etanercept,
adalimumab, infliximab) in patients with HBV infection is not recommended due to risk for
reactivation of infection. Risk for reactivation of HBV infection appears to be low for ustekinumab,
secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab, which makes
these biologics preferred over TNF inhibitors in patients with HBV infection (table 1).
Patients requiring biologic therapies should be managed in conjunction with a hepatologist. Initiation
of antiviral therapy is recommended prior to the start of biologic agents in HBsAg-positive patients
[1,29-31]. In addition, close laboratory monitoring for signs of reactivation of infection is indicated
during treatment; liver function tests and viral load should be routinely monitored [1,4].
Tumor necrosis factor-alpha inhibitors — TNF-alpha inhibitors usually do not induce direct
hepatotoxic effects [32]. Transaminase elevations develop only occasionally [33]. However,
reactivation of HBV infection is the major concern with the use of TNF inhibitors, and their use is
generally not recommended in patients with HBV infection.
Reactivation of HBV infection in patients treated with TNF-alpha inhibitors may be related to a
suppressive role of endogenous TNF-alpha on replication of HBV [4]. HBsAg-positive patients have
the greatest risk for disease reactivation. Reactivation occurs less frequently in HBsAg-negative
patients who have a prior history of HBV infection and is rare in HBsAg-negative patients who have
achieved full immunologic recovery (anti-HBs-positive and anti-HBc-positive (table 2B)) [4,32,34].
1347
The lack of clarity on the level of risk for HBV reactivation due to TNF-alpha inhibitor therapy for
psoriasis reflects the consistent exclusion of patients with HBV infection from trials evaluating the
efficacy and safety of these therapies. Reactivation of HBV infection in HBsAg-positive patients
treated with TNF-alpha inhibitors for psoriasis has been reported [35]. As an example, in one series
of seven HBsAg-positive patients with psoriasis or psoriatic arthritis who were treated with
etanercept or adalimumab for an average of 29 months, three patients, including one who had
undetectable HBV DNA levels prior to treatment, developed reactivation of HBV infection [36].
Antiviral prophylaxis was given to only one patient; reactivation of HBV infection did not occur in this
patient.
As a result of the paucity of treatment data in patients with moderate to severe psoriasis and HBV
infection, much of the knowledge of the use of these agents in the setting of HBV infection stems
from literature published in patients with conditions other than psoriasis. Most reported cases of
HBV reactivation have occurred in patients who were taking infliximab for rheumatologic conditions
[37,38], suggesting that infliximab may be the TNF-alpha inhibitor that is most likely to cause HBV
reactivation. It is unclear whether the disproportionate number of reports for infliximab compared
with other TNF-alpha inhibitors is related to its longer half-life or greater drug potency [4]. (See
"Treatment of psoriasis in adults", section on 'Etanercept' and "Treatment of psoriasis in adults",
section on 'Infliximab' and "Treatment of psoriasis in adults", section on 'Adalimumab'.)
Ustekinumab — Long-term data on ustekinumab have not shown an increase in HBV reactivation
rates [35]. Antiviral prophylaxis may be important in HBsAg-positive patients [30,31]. In a
retrospective study of patients treated with ustekinumab for psoriasis, reactivation of HBV infection
occurred in two of seven HBsAg-positive patients who did not receive antiviral prophylaxis, whereas
none of four HBsAg-positive patients given antiviral prophylaxis developed reactivation [31]. Of note,
reactivation of HBV infection also has been documented in a patient who was HBsAg-negative, anti-
HBc-positive, and anti-HBs-positive prior to ustekinumab therapy [39]. (See "Treatment of psoriasis in
adults", section on 'Ustekinumab'.)
Secukinumab, ixekizumab, and brodalumab — Clinical data on the effect of interleukin (IL) 17
inhibitors on reactivation of HBV infection are limited to case reports [40]. For example, based on
case reports, secukinumab has been used in patients with HBV and hepatitis C virus (HCV) infection
without viral reactivation or significant elevations in liver enzymes [40]. The mechanism of effect of
IL-17 inhibitors in patients with viral hepatitis is unknown. Thus, the benefit/risk assessment needs
to be carefully considered when using IL-17 inhibitors in patients with viral hepatitis. (See "Treatment
of psoriasis in adults", section on 'Secukinumab' and "Treatment of psoriasis in adults", section on
'Ixekizumab' and "Treatment of psoriasis in adults", section on 'Brodalumab'.)
1348
Guselkumab, tildrakizumab, and risankizumab — The effects of guselkumab, tildrakizumab, and
risankizumab on psoriasis patients with HBV infection are unknown due to excluding patients with
active hepatitis B from phase II and III studies. The use of IL-23 inhibitors must be carefully
monitored in patients with viral hepatitis. (See "Treatment of psoriasis in adults", section on
'Guselkumab' and "Treatment of psoriasis in adults", section on 'Tildrakizumab'.)
CHRONIC HEPATITIS C VIRUS INFECTION
Hepatitis C is a common blood-borne infection [41]. Similar to hepatitis B virus (HBV) infection, the
primary concerns for the treatment of moderate to severe psoriasis in hepatitis C virus (HCV)-
infected patients are exacerbation of the infection and drug-induced hepatotoxicity. Of note,
interferon, a treatment for HCV infection, may exacerbate psoriasis [42]. (See "Clinical manifestations
and natural history of chronic hepatitis C virus infection" and "Screening and diagnosis of chronic
hepatitis C virus infection", section on 'Introduction'.)
Our approach — Patients with HCV infection should be referred to a hepatologist for evaluation,
particularly given the existence of treatments that can eradicate the infection. (See "Overview of the
management of chronic hepatitis C virus infection".)
The paucity of data on the treatment of psoriasis in patients with HCV infection makes the
identification of the best approach to the treatment difficult. Ultraviolet B (UVB) phototherapy in
combination with topical therapy is considered safe and a preferred treatment for patients with
moderate to severe psoriasis and HCV infection [3]. Other treatment options that are likely to be well
tolerated include tumor necrosis factor (TNF)-alpha inhibitors, ustekinumab, and apremilast based
on the mechanisms of action of these drugs or evidence that suggests low risk for hepatotoxicity or
exacerbation of HCV infection. Use of newer biologic agents, including secukinumab, ixekizumab,
brodalumab, guselkumab, and tildrakizumab, may also be well tolerated, though a cautious approach
is indicated because of limited experience with these agents in patients with HCV infection. Selection
amongst the systemic therapies is also based upon consideration of factors such as other
comorbidities, clinician familiarity with specific agents, patient preference, treatment history, and
treatment availability (table 1). (See 'Phototherapy' below and 'Biologic agents' below.)
Phototherapy — Although the safety of phototherapy in patients with HCV infection has not been
specifically studied, UVB phototherapy generally is considered safe in these patients (table 1) [3].
Psoralen plus ultraviolet A (PUVA) is an additional therapeutic option; however, there have been
several reports of liver injury after PUVA therapy [13-17], and severe liver disease is considered a
relative contraindication for PUVA (table 3). (See 'Phototherapy' above and "Treatment of psoriasis in
adults", section on 'Ultraviolet light' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
1349
Oral agents — Methotrexate and acitretin are generally avoided in patients with HCV infection due to
safety concerns. Limited data suggest that apremilast is well tolerated. Caution is necessary for the
use of cyclosporine (table 1).
● Methotrexate – Methotrexate is contraindicated for the treatment of psoriasis in patients with

HCV infection due to an increased risk for hepatotoxicity [3]. (See "Major side effects of low-dose
methotrexate" and "Treatment of psoriasis in adults", section on 'Methotrexate'.)
● Acitretin – The safety of acitretin in patients with HCV infection has not been studied. Liver
function test abnormalities, and occasionally long-term hepatotoxic effects, can occur during
treatment [25]. A two-year study of pretreatment and post-treatment liver biopsies in patients
without hepatitis who were treated with acitretin for psoriasis failed to find clinically significant
toxic effects on the liver [25]. Nevertheless, due to the potential for hepatotoxicity, we do not use
acitretin unless other therapeutic options are not feasible. (See "Treatment of psoriasis in
adults", section on 'Retinoids'.)
● Apremilast – There are no known direct hepatotoxic effects of apremilast. A case report
describes successful use in a patient with HCV and HIV infections [43]. (See "Treatment of
psoriasis in adults", section on 'Apremilast'.)
● Cyclosporine – Traditionally, cyclosporine has been avoided in the treatment of psoriasis in

patients with HCV infection due to concerns that the drug's immunosuppressive effects might
exacerbate the infection [3]. However, in vitro studies have found that cyclosporine has
suppressive effects on HCV replication [44-46]. In addition, case reports have documented
improvements in both transaminase levels and psoriasis during treatment with cyclosporine in
patients with HCV infection [47-50]. These findings suggest that cyclosporine therapy may be
tolerated in patients with psoriasis and HCV infection. Consultation with a hepatologist should
be performed prior to starting treatment with cyclosporine. In addition, periodic laboratory
assessment for signs of reactivating disease is warranted. (See "Treatment of psoriasis in
adults", section on 'Systemic calcineurin inhibitors'.)
Biologic agents — Consultation with a hepatologist should be performed prior to starting treatment
with a biologic agent in patients with moderate to severe psoriasis and HCV infection. In addition,
biologic therapy should be accompanied by regular monitoring of viral hepatitis activity [1,32]. TNF
inhibitors and ustekinumab appear to be well tolerated provided liver function enzymes and viral load
are monitored.
Data on interleukin (IL) 17 and IL-23 inhibitors are lacking in patients with HCV infection. While the
mechanisms of these drugs do not suggest substantial adverse effects, due to the lack of data in
1350
this population, clinicians should use them with caution. Liver function enzymes and viral activity
should be monitored (table 1).
Tumor necrosis factor-alpha inhibitors — Although data on biologic therapy in patients with HCV
infection are limited, the available data from studies in patients with psoriasis and other diseases
suggest that patients with chronic HCV infection may tolerate TNF-alpha inhibitor therapy [35].
Interestingly, a small randomized trial found that patients who were given etanercept as an adjunct to
interferon and ribavirin for the treatment of HCV infection were more likely to achieve clearance of
HCV RNA than patients who received interferon, ribavirin, and a placebo [51]. (See "Tumor necrosis
factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Hepatitis C'.)
Data on the use of etanercept, the biologic agent most studied in patients with psoriasis and HCV
infection, primarily consist of case reports and small retrospective studies. A systematic review of
published reports between 1990 and 2010 identified 22 case reports of patients treated with
etanercept for psoriasis or psoriatic arthritis [52]. The review found that viral loads or transaminase
levels remained stable in 17 of these patients and decreased in 4 patients during treatment with
etanercept. Only one patient developed an increase in viral load.
Additional case reports and small retrospective studies have documented successful use of
etanercept, adalimumab, and infliximab for psoriasis in patients with HCV infection [35,52-60]. As an
example, a retrospective study of 20 adults with psoriasis and HCV infection who were treated with
etanercept (18 patients), adalimumab (4 patients), ustekinumab (3 patients), and/or infliximab (1
patient), found that these biologic agents were well tolerated by most patients [30]. (See "Treatment
of psoriasis in adults", section on 'Etanercept' and "Treatment of psoriasis in adults", section on
'Infliximab' and "Treatment of psoriasis in adults", section on 'Adalimumab'.)
Ustekinumab — Data on the use of ustekinumab in patients with HCV infection and psoriasis are
limited [30,31]. Long-term studies have not shown an increase in HCV reactivation rates in patients
treated with ustekinumab [31,61]. However, close monitoring and collaboration with a hepatologist
are indicated during treatment with ustekinumab for following HCV disease progression.
Secukinumab, ixekizumab, and brodalumab — Safety data on the use of IL-17 inhibitors in HCV-
infected patients are lacking because the phase II and III trials excluded patients with active hepatitis
C. However, there are no biologic mechanisms or postmarketing data suggesting increased risk
associated with use of IL-17 inhibitors in this population. Patients treated with IL-17 inhibitors should
be routinely monitored for viral hepatitis activity. (See "Treatment of psoriasis in adults", section on
'Secukinumab' and "Treatment of psoriasis in adults", section on 'Ixekizumab' and "Treatment of
psoriasis in adults", section on 'Brodalumab'.)
1351
Guselkumab, tildrakizumab, and risankizumab — Safety data on the use of the IL-23 inhibitors
guselkumab, tildrakizumab, and risankizumab in hepatitis C patients are lacking. However, there are
no biologic mechanisms or postmarketing data suggesting increased risk associated with use of
these drugs in the setting of HCV infection. Patients treated with guselkumab, tildrakizumab, or
risankizumab should be routinely monitored for viral hepatitis activity. (See "Treatment of psoriasis in
adults", section on 'Guselkumab' and "Treatment of psoriasis in adults", section on 'Tildrakizumab'.)
HIV INFECTION
HIV infection is a risk factor for severe psoriasis [6]. In some patients, psoriasis is the initial
presenting sign of HIV infection [5]. The immunosuppressive effects of psoriasis therapies are the
major concern in this population.
Our approach — Patients with HIV infection and moderate to severe psoriasis are best managed by
coordinated care with a dermatologist and infectious disease specialist. The Medical Board of the
National Psoriasis Foundation recommends phototherapy and antiretrovirals as first-line therapies
for patients with HIV infection and moderate to severe psoriasis, and acitretin is an appropriate
second-line treatment [6]. Recommendations in a 2015 update to the European S3-Guidelines are
fairly similar, supporting antiretroviral therapy plus skin-directed treatments, such as phototherapy
and topical agents, as first-line treatments and acitretin plus antiretroviral therapy as second-line
treatment [62].
Our typical first-line therapeutic approach to moderate to severe psoriasis in patients with HIV
infection consists of antiretroviral treatment along with phototherapy supplemented with topical
therapy. However, multiple phototherapy visits are inconvenient for many patients. Acitretin
supplemented with topical medication or apremilast supplemented with topical medication are well-
tolerated alternatives to phototherapy (table 1).
Therapies such as cyclosporine, methotrexate, and biologic drugs (tumor necrosis factor [TNF]-alpha
inhibitors, ustekinumab, secukinumab, ixekizumab, brodalumab, and guselkumab) should be
reserved for refractory cases and should be used cautiously; the status of the HIV infection should
be monitored closely during treatment.
Antiretroviral drugs — Psoriasis in HIV-infected patients may improve with antiretroviral therapy
[5,63-68]. As an example, in an open-label study in which 24 patients with HIV-associated psoriasis
were treated with zidovudine, 90 percent of the 19 patients who were followed for at least eight
weeks achieved either partial or complete improvement of psoriasis [63].
1352
Phototherapy — Phototherapy can be effective for HIV-associated psoriasis [2,69-71]. Although
ultraviolet radiation has been linked to activation of HIV in some in vitro and animal studies [72-74],
small case series and uncontrolled studies suggest that phototherapy administered to HIV-positive
patients is well tolerated and not associated with significant changes in viral load, CD4+, and CD8+ T
cells during or after therapy [69,71,75,76]. (See "Treatment of psoriasis in adults", section on
'Ultraviolet light'.)
Oral agents — Patients with HIV infection typically tolerate acitretin and apremilast. Methotrexate
and cyclosporine must be used with caution (table 1).
● Acitretin – Acitretin is an attractive therapeutic option for psoriasis in patients with HIV infection
because it is not an immunosuppressant. In a 20-week uncontrolled study in which 11 HIV-
positive men with moderate to severe psoriasis (including seven men with plaque-type
psoriasis) were treated with acitretin (up to 100 mg per day), four patients achieved at least 75
percent reduction in the Psoriasis Area and Severity Index (PASI) score, and an additional two
patients achieved at least 51 to 75 percent improvement. Two of the three patients who
discontinued treatment stopped treatment due to worsening psoriasis. The third patient stopped
treatment due to a myocardial infarction that was presumed to be unrelated to acitretin therapy
[77]. Of note, typical doses of acitretin for the treatment of psoriasis range from 25 to 50 mg per
day; higher doses are often poorly tolerated due to side effects. (See "Treatment of psoriasis in
adults", section on 'Retinoids'.)
● Methotrexate – Methotrexate is not commonly used for psoriasis in HIV-infected patients due to
concern about the drug's immunosuppressive effects [5,69,78]. Although case reports have
documented successful treatment in the setting of HIV infection [78], the risks and benefits of
therapy must be weighed carefully prior to treatment [5]. Treatment with methotrexate is usually
reserved for refractory cases. (See "Major side effects of low-dose methotrexate" and "Treatment
of psoriasis in adults", section on 'Methotrexate'.)
● Apremilast – Apremilast is considered a treatment option for HIV-infected patients because it

does not appear to have significant immunosuppressive effects [79]. Treatment was well
tolerated in a patient with HIV and hepatitis C virus (HCV) infections [43]. (See "Treatment of
psoriasis in adults", section on 'Apremilast'.)
● Cyclosporine – Case reports have documented the successful use of cyclosporine for psoriasis
in patients with HIV infection [80,81]. However, as with methotrexate, the immunosuppressive
effects are a concern. Treatment with cyclosporine is primarily reserved for short courses (up to
12 weeks) of treatment in patients with refractory disease. (See "Pharmacology of cyclosporine
1353
and tacrolimus", section on 'Side effects' and "Treatment of psoriasis in adults", section on
'Systemic calcineurin inhibitors'.)
Some authors have suggested an initial starting dose of 2.5 mg/kg per day of cyclosporine if the
drug is used in this population [5]. Trough levels of cyclosporine should be monitored carefully in
patients taking protease inhibitors, since these agents may increase the bioavailability of
cyclosporine [82].
Biologic agents — Data are limited on the safety of biologic therapies in patients with HIV infection.
Several cases of successful use of biologic TNF-alpha inhibitors for psoriasis or rheumatologic
conditions in patients with HIV infection have been reported [83-87]. Viral counts and immune status
remained stable in these patients. However, one report documented the eventual discontinuation of
etanercept due to the occurrence of multiple infections [87].
An additional case report has described successful treatment of psoriasis with ustekinumab [88].
The patient achieved great improvement in psoriasis, and treatment was well tolerated.
Tolerance of secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab in the setting of

HIV infection has not been evaluated. The mechanisms of action of these drugs suggest risk for
exacerbation of HIV infection would be low.
Further studies are necessary to determine the role biologic therapy should play in the management
of psoriasis in patients with HIV infection (table 1). In general, these agents should be used with
caution and reserved for HIV-infected patients who cannot be adequately treated with preferred
therapies, are receiving antiretroviral therapy, and can be regularly monitored. Concomitant
antiretroviral therapy is suggested to decrease the likelihood of opportunistic infections during
biologic treatment [5,6,83,89]. (See "Treatment of psoriasis in adults", section on 'Biologic agents'.)
Other therapies — Other drugs that have been reported to be useful in individual patients with HIV
infection and psoriasis include cimetidine, ranitidine, carbamazepine, antibiotics, nicotinamide, and
mycophenolate mofetil [5]. Ranitidine has been withdrawn from the United States market.
LATENT TUBERCULOSIS
Immunosuppressive treatment may result in reactivation of latent tuberculosis (TB) infection. Thus,
screening for TB infection is recommended prior to the administration of immunosuppressive
therapies for psoriasis (eg, biologic agents, methotrexate, and cyclosporine) [7,62,90]. These drugs
should be used with caution (table 1). Tumor necrosis factor (TNF)-alpha plays a particularly
important role in the immune defense against TB infection, raising particular concern about the use
of TNF-alpha inhibitor therapy. Use of therapies without systemic immunosuppressive effects, such
1354
as phototherapy, acitretin, and apremilast, are not considered to increase risk for TB reactivation
(table 1). (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on
'TNF-alpha and host defenses'.)
Screening for TB is performed through a patient interview and testing via a tuberculin skin test or
interferon-gamma release assay. A chest radiograph should be performed if the screening test is
positive. Screening for TB infection is not necessary prior to treatment with topical agents,
phototherapy, acitretin, or apremilast since these therapies do not appear to increase the risk for
reactivation of TB infection. (See "Approach to diagnosis of latent tuberculosis infection
(tuberculosis screening) in adults".)
Patients who have latent TB should be given treatment for this condition to reduce the risk for TB
[91,92]. Opinions vary on how long patients must be on treatment for latent TB before TNF-alpha
inhibitor therapy can be initiated. While some authors recommend completing the full course of
prophylactic TB therapy prior to biologic therapy [93], other sources, including the Medical Board of
the National Psoriasis Foundation, suggest initiation of immunologic therapies after the first one to
two months of prophylactic TB treatment if it is required by the clinical condition [2,7,94,95].
We agree with the National Psoriasis Foundation's approach. While the full course of prophylactic TB
treatment can be completed before initiating a biologic agent, we consider acceptable the initiation
of biologic therapy following at least one month of TB treatment, such that the patient will then
continue TB treatment concurrently with biologic therapy. (See "Treatment of latent tuberculosis
infection in HIV-uninfected nonpregnant adults".)
The risk for TB reactivation among patients who are treated with prophylactic therapy prior to the
start of biologic therapy appears to be low [91,96-100]. As an example, in an analysis of data from
five phase III trials of ustekinumab therapy for moderate to severe plaque psoriasis, none of the 167
patients with newly diagnosed latent TB infection who began TB prophylaxis before or at the time of
the first dose of ustekinumab developed active TB during a 28-week follow-up period [97]. The risk
for mycobacterial infections in patients treated with TNF-alpha inhibitors is reviewed in greater detail
separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)
MALIGNANCY
The immunosuppressive effects of systemic agents for psoriasis are the primary safety concerns for
systemic psoriasis therapy in patients with a history of internal malignancy. The best approach to the
treatment varies based upon the severity of psoriasis and the type of malignancy (table 1).
Consultation with the patient's oncologist and a thorough discussion with the patient about the risk-
benefit ratios of the therapeutic options should take place prior to deciding on a treatment.
1355
Methotrexate and cyclosporine may increase the risk for lymphoproliferative disorders. In long-term
studies in the psoriasis population, tumor necrosis factor inhibitors and ustekinumab do not appear
to increase risk for internal malignancies. (See "Pharmacology of cyclosporine and tacrolimus",
section on 'Risk of malignancy' and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and
"Comorbid disease in psoriasis", section on 'Malignancy' and "Major side effects of low-dose
methotrexate", section on 'Risk of lymphoproliferative disorders' and "Treatment of psoriasis in
Data have not shown an association between internal malignancies and the use of interleukin (IL) 17
inhibitors, such as secukinumab [101,102], ixekizumab [103], or brodalumab [104]. Similarly, short-
term data have not shown an association between internal malignancies and IL-23 inhibitors, such
as guselkumab [105], tildrakizumab [106], and risankizumab [107].
Nonimmunosuppressive therapies, such as phototherapy and acitretin, are generally considered safe
treatment options for patients with current or prior hematologic or solid tumor malignancies [2,62].
Patients with a history of melanoma or multiple nonmelanoma skin cancers are an exception since
these conditions are relative contraindications for phototherapy [10]. Of note, patients with a history
of multiple squamous cell skin cancers may benefit from the suppressive effect of acitretin on the
development of these lesions. (See "Epidemiology and risk factors for cutaneous squamous cell
carcinoma", section on 'Oral retinoids'.)
Long-term data on the risk of malignancy and apremilast are not available. Short-term data do not
suggest a link between internal malignancy and apremilast [79].
PREGNANCY
The management of psoriasis in pregnant women is reviewed separately. (See "Management of

psoriasis in pregnancy".)
1356
● Patients with moderate to severe psoriasis (psoriasis involving more than 5 to 10 percent of the
body surface area) generally require phototherapy, oral medications (eg, acitretin, methotrexate,
apremilast, cyclosporine), or biologics (eg, tumor necrosis factor [TNF]-alpha inhibitors,
ustekinumab, interleukin [IL] 17 inhibitors, guselkumab, tildrakizumab) for optimal management
of the disease. The potential adverse effects of these therapies must be considered carefully in
patients with comorbidities. (See 'Overview' above and "Treatment of psoriasis in adults", section
on 'Choice of therapy'.)
● The determination of the best approach to the management of psoriasis in patients with
hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, HIV infection, latent
tuberculosis (TB), and internal malignancy is challenging because data on psoriasis therapy in
these populations are limited. Recommendations for the management of these patients are
based upon data from patients with psoriasis, patients with other disorders treated with similar
therapies, and expert opinion (table 1). (See 'Overview' above and 'Chronic hepatitis B virus
infection' above and 'Chronic hepatitis C virus infection' above and 'HIV infection' above and
'Latent tuberculosis' above and 'Malignancy' above.)
• Narrowband ultraviolet B (UVB) phototherapy – Narrowband UVB phototherapy has

negligible effects on hepatic tissue and systemic immunity. Narrowband UVB phototherapy
is a safe treatment for psoriasis in patients with HBV infection, HCV infection, HIV infection,
latent TB, and internal malignancy. (See "Treatment of psoriasis in adults", section on
'Ultraviolet light'.)
• Acitretin – Acitretin lacks immunosuppressive effects and is typically well tolerated by

patients with HIV infection, latent TB, or malignancy. However, acitretin may have adverse
hepatic effects and is generally avoided in the setting of HBV or HCV infection. (See
"Treatment of psoriasis in adults", section on 'Retinoids'.)
• Methotrexate – Methotrexate has hepatotoxic and immunosuppressive effects and is not

recommended for the treatment of psoriasis in patients with HBV or HCV infection. In
patients with HIV infection or latent TB, methotrexate should be used with caution.
Methotrexate may increase risk for lymphoproliferative disorders. (See "Treatment of
psoriasis in adults", section on 'Methotrexate'.)
• Cyclosporine – Cyclosporine has immunosuppressive effects. The drug should be used

with caution; consultation with disease specialists and close monitoring are indicated for
patients with viral hepatitis, HIV, latent TB, or malignancy. Long-term use of cyclosporine is
generally not recommended due to renal toxicity. (See "Treatment of psoriasis in adults",
section on 'Systemic calcineurin inhibitors'.)
1357
• Apremilast – Apremilast appears to have minimal immunosuppressive effects. Apremilast
is one of the preferred therapies for psoriasis in patients with HBV infection, HCV infection,
HIV infection, and latent tuberculosis. Short-term data do not suggest an increased risk of
malignancy with apremilast. (See "Treatment of psoriasis in adults", section on 'Apremilast'.)
• TNF-alpha inhibitors – TNF-alpha inhibitors are generally avoided in patients with HBV
infection due to concerns for disease reactivation. In contrast, TNF-alpha inhibitor therapy is
one of the preferred biologic therapies for patients with HCV infection provided consultation
with a hepatologist and close monitoring are feasible. TNF-alpha inhibitors should be used
with caution and in conjunction with antiviral therapy and anti-TB therapy in patients with
HIV infection and latent TB, respectively. TNF-alpha inhibitors do not increase risk for
malignancy in the psoriasis population. (See "Treatment of psoriasis in adults", section on
'Etanercept' and "Treatment of psoriasis in adults", section on 'Infliximab' and "Treatment of
psoriasis in adults", section on 'Adalimumab'.)
• Ustekinumab – Ustekinumab is a preferred biologic therapy in patients with HBV or HCV

infection provided consultation with a hepatologist and close monitoring are feasible.
Among patients with HIV infection, ustekinumab is primarily reserved for refractory
psoriasis in patients who can be closely monitored for HIV activity. Ustekinumab is a
preferred biologic agent for patients with latent TB provided patients also receive anti-TB
therapy. Ustekinumab does not increase risk of internal malignancy in the psoriasis
population. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.)
• IL-17 inhibitors, guselkumab, and tildrakizumab – Caution is indicated for use of IL-17
inhibitors (secukinumab, ixekizumab, and brodalumab), guselkumab, and tildrakizumab in
patients with HBV, HCV, or HIV infection because of a lack of long-term data. Consultation
with disease specialists and close monitoring are indicated. IL-17 inhibitors, guselkumab,
and tildrakizumab are considered preferred biologic therapies in patients with latent TB
provided patients also receive anti-TB therapy. Short-term studies have not found increased
risk of internal malignancy in psoriasis patients treated with IL-17 inhibitors, guselkumab, or
tildrakizumab. (See "Treatment of psoriasis in adults", section on 'Secukinumab' and
"Treatment of psoriasis in adults", section on 'Ixekizumab' and "Treatment of psoriasis in
adults", section on 'Brodalumab' and "Treatment of psoriasis in adults", section on
'Guselkumab' and "Treatment of psoriasis in adults", section on 'Tildrakizumab'.)
1358
1359
GRAPHICS
Treatment options for moderate to severe psoriasis in special populations
Patients with: HBV infection HCV infection HIV Latent TB Malignancy
Phototherapy Preferred therapy: Preferred therapy: Preferred therapy Preferred therapy A preferred therapy
UVB generally UVB generally for patients with
considered safe and considered safe and internal
treatment of choice; treatment of choice; malignancies. Use
severe liver disease severe liver disease narrowband UVB
is a relative is a relative phototherapy with
contraindication for contraindication for caution in patients
PUVA PUVA with history of skin
cancer. PUVA
phototherapy is not
recommended for
patients with a
history of skin
cancer.
Methotrexate Not recommended Not recommended Use with caution, Use with caution Risk-benefit ratio
primarily reserved should be
for refractory cases considered; consult
with oncologist.
Acitretin Not recommended Not recommended Preferred therapy Preferred therapy Preferred therapy.
Apremilast Preferred therapy Preferred therapy Preferred therapy Preferred therapy Short-term data do
not suggest an
increased risk of
malignancy. Risk-
benefit ratio should
be considered;
consult with
oncologist.
Cyclosporine Use with caution Use with caution Use with caution, Use with caution Risk-benefit ratio
primarily reserved should be
for refractory cases considered; consult
with oncologist.
TNF inhibitors Not recommended Preferred therapy Use with caution, Use with caution No increased risk of
(adalimumab, primarily reserved (potentially greater internal malignancy
etanercept, for refractory cases risk of TB in psoriasis
infliximab) reactivation population. Risk-
compared with benefit ratio should
other classes of be considered;
biologics) consult with
oncologist.
IL-12/IL-23 Preferred therapy Preferred therapy Use with caution, Preferred therapy as No increased risk of
inhibitor primarily reserved long as patient is internal malignancy
(ustekinumab) for refractory cases concurrently treated in psoriasis
for latent TB population. Risk-
be considered;
consult with
oncologist.
IL-17A and IL-17RA Use with caution Use with caution Use with caution, Preferred therapy as Short-term data do
inhibitors primarily reserved long as patient is not suggest an
(secukinumab, for refractory cases concurrently treated increased risk of
for latent TB malignancy. Risk-
1360
ixekizumab, benefit ratio should
brodalumab) be considered;
consult with
oncologist.
IL-23 inhibitors Use with caution Use with caution Use with caution, Preferred therapy as Short-term data do
(guselkumab, primarily reserved long as patient is not suggest an
tildrakizumab, for refractory cases concurrently treated increased risk of
risankizumab) for latent TB malignancy. Risk-
be considered;
consult with
oncologist.
HBV: hepatitis B virus; HCV: hepatitis C virus; TB: tuberculosis; UVB: ultraviolet B; PUVA: psoralen plus ultraviolet A; TNF: tumor necrosis factor;
IL: interleukin.
1361
Serologic responses to HBV infection
Schematic representation of the serologic responses to acute and chronic hepatitis B virus (HBV) infection in
relation to the serum alanine aminotransferase (ALT) concentration. Left panel: Acute infection is
characterized initially by the presence of HBeAg (hepatitis B e antigen), HBsAg (hepatitis B surface antigen),
and HBV DNA beginning in the preclinical phase. IgM anti-HBc (hepatitis B core antigen) appears early in the
clinical phase; the combination of this antibody and HBsAg makes the diagnosis of acute infection. Recovery
is accompanied by normalization of the serum ALT, the disappearance of HBV DNA, HBeAg to anti-HBe
seroconversion, and subsequently HBsAg to anti-HBs seroconversion and switch from IgM to IgG anti-HBc.
Thus, previous HBV infection is characterized by anti-HBs and IgG anti-HBc. Right panel: Chronic infection is
characterized by persistence of HBeAg (for a variable period), HBsAg, and HBV DNA in the circulation; anti-
HBs is not seen (in approximately 20 percent of patients a non-neutralizing form of anti-HBs can be detected).
Persistence of HBsAg for more than six months after acute infection is considered indicative of chronic
infection.
1362
Diagnostic tests to determine phase of acute or chronic hepatitis B virus infection [1]
IgM Total
Anti- Anti-
HBsAg HBeAg anti- anti- HBV DNA ALT ¶ Interpretation
HBs HBe
HBc HBc*
Acute HBV infection
+ + + +++ Elevated Early phase
+ + Elevated Window phase
+ + + ± Normal Recovery phase
Chronic HBV infection (HBsAg-positive for >6 months)
+ + + - - +++ Normal or Immune-tolerant

(Serum HBV typically >1 mildly phase Δ
million international units/mL) elevated
+ + + - - +++ Persistently Immune-active,

(Serum HBV >20,000 elevated HBeAg-positive ◊
international units/mL)
+ - + - + ++ Elevated Immune-active,
(Serum HBV >2000 HBeAg-negative ◊
international units/mL)
+ - + + - to ++ Normal or Inactive chronic

(Serum HBV ≤2000 mildly HBV §
international units/mL) elevated
- - ± ± ± + in liver; - to + in serum Normal Occult HBV

(generally
+)
ALT: alanine aminotransferase; anti-HBc: antibody to hepatitis B core antigen; anti-HBe: antibody to hepatitis B e antigen; anti-HBs: antibody to
hepatitis B surface antigen; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus.
* This test is typically ordered as total anti-HBc, which includes IgM and IgG.
¶ The upper limits of normal for ALT in healthy adults are reported to be 29 to 33 units/L for males and 19 to 25 units/L for females. For healthy
children after infancy, the upper limits of normal are 25 to 38 units/L and 22 to 31 units/L for boys and girls, respectively.
Δ For patients with immune-tolerant chronic hepatitis B, liver biopsy or noninvasive tests show no fibrosis and minimal inflammation. This is the
initial phase seen in patients with perinatally acquired HBV infection.
◊ For patients with immune active chronic hepatitis B, liver biopsy or noninvasive tests show chronic hepatitis with moderate or severe
necroinflammation with or without fibrosis. For patients who are HBeAg positive, immune-active chronic hepatitis B (also known as the
clearance phase) can last for 10 to 20 years, and may be associated with the loss of HBeAg. For patients who are HBeAg negative, immune-
active chronic hepatitis B is associated with immune reactivation and is also referred to as HBeAg-negative chronic hepatitis B or HBeAg-
negative replicative phase.
§ Patients with inactive chronic hepatitis B are HBeAg negative. In such patients, liver biopsy confirms the absence of significant
necroinflammation, but biopsy or noninvasive testing show variable levels of fibrosis. This stage has also been referred to as the nonreplicative
or carrier phase.
References:
1. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B
guidance. Hepatology 2018; 67:1560.
1363
Interpretation of the hepatitis B serologic panel
Tests Results Interpretation
HBsAg Negative Susceptible
anti-HBc Negative
anti-HBs Negative
HBsAg Negative Immune due to natural infection
anti-HBc Positive
anti-HBs Positive
HBsAg Negative Immune due to hepatitis B vaccination*
anti-HBc Negative
anti-HBs Positive
HBsAg Positive Acutely infected
anti-HBc Positive
IgM anti-HBc Positive
anti-HBs Negative
HBsAg Positive Chronically infected
anti-HBc Positive
IgM anti-HBc Negative
anti-HBs Negative
HBsAg Negative Four interpretations possible ¶
anti-HBc Positive
anti-HBs Negative
HBsAg: hepatitis B surface antigen; anti-HBc: hepatitis B core antibody; anti-HBs: hepatitis B surface antibody; IgM: immunoglobulin M; HBV:
hepatitis B virus.
* Antibody response (anti-HBs) can be measured quantitatively or qualitatively. A protective antibody response is reported quantitatively as 10
or more milliinternational units (≥10 milliint. unit/mL) or qualitatively as positive. Postvaccination testing should be completed one to two
months after the third vaccine dose for results to be meaningful.
¶ Four interpretations:
1. Might be recovering from acute HBV infection.
2. Might be distantly immune and test not sensitive enough to detect very low level of anti-HBs in serum.
3. Might be susceptible with a false positive anti-HBc.
4. Might be undetectable level of HBsAg present in the serum, and the person is actually chronically infected.
Centers for Disease Control and Prevention, Hepatitis B information for health professionals: Interpretation of hepatitis B serologic test results. Available
from the CDC website.
1364
Contraindications to PUVA phototherapy
Absolute
Xeroderma pigmentosum
Lupus erythematosus with photosensitivity or positive Ro antibody
Pregnancy (category C)
Lactation
Relative
Photosensitivity and/photosensitizing medications
History or family history of melanoma
History of nonmelanoma skin cancer and/or extensive solar damage
Previous treatment with ionizing radiation or arsenic
Severe liver, renal, or cardiac disease
Young age
PUVA: psoralen plus ultraviolet A.
References:
1. Morison WL. Phototherapy and Photochemotherapy of Skin Disease, 3rd ed, Taylor and Francis, New York 2005.
2. Morison WL. PUVA Photochemotherapy. In: Comprehensive Dermatologic Drug Therapy, 2nd ed, Wolverton SE (Ed), Elsevier, Philadelphia 2007.
1365
Psoriasis in children: Epidemiology, clinical manifestations, and

diagnosis
Authors: Amy S Paller, MD, Emily Broun Lund, MD
Section Editors: Kristina Callis Duffin, MD, Moise L Levy, MD
INTRODUCTION
Psoriasis is a systemic, immune-mediated disease that is most often characterized by well-demarcated,

erythematous plaques with adherent, micaceous scale. The onset of psoriasis can occur during childhood or
adulthood.
Chronic plaque psoriasis is the most common clinical form of psoriasis in children; guttate, pustular, and
erythrodermic psoriasis are additional presentations. Certain distributions of plaque psoriasis are more
common in children than adults, including involvement of the face, scalp, and intertriginous skin. Psoriatic
diaper rash (also known as "napkin psoriasis") can be the initial manifestation of psoriasis in infants and
young children.
The epidemiology, clinical features, comorbidities, and diagnosis of psoriasis in children will be reviewed
here. Detailed discussions of specific clinical variants of psoriasis, psoriatic arthritis in children, and the
management of psoriasis in children are provided separately.
● (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

● (See "Erythrodermic psoriasis in adults".)
● (See "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis".)
● (See "Psoriatic juvenile idiopathic arthritis: Management and prognosis".)
● (See "Psoriasis in children: Management of chronic plaque psoriasis".)
1366
EPIDEMIOLOGY
Psoriasis is a common disorder that often begins in childhood. In a questionnaire survey of 5600 individuals
with psoriasis (median age 44 years, range 1 to 92 years), approximately one-third reported onset of disease
during the first two decades of life and 10 percent reported onset prior to the age of 10 years [1].
The prevalence of psoriasis varies geographically. Worldwide, prevalence estimates range from 0.51 to 11.3
percent of adults and 0 to 1.37 percent of children [2]. Psoriasis is more frequent in older children than young
children. A review of data from 1.3 million individuals within a German statutory health insurance
organization found an approximately linear increase in the proportion of patients with a diagnosis of
psoriasis from 0.12 percent at age 1 year to 1.24 percent at age 18 years [3].
As in adults, the incidence of psoriasis in children has increased over time. A population-based study in
Olmstead County, Minnesota, found that the annual incidence of pediatric psoriasis doubled between the
periods of 1970 to 1974 and 1995 to 1999 (29.6 per 100,000 to 62.7 per 100,000, respectively) [4]. The rising
prevalence of obesity, a risk factor for psoriasis, may contribute to this finding [4].
RISK FACTORS
A complex interplay of environmental and genetic factors contributes to risk for psoriasis. A family history of
psoriasis is a common risk factor; in a multicenter study of 409 children with psoriasis, approximately 30
percent reported an immediate family member with psoriasis [5].
The most common predisposing genetic risk factor for early-onset psoriasis (onset under the age of 40
years) is the human leukocyte antigen (HLA) type Cw6 (PSOR1) [6]. Less common is a pathogenic mutation in
CARD14 (caspase recruitment domain family 14; PSOR2), which is transmitted in an autosomal dominant
fashion and may manifest as pityriasis rubra pilaris, erythrodermic psoriasis, pustular psoriasis, or plaque
psoriasis [7,8].
Multiple environmental factors may trigger or exacerbate psoriasis [9]. Examples include skin trauma
(Koebner phenomenon), infections (eg, streptococcal [most common], staphylococcal, and varicella zoster
infections), Kawasaki disease, certain medications, and psychologic and physical stress [10-15].
Greater detail on the genetic and environmental risk factors for psoriasis is provided separately. (See
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Risk factors'.)
PATHOGENESIS
Cutaneous inflammation in psoriasis is mediated by both the innate and adaptive immune systems.
Activation of myeloid dendritic cells by tumor necrosis factor (TNF)-alpha, interferon-gamma, interleukin
(IL)-6, and IL-1-beta stimulates the adaptive immune system via IL-23. The adaptive immune response is
1367
characterized by expression of primarily Th17 and TNF/IL-17 synergistic cytokines, in contrast to the Th2
response that predominates in atopic dermatitis. These proinflammatory cytokines stimulate further release
of inflammatory mediators (including TNF) from keratinocytes, perpetuating the immune activation and
resulting in the brightly erythematous, scaly plaques of psoriasis [16,17]. The pathophysiology of psoriasis is
reviewed in greater detail separately. (See "Pathophysiology of plaque psoriasis".)
The classic erythematous and scaly plaques of psoriasis can occur in various forms and distributions. The
major clinical variants of psoriasis include chronic plaque psoriasis, guttate psoriasis, pustular psoriasis, and
erythrodermic psoriasis. In addition, certain distributions of psoriasis are more common in children than in
adults, including face, scalp, intertriginous, and diaper area involvement.
Chronic plaque psoriasis — Chronic plaque psoriasis is the most common presentation of psoriasis in both
children and adults [18-20]. The classic cutaneous findings are round, brightly erythematous, well-
demarcated plaques covered with silvery-white (mica-like or "micaceous") scale (picture 1A-D). Children may
also present with plaques with less distinct borders or thinner scale. In patients with highly pigmented skin
(Fitzpatrick skin type V or VI (table 1)), erythema may not be prominent and plaques may appear violaceous
or hyperpigmented rather than erythematous.
Plaque psoriasis may present with few plaques or in a more generalized distribution, but the distribution is
often symmetric. As in adults, the elbows and knees are the most common sites for chronic plaque psoriasis.
Other common areas of involvement include the scalp, lower back, and the anogenital region. Formation of
psoriasis plaques in sites of cutaneous trauma, termed the "Koebner phenomenon," is also characteristic.
(See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Chronic plaque psoriasis'.)
Guttate psoriasis — Guttate psoriasis is a common initial presentation of psoriasis in children. In a

multicenter study of 181 children with psoriasis, approximately 30 percent had a history of a guttate
presentation [21].
Guttate psoriasis is characterized by the acute and generalized eruption of small, round, erythematous, and
"drop-like" scaly papules (picture 2). As with chronic plaque psoriasis, plaques may appear violaceous or
hyperpigmented in patients with darkly pigmented skin. Guttate psoriasis often occurs in association with
group A streptococcal infection. (See "Guttate psoriasis".)
Pustular and erythrodermic psoriasis — Generalized pustular psoriasis and erythrodermic psoriasis are
severe forms of psoriasis. These variants are rare in children.
Generalized pustular psoriasis is characterized by a generalized acute or subacute annular eruption of

erythematous, thin plaques with numerous discrete pustules (picture 3). Children can present with pustules
on preexisting psoriatic plaques or, more commonly, on previously normal skin. The pustules are usually
sterile but can become secondarily infected. The pustules progress to crusts, and patients with acute disease
ultimately progress to generalized erythroderma and exfoliation. Nail and mucous membrane involvement is
1368
not uncommon. Hospitalization is often required for acute generalized pustular psoriasis due to associated
abnormalities in temperature regulation and cardiovascular stability. (See "Pustular psoriasis: Pathogenesis,
Pustular psoriasis may also present with involvement limited to the palms and soles (pustulosis palmaris et
plantaris) or intertriginous distribution that begins in infancy [22]. (See "Palmoplantar pustulosis:
Pustular psoriasis may be an indicator of rare genetic syndromes. Pustular psoriasis in infancy, especially
when there is associated sterile osteomyelitis or periostitis, should raise suspicion for abnormalities of
interleukin (IL)-1 (deficiency of IL-1 receptor antagonist [DIRA]) or IL-36 (deficiency of IL-36 receptor
antagonist [DITRA]), rare autosomal recessive disorders that present with pustular psoriasis [23-27]. Pustular
psoriasis is also a less common manifestation of a CARD14 mutation [7,8].
The presentation of erythrodermic psoriasis overlaps with pustular psoriasis. Erythrodermic psoriasis is
characterized by widespread cutaneous erythema and associated scale and exfoliation. (See "Neonatal and
infantile erythroderma", section on 'Psoriasis' and "Erythrodermic psoriasis in adults".)
Special sites — Facial, scalp, intertriginous, and diaper area involvement are particularly common
distributions of psoriasis in children:
● Facial involvement – Facial psoriasis is more common in children than in adults and is the sole
manifestation of psoriasis in 4 to 5 percent of children [11,20,28,29]. In children, facial psoriasis often
presents as erythematous, scaly patches or plaques on the eyebrows, nasolabial folds, perioral skin, or
other facial areas [29].
● Scalp involvement – Scalp psoriasis is common in children with psoriasis, occurring in up to 79 percent
[21]. Scalp psoriasis is more common in girls than boys, which may be secondary to the Koebner
phenomenon (lesion development in sites of skin trauma) induced by frequent combing, brushing, or
vigorous shampooing [21].
Well-demarcated, erythematous, scaly plaques are typical, although the plaques may also have a salmon-
colored, greasy appearance similar to seborrheic dermatitis (picture 4A). While seborrheic dermatitis
tends to remain within the hairline, psoriasis plaques often extend beyond the hairline to the upper
forehead, pre- and postauricular skin, and nuchal areas (picture 5).
● Inverse psoriasis – Inverse psoriasis occurs more frequently in the pediatric population than in adults.
Shiny, erythematous, thin plaques occur in a flexural distribution (eg, axillae, inguinal skin, gluteal cleft),
sparing the extensor surfaces (picture 4B) [30]. Scale is minimal or absent.
● Diaper area involvement – Psoriatic diaper rash (also known as "napkin psoriasis") may be the initial
manifestation of psoriasis in young children, with or without psoriasis present elsewhere on the body
[20]. Children typically have brightly erythematous and well-demarcated plaques on skin covered by the
diaper (picture 6A-C). Scale is often masked by the increased moisture in the diaper area. Psoriatic
1369
diaper rash often resolves with toilet training, suggesting that the Koebner phenomenon contributes to
development. Children may continue to have anogenital psoriasis past infancy.
● Nail psoriasis – Nail involvement affects 25 to 50 percent of children with psoriasis and is more
common in boys than girls [21]. Pitting is the most common manifestation but discoloration,
onycholysis, and subungual hyperkeratosis also occur (picture 7A-B). (See "Nail psoriasis" and "Overview
of nail disorders".)
COMORBIDITIES
Pediatric psoriasis is associated with increased risk for various comorbidities, including obesity and other
cardiovascular risk factors, arthritis, psychiatric disorders, and other diseases [9].
Obesity and cardiovascular risk — Obesity is the most common comorbidity of pediatric psoriasis. In an
international, cross-sectional study of 409 children with psoriasis, children with psoriasis were significantly
more likely to be obese (body mass index [BMI] ≥95th percentile) than controls (odds ratio [OR] 4.29, 95% CI
1.96-9.39) [5]. Both children with severe psoriasis and children with milder psoriasis exhibited elevated risk
for obesity (OR 4.92, 95% CI 2.20-10.99 and OR 3.60, 95% CI 1.56-8.30).
Children with psoriasis also appear to have increased risk for other components of the metabolic syndrome.
Population-based studies have found increased rates of hyperlipidemia, hypertension, and diabetes in
children with psoriasis [3,31].
However, although psoriasis is independently associated with an increased risk of metabolic syndrome, this
risk appears to be largely driven by obesity. In a retrospective cohort study using administrative claim data
from a large database of privately insured patients over a 10-year period, nearly 30,000 children with
psoriasis were compared with a similar-size cohort of age- and sex-matched children without psoriasis [32].
Nonobese children with psoriasis had an approximately 40 to 75 percent increased risk of elevated lipid
levels, hypertension, diabetes, and metabolic syndrome compared with nonobese children without psoriasis.
In contrast, these risks were 6 to 20 times higher in children with psoriasis who were also obese and were
similar to those estimated in obese children without psoriasis.
Psoriatic arthritis — The prevalence of psoriatic arthritis among children with psoriasis is unclear. Psoriatic
arthritis may precede or follow the onset of cutaneous manifestations of psoriasis. Younger children tend to
have dactylitis and small joint involvement, while older children more often have enthesitis and axial joint
disease [33,34]. Psoriatic arthritis in children is reviewed in detail separately. (See "Psoriatic juvenile
idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis".)
Psychosocial effects — Psoriasis has a negative effect on the quality of life of both affected children and
their families [35,36]. In a study of 208 children (ages 4 to 17 years) with moderate-to-severe plaque psoriasis,
health-related quality of life was similar to children with arthritis and asthma and worse than children with
diabetes [37]. Children with psoriasis also have an increased risk of anxiety and depression [38,39].
1370
Other — Less common disorders that may occur with increased frequency in children with psoriasis include
Crohn disease (but not ulcerative colitis), rheumatoid arthritis, and uveitis [3,40,41].
A general review of comorbidities of psoriasis is provided separately. (See "Comorbid disease in psoriasis".)
DIAGNOSIS
The diagnosis of psoriasis in children usually can be made based upon the clinical features. A skin biopsy is
not necessary for the diagnosis of most patients.
Clinical assessment — Performance of a full skin examination is helpful for diagnosis and assessing the
extent of disease. The classic clinical findings of psoriasis are well-demarcated, erythematous plaques. Of
note, erythema may be less obvious in patients with highly pigmented skin (Fitzpatrick skin type V or VI).
Plaques may appear violaceous or hyperpigmented rather than erythematous in these patients.
Certain features strongly suggest specific clinical forms of psoriasis:
● Chronic plaque psoriasis: Presents with erythematous plaques with micaceous scale and sharply
demarcated borders, often involving sites such as the elbows, knees, scalp, or lower back (picture 1A-B,
1D). Children may also exhibit plaques with thinner scale or less distinct borders. Removal of scale from
plaques often results in pinpoint areas of bleeding (Auspitz sign). Facial, intertriginous, and diaper-area
involvement are also common in children; however, scale may be minimal or absent in these areas.
● Guttate psoriasis: Presents with numerous, small, "drop-like," erythematous papules and plaques,
particularly when involving the trunk and proximal extremities (picture 2). Plaques are erythematous.
● Generalized pustular psoriasis and erythrodermic psoriasis: Acute generalized pustular psoriasis
presents with widespread erythema, pustules, and scale. Erythrodermic psoriasis presents with
widespread erythema and scale. Patients with these disorders often appear systemically ill.
● Inverse psoriasis: Presents with well-demarcated, shiny, erythematous, thin plaques within skin folds
and/or on anogenital skin (picture 4B). Scale is minimal or absent.
● Diaper area (napkin) psoriasis: Presents with shiny, erythematous patches involving skin covered by
diaper; there is minimal or absent scale (picture 7A-B). Psoriasis involving other sites also may be
present.
Additional features that support a diagnosis of psoriasis, but are not required for diagnosis, include:
● Family history of psoriasis
● Concomitant nail dystrophy consistent with nail psoriasis (see "Nail psoriasis")
● Onset associated with known disease trigger (eg, streptococcal infection) (see 'Risk factors' above)
● History of the Koebner phenomenon (development of skin disease in sites of skin trauma)
1371
● Joint or axial symptoms or signs suggestive of psoriatic arthritis (see "Psoriatic juvenile idiopathic
arthritis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations')
Skin biopsy — Skin biopsies are almost never performed in children with psoriasis. When the diagnosis is in
question, however, a confirmatory biopsy can be performed; this is most often necessary with pustular
psoriasis. The histologic findings of psoriasis include epidermal thickening, retention of nuclei in the stratum
corneum (parakeratosis), and a mononuclear infiltrate with collections of neutrophils in the stratum corneum
and/or subcorneal layer.
The differential diagnosis of psoriasis includes atopic dermatitis as well as other papulosquamous disorders
that can occur in children. Most often, the history and physical examination are sufficient to distinguish
psoriasis from these conditions, but a skin biopsy can be helpful in ambiguous presentations.
Disorders commonly in the differential diagnosis of guttate and plaque psoriasis include:
● Atopic dermatitis – Atopic dermatitis is common in children. In infants, atopic dermatitis often manifests
as erythematous, scaly patches on the face, extensor surfaces, and/or scalp (picture 8A-B). The diaper
area is usually spared (picture 8B). Older children usually have erythematous patches or lichenified
plaques in flexural areas (eg, antecubital and popliteal fossae, volar wrists, ankles, or neck (picture 9)).
Occasionally, children present with an overlap of atopic dermatitis and psoriasis, consisting of lesions
with intermediate morphology or the presence of lesions characteristic of each condition, which can
complicate a clinical diagnosis [20]. The plaques of psoriasis tend to be more well-defined and less
pruritic than those of atopic dermatitis. (See "Atopic dermatitis (eczema): Pathogenesis, clinical
● Pityriasis rosea – Pityriasis rosea is a benign, self-limited disorder that may be confused with guttate
psoriasis. Pityriasis rosea often begins with a single lesion ("herald patch") followed by a secondary
eruption. The herald patch tends to be a well-demarcated, scaly patch on the trunk, upper arm, neck, or
thigh with a slightly elevated outer border. The secondary eruption consists of smaller, often pruritic
papules with a collarette of scale (picture 10A-B). The papules most often occur in a characteristic
"Christmas tree" distribution on the trunk, usually sparing the face and distal extremities. Spontaneous
resolution usually occurs within a few months. The histopathologic features of pityriasis rosea are not
diagnostic, but the characteristic distribution and natural history helps to distinguish this condition from
guttate psoriasis. (See "Pityriasis rosea".)
● Pityriasis lichenoides chronica – Pityriasis lichenoides chronica (PLC) is rare inflammatory skin
condition, which is part of the spectrum of pityriasis lichenoides. PLC can develop de novo or progress
from pityriasis lichenoides et varioliformis acuta (PLEVA). Clinically, PLC consists of multiple and diffuse,
scaly, erythematous to brown papules and plaques that remit (with residual dyspigmentation) and
relapse over months to years (picture 11). Unlike psoriasis, PLC tends not to improve with topical
1372
corticosteroids but may resolve with systemic antibiotic therapy. Histopathologic evaluation of biopsy
specimens can further distinguish PLC from psoriasis if clinical assessment is insufficient. (See
"Pityriasis lichenoides chronica".)
● Pityriasis rubra pilaris – Pityriasis rubra pilaris (PRP) is a skin condition typically characterized by
follicular papules coalescing into hyperkeratotic plaques and accompanied by salmon-colored
palmoplantar keratoderma (picture 12). The clinical course varies from resolution within 6 to 12 months
to a more protracted course, with remissions and exacerbations similar to psoriasis. When unable to
distinguish psoriasis and PRP morphologically, pathology can be helpful. Biopsy of follicular-based PRP
lesions reveals follicular keratosis, alternating epidermal parakeratosis and orthokeratosis, and dermal
mononuclear cell infiltrates. Some patients may at times show features of PRP and at other times
psoriasis; it is possible that these patients harbor a heterozygous mutation in CARD14, which may
variably manifest as PRP, psoriasis, or erythrodermic psoriasis with pustules [7,8]. (See "Pityriasis rubra
pilaris".)
The differential diagnosis of localized and generalized pustular psoriasis includes other pustular disorders
that can occur in children, such as infectious pustulosis, eosinophilic pustular folliculitis in infants, and
infantile acropustulosis. A culture can distinguish infectious pustulosis from the sterile pustules of pustular
psoriasis. Eosinophilic pustular folliculitis in infancy typically begins within the first few weeks of life and is
characterized by recurrent crops of pustules on the scalp and face. Less frequently, other body areas are
involved. Acropustulosis of infancy usually begins within the first several months of life and presents with
recurrent crops of pruritic vesicles and pustules, with a predilection for acral skin (picture 13). A skin biopsy
can help to distinguish eosinophilic folliculitis and infantile acropustulosis from pustular psoriasis when
needed. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)
ADDITIONAL EVALUATION
Psoriatic arthritis is a common comorbidity of psoriasis. Children should be assessed for signs or symptoms
of psoriatic arthritis at the time of diagnosis of psoriasis and periodically thereafter. Helpful screening
questions include inquiring about joint redness and swelling, limp, and joint pain and stiffness after inactivity.
Suggestive clinical findings include oligoarthritis, spinal or sacroiliac arthritis, enthesitis, dactylitis, and
uveitis. The diagnosis of psoriatic arthritis in children is reviewed separately. (See "Psoriatic juvenile
idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
Given the association of psoriasis with increased risk for other diseases (eg, obesity, hypertension,
hyperlipidemia, diabetes), clinicians treating children for psoriasis should be cognizant of recognizing
children who may benefit from screening for comorbidities [42]. (See 'Comorbidities' above.)
Psoriasis can have negative psychosocial effects. Asking children about their feelings about their psoriasis
may help to identify children who may benefit from emotional support or other interventions. National
support groups, such as the National Psoriasis Foundation, offer education and support. (See 'Psychosocial
effects' above.)
1373
In sum, we agree with the pediatric psoriasis comorbidity screening guidelines outlined in the joint American
Academy of Dermatology-National Psoriasis Foundation (AAD-NPF) guidelines of care for the management
and treatment of psoriasis in pediatric patients [9]. Some of the recommendations for screening for specific
disorders, including insulin resistance, dyslipidemia, hypertension, nonalcoholic fatty liver disease, and
mental health, overlap with recommendations for children without psoriasis, and screening can be performed
as part of routine health assessment visits in the primary care setting.
The AAD-NPF screening guidelines for children with psoriasis include:
● Obesity – Routinely assess for obesity status. Routinely assess obese patients for comorbidities of
obesity. (See "Clinical evaluation of the obese child and adolescent".)
● Cardiovascular disease – Screen for cardiovascular risk factors when history and physical examination
findings show a potential risk. Patients who have cardiovascular risk factors (eg, obesity, dyslipidemia,
diabetes, hypertension, or metabolic syndrome) should be referred to appropriate specialists for
additional evaluation and management. (See "Pediatric prevention of adult cardiovascular disease:
Promoting a healthy lifestyle and identifying at-risk children", section on 'Identifying children at risk for
cardiovascular disease'.)
● Insulin resistance – Screen or refer for screening for insulin resistance and diabetes mellitus every three
years in obese children (or overweight children with other risk factors for insulin resistance) beginning at
age 10 or the onset of puberty, whichever is first. (See "Epidemiology, presentation, and diagnosis of type
2 diabetes mellitus in children and adolescents", section on 'Screening'.)
● Dyslipidemia – Screen or refer for screening for dyslipidemia (total cholesterol, high-density lipoprotein
cholesterol, low-density lipoprotein cholesterol, and triglyceride levels) between the ages of 9 and 11
years and between the ages of 17 and 21 years. Patients with increased risk for dyslipidemia may be
screened more often based upon the clinician's discretion. Refer patients with dyslipidemia to their
primary care clinician or an endocrinologist for additional evaluation and management. (See
"Dyslipidemia in children: Definition, screening, and diagnosis".)
● Hypertension – Screen for hypertension annually beginning at three years of age. (See "Definition and
diagnosis of hypertension in children and adolescents".)
● Nonalcoholic fatty liver disease – Obtain or refer for obtainment of alanine aminotransferase
measurement starting at nine years of age for obese children and overweight children. Screening should
be repeated every two to three years. (See "Nonalcoholic fatty liver disease in children and adolescents",
section on 'Screening'.)
● Psoriatic arthritis – Screen for arthritis through a thorough history and physical examination as part of
standard ongoing management of children with psoriasis. Patients who show signs and symptoms of
inflammatory arthritis should be referred to a rheumatologist with pediatric expertise, if available, for
additional evaluation and management. (See "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical
manifestations, and diagnosis", section on 'Diagnosis'.)
1374
● Mental health – Routinely screen or refer for screening for depression and anxiety in all children with
psoriasis. Screen yearly for substance abuse beginning at 11 years of age. Refer patients with mental
health or substance abuse concerns to an appropriate health care professional for assessment and
management. (See "Screening tests in children and adolescents", section on 'Depression screening' and
"Screening tests in children and adolescents", section on 'Nicotine, alcohol, and substance use'.)
● Inflammatory bowel disease – For patients with signs and symptoms of inflammatory bowel disease,
consider consultation with a gastroenterologist with pediatric expertise, if available, for further
evaluation and management. (See "Clinical presentation and diagnosis of inflammatory bowel disease in
children".)
● Basics topics (see "Patient education: Psoriasis (The Basics)" and "Patient education: Psoriatic arthritis
in children (The Basics)")
● Beyond the Basics topics (see "Patient education: Psoriasis (Beyond the Basics)" and "Patient education:
Psoriatic arthritis (Beyond the Basics)")
● Psoriasis is a common immune-mediated disease that may begin during childhood or adulthood.
Approximately one-third of adults with psoriasis have a history of disease onset during the first two
decades of life. (See 'Epidemiology' above.)
1375
● A complex interplay of environmental and genetic factors contributes to risk for psoriasis. The human
leukocyte antigen type Cw6 (PSOR1) is the most common predisposing genetic risk factor for early-onset
psoriasis (psoriasis before age 40 years). (See 'Risk factors' above.)
● The major clinical forms of psoriasis are similar in children and adults. Chronic plaque psoriasis is the
most common form of psoriasis in children. Guttate, pustular, and erythrodermic psoriasis are less
frequent. (See 'Clinical presentation' above.)
● Chronic plaque psoriasis is characterized by the presence of well-demarcated, erythematous plaques

with silvery-white, mica-like scale (picture 1A-D). In children with highly pigmented skin (Fitzpatrick skin
type V or VI), erythema may be less prominent and plaques may appear violaceous or hyperpigmented.
(See 'Chronic plaque psoriasis' above.)
● Children with psoriasis are more likely to present with psoriasis involving the face, scalp, or intertriginous
skin than adults (picture 4A-B). Involvement of the diaper area (also known as "napkin psoriasis") can be
the initial manifestation of psoriasis in infants and young children (picture 6A-C). (See 'Special sites'
above.)
● Children with psoriasis have increased risk for a variety of other diseases. Examples include psoriatic
arthritis, obesity, hypertension, diabetes, hyperlipidemia, depression, and anxiety. (See 'Comorbidities'
above.)
● The diagnosis of psoriasis in children usually can be made based upon the clinical features. Skin
biopsies are reserved for patients in whom the diagnosis remains uncertain after the clinical evaluation.
1376
GRAPHICS
Clusters of small plaques on the knees.
1377
Thick, well-demarcated plaques of psoriasis on the lower legs of an obese adolescent girl.
1378
Resolving psoriasis plaque with associated postinflammatory hypopigmentation.
1379
Annular psoriasis plaque.
1380
1381
Guttate psoriasis
Drop-like guttate psoriasis on the lower back. Some lesions have cleared, leaving postinflammatory hypopigmentation.
1382
Tiny pustules with surrounding erythema studding the back, some in an annular configuration.
1383
1384
Characteristic areas of psoriasis involvement on the periphery of the scalp, postauricular area, conchal
area of the ear, and neck.
1385
Inverse psoriasis
Inverse psoriasis involving the axillae in a child.
1386
Infantile psoriasis
Erythematous and scaling plaques in an infant with psoriasis. Note the involvement of the diaper area, usually spared
in infants with atopic dermatitis.
1387
Psoriasis
Erythematous, scaly papules and plaques and associated postinflammatory hypopigmentation on the diaper area, extremities, and trunk of
an infant with psoriasis.
1388
Infantile psoriasis of the diaper area
Sharply defined plaques with silvery scales in an infant with psoriasis of the diaper area.
1389
Nail psoriasis
Multiple dystrophic fingernails and toenails.
1390
Nail psoriasis
Pitting, ridging, and discoloration of the nail.
1391
Hyperpigmented, lichenified patches are present on the face of this infant with atopic
dermatitis.
1392
The diaper area is relatively spared in this infant with widespread atopic dermatitis.
1393
Atopic dermatitis
Atopic dermatitis involving the sides of the neck. Note the scaling and characteristic reticular pigmentation.
1394
Pityriasis rosea
Erythematous plaques with trailing collarettes of scale.
1395
Pityriasis rosea
Hyperpigmented oval plaques on the trunk in a "Christmas tree" distribution.
1396
Multiple red-brown papules with adherent scale and hypopigmented macules on the legs.
1397
Salmon-colored palmoplantar keratoderma.
1398
Acropustulosis of infancy
Multiple small pustules are present on the foot.
Reproduced with permission from www.visualdx.com. Copyright VisualDx. All rights reserved.
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Psoriasis in children: Management of chronic plaque psoriasis

Authors: Amy S Paller, MD, Emily Broun Lund, MD
Section Editors: Kristina Callis Duffin, MD, Moise L Levy, MD
INTRODUCTION
Psoriasis is a systemic immune-mediated disease that can negatively impact the quality of life of affected
children and their families (picture 1A-F). In most children, psoriasis can be adequately treated with topical
medications. However, children with moderate to severe psoriasis often require phototherapy or systemic
therapy.
Although many of the therapies commonly administered for psoriasis in children and adults are similar, high-
quality efficacy and safety trials to guide the best approach to psoriasis in children are more limited. As a
result, the development of guidelines for the treatment of pediatric psoriasis is challenging. In clinical
practice, consideration of patient-specific factors, such as patient age, severity of disease, comorbidities, and
tolerance of the risks and side effects of specific medications, guides the approach to treatment (algorithm
1).
The management of chronic plaque psoriasis, the most common clinical variant of psoriasis in children, will
be reviewed here. The diagnosis of psoriasis in children and the approach to treatment of other clinical
variants of psoriasis and psoriatic arthritis are reviewed separately.
● (See "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis".)

● (See "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis" and
"Psoriatic juvenile idiopathic arthritis: Management and prognosis".)
PATIENT ASSESSMENT
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The severity of psoriasis influences the approach to treatment. Most children have mild to moderate
psoriasis, which often can be adequately treated with topical medications such as corticosteroids,
calcineurin inhibitors, and vitamin D analogs. Approximately 10 to 20 percent of children have moderate to
severe psoriasis, defined as psoriasis that involves more than 10 percent of the body surface area or
psoriasis that cannot be adequately improved with topical therapy. Moderate to severe psoriasis often
requires phototherapy or systemic therapy (algorithm 1).
Other patient-specific factors can influence treatment selection. The concomitant presence of psoriatic
arthritis can justify use of systemic antipsoriatic therapy in children with mild skin involvement, and
modifications to the therapeutic approach are indicated when treating very young children. (See "Psoriatic
juvenile idiopathic arthritis: Management and prognosis" and 'Very young children' below.)
MILD TO MODERATE PLAQUE PSORIASIS IN CHILDREN AT LEAST FOUR YEARS OF AGE
Mild to moderate plaque psoriasis is generally defined as psoriasis involving less than 10 percent of the total
body surface area. Given the limited amount of skin involvement, topical therapy is usually manageable for
patients and their caregivers (algorithm 1). Modifications for treating psoriasis in special sites, including the
face, intertriginous skin, and scalp, are reviewed below. (See 'Face and intertriginous skin' below and 'Scalp'
below.)
First-line therapies — Topical corticosteroids are the mainstay for pediatric psoriasis based upon the
extensive clinical experience that supports efficacy for this indication and wide availability and affordability
of some of these agents [1]. However, long-term corticosteroid therapy is associated with increased risk for
side effects such as skin atrophy. Thus, nonsteroidal topical agents (eg, topical calcineurin inhibitors, topical
vitamin D analogs) are often added to (or substituted for) topical corticosteroid therapy to reduce
corticosteroid exposure.
Topical corticosteroids — Plaque psoriasis usually responds to topical corticosteroid therapy provided the
agent selected has adequate potency:
● Administration – Psoriasis plaques on the trunk and extremities in children can be treated with high-
potency to medium-potency (group 2 to 4 (table 1)) topical corticosteroids applied twice daily. Signs of
improvement (reduced erythema and plaque thickness) are sometimes evident within the first one to two
weeks, with additional improvement occurring with continued use. We continue daily treatment for up to
four weeks. Once sufficient improvement occurs, the topical corticosteroid can be discontinued or
tapered to intermittent use (two consecutive days per week [eg, weekends]) to maintain the response, if
needed. Daily application for up to four weeks is resumed for subsequent flares.
If psoriasis plaques on the trunk or extremities do not respond sufficiently within four weeks of daily
treatment with a group 2 to 4 topical corticosteroid, a short course (≤2 weeks) of a super-high potency
(group 1 (table 1)) topical corticosteroid may lead to improvement. After two weeks of use, application
1401
should be tapered to intermittent use (eg, two consecutive days per week). Alternatively, the patient can
be transitioned to a lower potency corticosteroid.
We often incorporate a vitamin D analog in the treatment regimen when feasible. Patients or caregivers
can apply the vitamin D analog simultaneously with the topical corticosteroid during treatment of acute
flares. Once the frequency of topical corticosteroid application is reduced to two days per week,
application of the topical vitamin D analog may continue on the remaining five days. (See 'Topical
vitamin D analogs' below.)
Topical corticosteroids are available in a wide variety of vehicles (eg, ointment, cream, lotion, gel,
solution, spray, foam). In general, ointments are preferred over other vehicles to enhance penetration of
psoriatic scale. However, patient preferences and certain sites (eg, hair-bearing scalp) warrant
consideration of other vehicles to maximize the likelihood of adherence to therapy. (See 'Scalp' below.)
Inadequate penetration of topical corticosteroids can lead to poor responses in children with markedly
hyperkeratotic plaques. Compounding topical corticosteroids with keratolytics, like 6% salicylic acid, with
or without topical tar can facilitate treatment of these plaques.
Topical corticosteroids should be used with caution on facial and intertriginous skin due to increased
risk for cutaneous side effects. Use of medium to high-potency topical corticosteroids should be avoided
in these areas. (See 'Face and intertriginous skin' below.)
● Efficacy – Use of topical corticosteroids for pediatric psoriasis is primarily based upon extensive clinical
experience that supports efficacy of these agents and data from randomized trials in adults [2-4]. There
is a paucity of randomized trial data in children. In a phase 3 randomized trial that compared clobetasol
emulsion formulation foam with vehicle and clobetasol ointment for moderate to severe plaque psoriasis
in individuals 12 years and older, among participants ages 12 to 17 years, two of eight children in the
clobetasol foam group compared with zero of one children in the vehicle group achieved clearance or
near clearance after two weeks [5].
● Adverse effects and precautions – Cutaneous atrophy and striae are potential side effects of topical
corticosteroid therapy. Risk for these side effects can be reduced by limiting the duration of application,
avoiding excessive application (thin layer is sufficient), and avoiding use of potent corticosteroids on the
face and intertriginous areas. (See 'Face and intertriginous skin' below.)
Systemic absorption of topical corticosteroids may also lead to hypothalamic pituitary axis suppression,
particularly in children. To minimize risk of this side effect, avoidance of long-term daily use of topical
corticosteroids on large skin areas is prudent. (See "Topical corticosteroids: Use and adverse effects",
section on 'Systemic'.)
Topical calcineurin inhibitors — Topical calcineurin inhibitors are an additional first-line treatment option
for psoriasis in children. These agents are primarily used as an alternative to topical corticosteroid therapy
for psoriasis in sites with the greatest risk for corticosteroid-induced skin atrophy, including the face and
intertriginous areas. (See 'Face and intertriginous skin' below.)
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Topical vitamin D analogs — Topical vitamin D analogs utilized for psoriasis include calcipotriene,
calcitriol, and tacalcitol. Tacalcitol is not available in the United States:
● Administration – The onset of action of topical vitamin D analogs is relatively slow (six to eight weeks).
Thus, these agents are generally used in conjunction with or after faster-acting topical corticosteroid
therapy. Common regimens include:
• As adjunctive treatment: Simultaneous, twice daily application with a potent corticosteroid. Patients
may mix the two agents in their hands prior to application or use a commercially available
combination medication (eg, calcipotriene 0.005% and betamethasone dipropionate 0.064%).
• As a corticosteroid-sparing agent: Twice daily application of the topical vitamin D analog five days
per week (eg, Monday to Friday) and application of a topical corticosteroid two days per week (eg,
weekends).
● Efficacy – Topical vitamin D analogs have demonstrated efficacy and safety in randomized trials in
adolescents and adults with psoriasis [6,7]. (See "Treatment of psoriasis in adults", section on 'Topical
vitamin D analogs'.)
Randomized trial data in children under the age of 12 are limited. In an eight-week randomized trial in
which 77 children with psoriasis (<30 percent body surface area involvement, ages 2 to 14 years) were
randomly assigned to apply either calcipotriol ointment or vehicle twice daily, greater reductions in
redness and scaliness occurred in the calcipotriol group than in the placebo group, but significant
differences in plaque thickness and the Psoriasis Area and Severity Index (PASI) score were not
observed between the two groups [8]. Uncontrolled studies also suggest benefit in children with plaque
psoriasis [9,10].
● Adverse effects and precautions – Topical vitamin D analogs are generally well tolerated. Skin irritation
is a potential side effect that can limit use in some children. Daily use of an emollient may help to reduce
skin irritation [1]. Reversible hypercalcemia is an additional potential side effect when topical vitamin D
analogs are used on large areas of the body.
Emollients — The application of emollients is an important adjunctive measure for psoriasis. Moisturizing
the skin can make scale less prominent and reduce pruritus and fissuring. Emollients may also help to
minimize the Koebner phenomenon (occurrence of new psoriasis plaques in sites of skin trauma) through
reducing the likelihood of skin irritation.
Other therapies — Other topical agents, such as tazarotene, tar, and anthralin, are less frequently used for
pediatric psoriasis because of side effects. Skin irritation often limits the use of tazarotene and anthralin in
children. Tar is malodorous and can stain skin and clothing:
● Tazarotene – Although randomized trial data support the efficacy of once daily application of tazarotene
for plaque psoriasis in adults, such data are lacking in children. A case report describes successful
1403
treatment of nail psoriasis in a child with tazarotene 0.05% [11]. (See "Treatment of psoriasis in adults",
section on 'Tazarotene'.)
● Tar – Tar has anti-inflammatory and antiproliferative effects that can lead to improvement in psoriasis
[12]. Tar is commercially available in a variety of products, including coal tar-containing solutions (liquid
carbonis detergens [LCD]), crude coal tar, coal tar extract, coal tar distillate, and tar blends [13]. In
addition, tar may be compounded with topical corticosteroids and/or salicylic acid. Its objectionable
smell, tendency to stain skin and clothing, and associated risk for folliculitis make tar a less appealing
treatment option for psoriasis on the face, trunk, or extremities. However, coal tar is commonly used in
shampoo formulations for scalp psoriasis. (See 'Scalp' below and "Treatment of psoriasis in adults",
section on 'Tar'.)
● Anthralin – Similar to tar, anthralin, or dithranol, has antiproliferative and anti-inflammatory effects and
can improve psoriasis [14-16]. Anthralin is applied for increasing lengths of time, as tolerated, until
effectiveness is achieved. Anthralin can cause skin irritation and may stain skin and clothing, making it a
less desirable treatment. Use of anthralin is uncommon in the United States; the drug is more frequently
used in Europe. (See "Treatment of psoriasis in adults", section on 'Anthralin'.)
Special sites — Facial, intertriginous, and scalp involvement are common in children with psoriasis (picture
1C-D). Modifying the approach to treatment for these areas is helpful for maximizing results and minimizing
side effects.
Face and intertriginous skin — Both topical corticosteroids and topical calcineurin inhibitors are effective
for facial and intertriginous psoriasis and are commonly used for these indications (picture 1C). Topical
calcineurin inhibitors are favored for long-term treatment of these sites given the elevated risk for
corticosteroid-induced skin atrophy in these areas. However, topical calcineurin inhibitors are typically more
expensive than topical corticosteroids (see "Topical corticosteroids: Use and adverse effects", section on
'Adverse effects'):
● Administration – When treating facial or intertriginous psoriasis in children, we generally initiate

treatment with a topical calcineurin inhibitor (tacrolimus 0.1% ointment or pimecrolimus 1% cream).
Tacrolimus is also available as a 0.03% ointment; we typically reserve use of the 0.03% ointment for
children who cannot tolerate the 0.1% formulation due to skin irritation. The topical calcineurin inhibitor
is applied twice daily until satisfactory improvement. Improvement is expected within the first month of
treatment. Once resolution has occurred, treatment can be stopped. Application is resumed upon
recurrence of disease.
Alternatively, topical corticosteroids can be used for psoriasis on the face or intertriginous skin. The
agent selected should have a low potency (group 6 or 7). The corticosteroid is applied twice daily for up
to two weeks. If sufficient improvement is obtained, treatment can be stopped with the plan to resume
treatment during subsequent flares. If the response is insufficient or disease recurs rapidly (eg, within a
few weeks), we favor transitioning the patient to topical calcineurin inhibitor therapy.
1404
● Efficacy – Although randomized trials support the efficacy of topical calcineurin inhibitors for facial and
intertriginous psoriasis in adults, there are no randomized trials evaluating these agents for psoriasis in
children. A six-month uncontrolled study that evaluated the efficacy of tacrolimus 0.1% ointment for
facial or inverse psoriasis in 11 children (ages 6 to 15 years) supports benefit in children [17]. Among the
eight patients who completed the study, all improved, with the most improvement occurring within the
first 30 days. By day 30, one patient achieved complete clearance, and the remainder had excellent
improvement. Successful treatment of facial or genital psoriasis in children with pimecrolimus cream is
documented in case reports [18,19]. (See "Treatment of psoriasis in adults", section on 'Calcineurin
inhibitors'.)
● Adverse effects and precautions – Topical calcineurin inhibitor therapy is generally well tolerated.
Transient burning sensations, erythema, and pruritus are the most common side effects. Concerns have
been raised regarding the long-term safety of calcineurin inhibitors, particularly in regard to cancer risk.
However, a causative relationship between these agents and malignancy has not been established. (See
"Treatment of atopic dermatitis (eczema)", section on 'Long-term safety concerns'.)
Scalp — Although scalp psoriasis will typically respond to the same topical medications as plaque
psoriasis on the trunk or extremities, the presence of abundant terminal hair demands consideration of the
best way to deliver therapy (picture 1D). Topical corticosteroids, topical vitamin D analogs, tar, and
keratolytics are commonly used for therapy.
Often, patients find medications in shampoos, foams, solutions, gels, sprays, or oils preferable for application
to the scalp. The vehicle options should be discussed with the child or caregiver to identify the most
acceptable regimen. Oils can be particularly helpful for gentle removal of adherent scale.
We find the following initial regimen useful when performed daily for two weeks during flares:
● Apply fluocinolone 0.01% in oil to a wet scalp under a shower cap for one to two hours
● Wash the hair with one of the following:
• Tar shampoo (eg, 0.5 or 1% coal tar)
• Keratolytic shampoo (eg, 2, 3, or 6% salicylic acid)
A common alternative approach is treatment with a potent topical corticosteroid alone (eg, clobetasol
propionate, fluocinonide, betamethasone dipropionate) or in combination with a topical vitamin D analog.
Uncontrolled studies support efficacy of the combination calcipotriene and betamethasone dipropionate for
scalp psoriasis in children [20-22]. As with treatment of the trunk or extremities, daily application of high-
potency corticosteroids on the scalp is typically limited to two to four weeks during flares, depending on the
potency of the agent selected. (See 'Topical corticosteroids' above.)
MODERATE TO SEVERE PLAQUE PSORIASIS IN CHILDREN AT LEAST FOUR YEARS OF AGE
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Topical therapy is often inadequate for children with moderate to severe disease. Frequent application of
topical medications to large skin areas is difficult for patients and caregivers and may increase risk for side
effects of topical therapies.
The major therapeutic options for this population include immunosuppressants (methotrexate, cyclosporine),
phototherapy, biologic agents, and oral retinoids. The topical agents used for milder disease are often used in
conjunction with phototherapy and systemic therapy to maximize the response to therapy. (See 'Mild to
moderate plaque psoriasis in children at least four years of age' above.)
Oral corticosteroid therapy should be avoided due to the potential for precipitating severe psoriasis flares
upon withdrawal.
Our approach — Guidelines on the therapeutic approach to moderate to severe psoriasis in children are
lacking. Selection among the available treatments is dependent upon consideration of patient-specific factors
such as severity of disease, comorbidities, tolerance of risks and side effects, and prior treatment history
(algorithm 1). Our general approach to psoriasis in children over the age of four years is outlined here. Other
approaches may be reasonable. Special considerations for younger children are reviewed below. (See 'Very
young children' below.)
Although topical therapy is frequently inadequate for children with moderate to severe plaque psoriasis, we
typically attempt topical therapy (eg, trial of combination therapy with a potent topical corticosteroid and
topical vitamin D analog for two to three months) prior to initiating other interventions (algorithm 1). This
allows us to identify those children for whom topical therapy is inadequate. (See 'First-line therapies' above.)
Our most frequent initial therapies for pediatric plaque psoriasis that cannot be managed with topical therapy
are methotrexate, narrowband ultraviolet B (UVB) phototherapy, etanercept, and adalimumab. Globally,
methotrexate is the most common systemic medication used for psoriasis in children. Advantages of
methotrexate include a long history of use for pediatric psoriasis, availability of an oral formulation, and low
cost compared with other psoriasis therapies. Disadvantages of methotrexate include a relatively slow onset
of action, the need for laboratory monitoring during treatment, and the potentially serious side effect of
hepatotoxicity. In addition, methotrexate may be less effective than some biologic agents. A randomized trial
found methotrexate inferior to adalimumab for severe chronic plaque psoriasis in children [23]. Of note, the
average methotrexate dose given in the trial was relatively low. (See 'Biologic agents' below and "Treatment of
psoriasis in adults", section on 'Systemic therapies'.)
Ideal candidates for methotrexate therapy are children with relatively stable psoriasis who can tolerate a
delayed onset of action, can tolerate laboratory monitoring, and lack risk factors for methotrexate-induced
hepatotoxicity. Methotrexate should be used with caution in female adolescents due to risk for teratogenicity.
(See "Treatment of psoriasis in adults" and "Treatment of psoriasis in adults", section on 'Hepatotoxicity and
liver biopsy'.)
Our favored use of phototherapy for moderate to severe plaque psoriasis is based upon the absence of risk
for the serious systemic side effects that may occur with systemic therapies. However, phototherapy requires
1406
frequent office visits (unless home phototherapy is implemented), which is difficult for some families, and
phototherapy is not recommended for very young children. In addition, there is some uncertainty regarding
long-term risk for skin cancer in children treated with narrowband UVB phototherapy. Ideal candidates for
narrowband UVB phototherapy are children who can come for frequent visits and who are old enough to
follow instructions and safely remain in a light booth alone. We typically consider phototherapy in children
over the age of six years (most commonly, preadolescents and adolescents), although even young children
can be treated when a parent accompanies the child in the booth and can provide entertainment.
Phototherapy is also a useful option for children and families who desire to avoid systemic therapy.
Emerging data suggest that biologic agents are safer and more effective than nonspecific
immunosuppressants (eg, methotrexate, cyclosporine) for pediatric psoriasis [24]. We often use etanercept
as our first-line biologic agent given that it is the biologic agent with the longest history of use in children with
psoriasis. Disadvantages of etanercept therapy include the need for weekly injections and lesser efficacy
compared with other biologic agents based upon data in adults [25,26]. Our second-line option for biologic
therapy is adalimumab (although we often use this agent as a first line for older teenagers, given the greater
potency relative to etanercept suggested in adult studies). Ustekinumab is an additional treatment option
based upon randomized trial data that support efficacy and safety in adolescents with psoriasis [27]. Data on
the use of other antipsoriatic biologic agents in children are more limited [24]. (See "Treatment of psoriasis in
adults", section on 'Biologic agents'.)
Cyclosporine can be rapidly effective for psoriasis. However, the drug has the potential for serious adverse
effects and is generally reserved for children with acute, severe flares of disease that require immediate relief
and severe psoriasis types such as acute generalized pustular psoriasis and erythrodermic psoriasis. The
side effects of cyclosporine limit the recommended duration of therapy to less than one year. The low cost of
cyclosporine compared with biologic therapy is an advantage of this therapy.
Oral retinoids can be effective for psoriasis but are less favored for chronic plaque psoriasis based upon
lower efficacy as monotherapy compared with other agents. Advantages of oral retinoids include oral
administration and lack of immunosuppression. Teratogenicity of oral retinoids is a concern for female
adolescent patients, particularly for treatment with acitretin. Pregnancy should be avoided for three years
after acitretin treatment.
Children with moderate to severe plaque psoriasis and psoriatic arthritis can benefit from therapies that
simultaneously treat skin and joint disease. (See 'Children with psoriatic arthritis' below and "Psoriatic
juvenile idiopathic arthritis: Management and prognosis".)
Treatment options
Methotrexate — Methotrexate, the most common therapy used for pediatric psoriasis, is a low-cost
therapy that is typically given orally or subcutaneously once per week. Daily folic acid supplementation (1 mg
per day) is indicated during methotrexate therapy:
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● Administration – The starting dose is typically 0.3 mg/kg given once weekly and can subsequently be
increased up to 0.7 mg/kg once weekly to a maximum of 25 mg. Improvement can occur within the first
month, but more often, the onset of action takes at least 10 weeks. We generally assess the response
every three months and increase the weekly dose by 0.1 to 0.2 mg/kg (up to the maximum total dose of
0.6 mg/kg per week) if the child is tolerating the methotrexate but has an inadequate response.
Once excellent improvement has been achieved, weaning from the drug can be attempted to achieve the
lowest effective dose for maintenance of the response. If disease control is maintained at a stable dose
for six months, we typically begin to taper the weekly dose by 0.1 mg/kg each month as tolerated. Most
children require continued treatment to maintain improvement. If flares occur during tapering, increasing
the maintenance dose by 0.1 mg/kg above the dose at which the flare occurred often regains control of
disease.
● Efficacy – Uncontrolled studies support benefit of methotrexate for pediatric psoriasis [28-30]. In a
series of 25 children treated with methotrexate (maximum dose ranging from 0.14 to 0.63 mg/kg per
week) for moderate to severe plaque psoriasis, 4 percent achieved at least 75 percent improvement in
the Psoriasis Area and Severity Index (PASI) score 12 weeks after the start of treatment [28]. After 24
weeks, approximately one-third of children achieved this outcome. Benefit of methotrexate is also
documented in a retrospective study in which 24 children with psoriasis (including 17 with plaque
psoriasis) received methotrexate (0.2 to 0.4 mg/kg per week). All but two children achieved at least a 75
percent improvement in the PASI score during treatment (mean duration of use 4.97 months, range 2 to
16 months) [29].
● Adverse effects and precautions – The most common side effects are gastrointestinal upset, upper
respiratory infections, fatigue, and headaches. Bone marrow suppression and transaminase
abnormalities may also occur. Administration of folic acid and subcutaneous, rather than oral
administration, of methotrexate may help to diminish the gastrointestinal side effects [31]. The typical
dose of folic acid is 1 mg per day. Concomitant sulfa drugs should be avoided.
Baseline and subsequent laboratory monitoring to assess for hematologic and hepatic adverse effects is
necessary for methotrexate therapy. Tuberculosis screening should be performed prior to therapy.
Female adolescent patients should be counseled about the drug's teratogenicity, and all children should
avoid live vaccines while on methotrexate.
Phototherapy — Controlled administration of artificial ultraviolet light, specifically narrowband UVB, can be
an appropriate therapy for some children. Phototherapy options include narrowband UVB and targeted
phototherapy with the excimer laser. Of these, narrowband UVB is more commonly used for the treatment of
children. The excimer laser provides the advantage of minimizing exposure of unaffected skin to UVB, but
data on the efficacy and safety of the excimer laser in children are limited. Psoralen plus ultraviolet A (PUVA)
phototherapy is rarely used in children due to concern for greater risk for side effects compared with
narrowband UVB (see "UVB therapy (broadband and narrowband)" and "Targeted phototherapy" and
"Psoralen plus ultraviolet A (PUVA) photochemotherapy"):
1408
● Administration – Phototherapy is usually administered in the outpatient setting two to three times per
week. Once satisfactory improvement is achieved, the frequency of treatments is tapered as tolerated.
The child must be able to follow instructions and should be comfortable with standing still in an
enclosed space alone. School-age children are typically able to manage phototherapy; some younger
children are reasonable candidates as well [32]. The multiple office visits can be time-consuming and
logistically challenging for some families.
Home phototherapy is a convenient alternative for children who have had phototherapy safely and
effectively initiated in an outpatient setting. Patients and caregivers should be given clear instructions
for the advancement of ultraviolet light exposure and intermittent clinical follow-up is necessary. (See
"Treatment of psoriasis in adults", section on 'Home phototherapy'.)
● Efficacy – Uncontrolled studies support the efficacy of narrowband UVB phototherapy for psoriasis in
children [33-35]. One of the largest studies is a retrospective study that included 88 children treated with
narrowband UVB for psoriasis [33]. Of the 79 children available for final analysis, 73 (92 percent)
achieved at least 75 percent clinical improvement, including 40 children (51 percent) who achieved
complete clearance of skin lesions. The mean duration of treatment was approximately three months,
and the median duration of remission was approximately 20 months.
● Adverse effects and precautions – Potential side effects of narrowband UVB phototherapy include
cutaneous erythema, dryness, pruritus, and blistering. Available data suggest that narrowband UVB does
not increase long-term risk for skin cancer; however, additional studies are necessary to confirm this,
particularly in children. Topical vitamin D analogs should be applied after (not before) phototherapy
sessions. Xeroderma pigmentosum and lupus erythematosus are absolute contraindications to
phototherapy. (See "UVB therapy (broadband and narrowband)", section on 'Short- and long-term adverse
effects' and "UVB therapy (broadband and narrowband)", section on 'Contraindications'.)
Biologic agents — Biologic agents available for the treatment of psoriasis in adults include the tumor
necrosis factor (TNF)-alpha inhibitors etanercept, adalimumab, infliximab, and certolizumab pegol, as well as
ustekinumab (an inhibitor of interleukin [IL] 12 and IL-23), secukinumab (an anti-IL-17A agent), ixekizumab
(an anti-IL-17A agent), brodalumab (an anti-IL-17 receptor A agent), and the anti-IL-23 agents targeting the
p19 subunit of IL-23, which include guselkumab, tildrakizumab, and risankizumab. Only etanercept,
ustekinumab, and adalimumab have been evaluated in randomized trials for the treatment of pediatric
psoriasis [27,36,37]. Only etanercept and ustekinumab are approved by the US Food and Drug Administration
(FDA) for the treatment of psoriasis in children. FDA approval of etanercept and ustekinumab is limited to
children at least 4 years old and 12 years old, respectively:
● Administration – TNF-alpha inhibitors are used more frequently for pediatric psoriasis than other
biologic agents.
Typical pediatric dose regimens for biologic agents are:
• Etanercept: 0.8 mg/kg given once weekly up to a maximum dose of 50 mg
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• Adalimumab: 0.8 mg/kg given at weeks 0 and 1 and then every other week to a maximum dose of 40
mg
• Ustekinumab: Weight-based dosing; for children ≤60 kg, 0.75 mg/kg; for children >60 kg to ≤100 kg,
45 mg; for children >100 kg, 90 mg; ustekinumab is given at weeks 0, 4, then every 12 weeks
● Efficacy – Published randomized trials have demonstrated efficacy and safety of etanercept,
adalimumab, and ustekinumab. Brief summaries of these trials are provided below:
• Etanercept – In a 48-week trial in which 211 children with moderate to severe plaque psoriasis (ages
4 to 17 years) were randomly assigned to receive either etanercept (0.8 mg/kg [maximum dose 50
mg]) or placebo once weekly for 12 weeks, more children treated with etanercept achieved at least
75 percent improvement in the PASI score than children in the placebo group (57 versus 11 percent)
at 12 weeks [36]. In addition, sustained efficacy of etanercept for pediatric psoriasis has been
demonstrated through 96 weeks [38].
• Adalimumab – In a trial in which 114 children (ages 4 to 17 years) were randomly assigned to
methotrexate (0.1 to 0.4 mg/kg per week) or one of two dose regimens of adalimumab (0.4 or 0.8
mg/kg every other week), more patients in the adalimumab 0.8 mg/kg dose group achieved 75
percent improvement in the PASI score than patients in the methotrexate group (58 versus 32
percent) after 16 weeks [23]. Sustained efficacy of adalimumab over 52 weeks in children aged 4 to
18 years has also been reported [39].
• Ustekinumab – In a trial in which 110 adolescents with moderate to severe plaque psoriasis (ages
12 to 17 years) were randomly assigned to one of two regimens of ustekinumab (standard dosing or
half-standard dosing), adolescents who received standard or half-standard dosing were more likely
to achieve at least 75 percent improvement in the PASI score than children treated with placebo (81,
78, and 11 percent, respectively) [27].
The efficacy and safety of other antipsoriatic biologic agents, including secukinumab, ixekizumab,
brodalumab, and guselkumab, for pediatric psoriasis remains to be determined.
● Adverse effects and precautions – The most common side effects of biologic agents are injection site
reactions and upper respiratory tract infections. Although there is concern for increased risk of
opportunistic infections and malignancies, serious adverse events are rare in children. In the randomized
trial that compared adalimumab with methotrexate, rates of infection were similar among the treatment
groups [23]. Increased risk of malignancy has not been documented in children treated with biologic
agents for psoriasis. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
Children treated with biologic agents should be screened for tuberculosis annually. In addition, live
vaccines should be avoided during therapy.
Cyclosporine — Cyclosporine is generally reserved for severe and refractory psoriasis:
1410
● Administration – Cyclosporine is typically given orally at a dose of 4 to 5 mg/kg per day in two divided
doses. Improvement can be rapid, with marked improvement often occurring within the first month of
treatment. Once the disease is controlled, the dose can be tapered as tolerated. The duration of
treatment should be limited to less than one year because of toxicities, particularly hypertension, renal
and hepatic injury, and future malignancies.
● Efficacy – Although cyclosporine has a long history of use for adult psoriasis, data on use for pediatric
plaque psoriasis are limited [40]. In a retrospective study of 38 children and adolescents with
cyclosporine for plaque psoriasis (median daily dose 3.2 mg/kg, range 2 to 5 mg/kg), 15 (39 percent)
achieved at least 75 percent improvement in the PASI score after 16 weeks [41]. Eight patients had to
discontinue treatment due to side effects. (See "Treatment of psoriasis in adults", section on 'Systemic
calcineurin inhibitors'.)
● Adverse effects and precautions – Serious side effects of cyclosporine include nephrotoxicity,
hypertension, hepatotoxicity, hyperlipidemia, metabolic abnormalities, and increased risk for infections
and malignancy. Laboratory monitoring to detect side effects and blood pressure checks are required
during treatment. Live vaccines and macrolide antibiotics, which increase cyclosporine levels, should be
avoided during treatment.
Retinoids — Oral retinoids are accepted effective treatments for pustular, palmoplantar, and erythrodermic
psoriasis but are generally considered less effective for plaque psoriasis than other systemic therapies
[42,43]. Acitretin is the oral retinoid of choice for psoriasis. In our practice, we most often use acitretin for
pustular psoriasis:
● Administration – Acitretin is typically given at a dose of 0.5 to 1 mg/kg per day for plaque psoriasis and
typically takes two to three months for efficacy. Improvement is usually evident within two to three
months [1]. Upon achievement of a satisfactory response, dosing can be tapered to the lowest dose
necessary to maintain improvement.
● Efficacy – Efficacy data for pediatric plaque psoriasis are limited [40,44,45]. In a retrospective study of
154 children treated with systemic therapy for moderate to severe psoriasis, of the 78 children treated
with acitretin for plaque psoriasis, 27 (35 percent) achieved at least 75 percent clearance of skin disease
[45].
● Adverse effects and precautions – The most common side effects are skin and mucosal membrane
dryness and elevation of serum triglyceride levels. Laboratory monitoring for hematologic abnormalities,
hepatotoxicity, and hyperlipidemia is necessary during treatment. Oral retinoids are teratogenic and
pregnancy must be avoided for three years after cessation of acitretin.
Other therapies
Fumaric acid esters — Fumaric acid esters are used for the treatment of psoriasis in Europe. Data from
retrospective studies, case series, and case reports support efficacy in children [40]. One of the largest
studies, a retrospective study of 127 children (ages 6 to 17 years) treated with fumaric acid esters for
1411
psoriasis (including 96 children with plaque psoriasis), found that disease severity improved during treatment
[46]. An approximately 50 percent improvement in the mean PASI score occurred within the first three months
of treatment. Gastrointestinal disorders and flushing were the most common side effects.
In a separate case series of 14 children with recalcitrant plaque psoriasis, treatment with fumaric acid esters
(maximum daily dose 180 to 1200 mg per day and mean treatment duration of 48.6 weeks, range 12 to 124
weeks) was associated with improvement in the PASI score in 9 children (64 percent) [47].
Lymphopenia is potential side effect of fumaric acid esters. Progressive multifocal leukoencephalopathy has
been reported in lymphopenic patients who continued fumaric acid ester therapy [48-50].
Apremilast — Limited data suggest that apremilast, an oral phosphodiesterase 4 inhibitor, may be an
option for chronic plaque psoriasis in children. A phase 2, open-label study in which 42 pediatric patients
aged 6 to 17 years with moderate to severe plaque psoriasis received apremilast (20 or 30 mg given twice
daily based upon weight and age) for two weeks, followed by a 48-week extension phase in which treatment
was continued, found a mean improvement in the week 12 PASI score of 68 percent among adolescents (age
12 to 17 years) and 79 percent among children (age 6 to 11 years) [51]. The most common adverse events
were nausea, headache, abdominal pain, nasopharyngitis, diarrhea, and vomiting.
Of the 42 patients, 31 completed the treatment extension phase. Five patients had adverse events that led to
temporary drug interruption, and two patients had adverse events that led to drug withdrawal. Other reasons
for treatment cessation included study withdrawal by the patient (six patients), loss to follow-up (one patient),
dissatisfaction with response to treatment (one patient), and patient-reported suicidal ideation (one patient).
Of note, dose titration at the start of therapy, which is often utilized to reduce adverse events from apremilast
in adults, was not performed.
Additional study is necessary to confirm efficacy and safety of apremilast for plaque psoriasis in children.
(See "Treatment of psoriasis in adults", section on 'Apremilast'.)
CHILDREN WITH PSORIATIC ARTHRITIS
Appropriate management of psoriatic arthritis is important to minimize risk for poor outcomes and disability.
Often, joint disease warrants systemic therapy that improves concomitant skin disease (eg, methotrexate or
biologic tumor necrosis factor [TNF]-alpha inhibitors). (See "Psoriatic juvenile idiopathic arthritis:
Management and prognosis".)
VERY YOUNG CHILDREN
Although mild to moderate plaque psoriasis in children under the age of four years is likely to respond to the
general approach described above, modifications are appropriate for this population. In general, less potent
topical corticosteroids (groups 4 to 7) are preferred over higher-potency agents. For children in diapers,
treatment of this area with topical corticosteroids should be monitored closely since the occlusive effect of
1412
the diaper may increase risk for cutaneous side effects (picture 1F). (See 'Face and intertriginous skin'
above.)
As with older children, the primary treatments for facial and intertriginous psoriasis are topical calcineurin
inhibitors and low-potency topical corticosteroids. We prefer to use topical calcineurin inhibitors (tacrolimus
0.03% or pimecrolimus 1%) for facial and intertriginous psoriasis, particularly when continuous corticosteroid
therapy is required for disease control or side effects from topical corticosteroid therapy have occurred.
Safety concerns regarding the use of topical calcineurin inhibitors are reviewed separately. (See "Treatment
of atopic dermatitis (eczema)", section on 'Long-term safety concerns' and "Treatment of atopic dermatitis
(eczema)", section on 'Off-label use in infants'.)
Topical vitamin D analogs and topical retinoids are rarely used in the treatment of infants because of the
common side effect of skin irritation.
Our approach to moderate to severe psoriasis in children under the age of four primarily consists of
optimization of topical therapy. We typically avoid phototherapy and systemic therapies in this age group
because of safety concerns with use in this population. However, use of these interventions is necessary in
rare, refractory cases.
COMORBIDITIES
Psoriasis is associated with a variety of comorbidities. Clinician awareness of these disease associations
facilitates identification of children who may benefit from screening for associated disease [1,52]. (See
"Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Comorbidities' and
"Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Additional
evaluation'.)
PROGNOSIS
Psoriasis in children is typically chronic, but its course is unpredictable. Spontaneous remissions and
exacerbations are common. Occasionally, alleviating conditions, such as sun exposure during the summer
months, or triggers, including infections and trauma, can be identified. The available therapies provide
satisfactory disease control for the majority of pediatric patients.
PATIENT SUPPORT
The National Psoriasis Foundation is a useful informational and support resource for patients and their
families.
1413
● Basics topics (see "Patient education: Psoriasis (The Basics)" and "Patient education: Psoriatic arthritis
in children (The Basics)")
● Beyond the Basics topics (see "Patient education: Psoriasis (Beyond the Basics)" and "Patient education:
Psoriatic arthritis (Beyond the Basics)")
● Psoriasis is an immune-mediated disease that occurs in children and adults. Chronic plaque psoriasis is
the most common type of psoriasis in children (picture 1A-B). (See 'Introduction' above and "Psoriasis in
children: Epidemiology, clinical manifestations, and diagnosis".)
● Many of the treatments used for children and adults with psoriasis are similar; however, efficacy and
safety data in children are more limited. (See 'Introduction' above.)
● Disease severity influences the therapeutic approach to plaque psoriasis (algorithm 1). For children with
mild to moderate plaque psoriasis (psoriasis involving less than 10 percent of the body surface area), we
recommend topical agents as initial therapy rather than systemic therapy or phototherapy (Grade 1B).
Topical corticosteroids are the mainstay of treatment. Topical calcineurin inhibitors and topical vitamin D
analogs are additional common treatments. Tazarotene, tar, and anthralin are less frequently used
topical treatments. (See 'Mild to moderate plaque psoriasis in children at least four years of age' above.)
● Modification of the approach to topical treatment of psoriasis is helpful for optimizing treatment of
psoriasis on the face, intertriginous skin, and scalp (picture 1C-D). Topical calcineurin inhibitors are
commonly used as first-line agents for the treatment of facial and intertriginous psoriasis because of
1414
increased risk for topical corticosteroid-induced skin atrophy in these areas. For scalp psoriasis, it is
important to select drug vehicles that the child and/or caregivers find acceptable for use in the hair. (See
'Special sites' above.)
● Children with moderate to severe plaque psoriasis (psoriasis involving more than 10 percent of the body
surface area that cannot be successfully treated with topical therapy) often require systemic therapy or
phototherapy (algorithm 1). Our typical first-line treatment choices for children at least four years of age
are methotrexate, narrowband ultraviolet B (UVB) phototherapy, or the biologic agent etanercept.
Adalimumab and ustekinumab are additional biologic agents that have demonstrated efficacy for
psoriasis in children. Cyclosporine, oral retinoids, and fumaric acid esters (not available in the United
States) also have been used for the treatment of pediatric psoriasis. (See 'Moderate to severe plaque
psoriasis in children at least four years of age' above.)
● Modifications to the approach to treatment are indicated for the treatment of very young children. (See
'Very young children' above.)
1415
GRAPHICS
Clusters of small plaques on the knees.
1416
Thick, well-demarcated plaques of psoriasis on the lower legs of an obese adolescent girl.
1417
Inverse psoriasis
Inverse psoriasis involving the axillae in a child.
1418
1419
Characteristic areas of psoriasis involvement on the periphery of the scalp, postauricular area, conchal
area of the ear, and neck.
1420
Psoriasis
Erythematous plaques in the diaper area in an infant with psoriasis.
1421
Initial management of psoriasis in children
* Refer to UpToDate topics on the management of psoriatic juvenile idiopathic arthritis.

¶ Topical therapy is often inadequate for children with moderate to severe disease; however, we typically attempt topical therapy prior to initiating
phototherapy or systemic therapy to identify those children who can be sufficiently managed with topical therapy.
Δ All listed treatments are reasonable first-line choices. Selection among these agents is dependent upon factors such as patient age, disease severity,
comorbidities, tolerance of risks and side effects, and prior treatment history. Refer to UpToDate topics on the management of plaque psoriasis in children
for additional information on treatment selection. Alternative systemic therapies include acitretin, cyclosporine, and fumaric acid esters.
◊ Phototherapy and systemic therapy are generally avoided in children under the age of four due to safety concerns. However, use of these interventions
may be necessary in rare, refractory cases.
§ Refer to UpToDate table on topical corticosteroids.
¥ Topical calcineurin inhibitors are preferred over topical corticosteroids for long-term therapy.
‡ Often, patients find medications in shampoos, foams, solutions, gels, sprays, or oils preferable for application to the scalp. The vehicle options should be
discussed with the child or caregiver to identify the most acceptable regimen.
1422
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12
Diflucortolone valerate (not Cream, oily cream, Nerisone (Canada, United 0.1
available in United States) ointment Kingdom, others)

Triderm

1423

solution

Gel Desonate 0.05

solution

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

(group 7)
Scalacort
Hydrocortisone (base, <2%) Ointment Cortaid, Cortizone 10, 1

Hytone, Nutracort

Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
1424
Spray Cortaid 1
Lotion Nucort 2
US: United States.

¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available generically in the
United States.
Data from:
1425
Management of psoriasis in pregnancy

Authors: Miriam Keltz Pomeranz, MD, Bruce E Strober, MD, PhD
Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Louise Wilkins-Haug, MD, PhD, Kristina Callis Duffin, MD
INTRODUCTION
Psoriasis is a chronic skin disorder characterized by well-demarcated erythematous papules and

plaques with a silver scale, although atypical or nonclassic forms also exist. It commonly occurs on
the extensor surface of the elbows or knees, or the scalp (picture 1A-C). Psoriasis commonly occurs
in women of reproductive age because three-quarters of patients develop the disease before
reaching age 40 years [1]. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
The management of psoriasis in pregnant women will be reviewed here. The general treatment of
psoriasis and pustular psoriasis of pregnancy, a severe pustular form of psoriasis, is discussed
separately. (See "Treatment of psoriasis in adults" and "Dermatoses of pregnancy".)
SPECIAL CONSIDERATIONS
The presence of psoriasis in a woman who is pregnant raises unique considerations. Examples
include the impact of maternal psoriasis on the fetus, therapeutic restrictions during pregnancy, and
the effects of pregnancy on psoriasis severity [2].
● Impact of psoriasis on pregnancy outcomes – Few studies have investigated the impact of
psoriasis on pregnancy outcomes, leaving the relationship between psoriasis and pregnancy
outcomes unclear [3,4]. A 2016 systematic review of observational studies that evaluated the
relationship between psoriasis and pregnancy outcomes found that four of the nine included
studies reported increased risk for at least one adverse fetal outcome (spontaneous abortion,
caesarean delivery, low birth weight, macrosomia, large-for-gestational age, or a composite
1426
outcome that included prematurity and low birth weight) [3]. However, study results were
inconsistent.
● Impact of pregnancy on treatment choices – Choosing drug therapies that pose the least risk to
the fetus is the major issue in managing the pregnancies of affected women. Ideally, women
should try to plan pregnancy when they are in remission and they are off medication or are
taking the minimum effective dose of medications that have the best fetal safety profiles.
Because many women with moderate to severe psoriasis do not achieve complete remissions,
postponing pregnancy until a period of remission often is unrealistic in this population. The
selection of treatments with good fetal safety profiles is particularly important for these patients.
(See 'Treatment principles' below.)
● Impact on severity of psoriasis – Psoriasis improves during pregnancy in 40 to 60 percent of

women, worsens in 10 to 20 percent, and remains stable in the remainder. Improvement may be
dramatic. In a prospective study, among 16 women with greater than 10 percent body surface
area involvement with psoriasis who experienced improvement in psoriasis during pregnancy,
the mean reduction in psoriatic lesions between 10 and 30 weeks gestation was 84 percent [5].
In the postpartum period, psoriasis severity remains the same or worsens in most women [5-7].
● Impact on risk of psoriasis in biological children – Children of women with psoriasis have an
increased risk for the development of the disorder. (See "Psoriasis: Epidemiology, clinical
manifestations, and diagnosis", section on 'Genetic factors'.)
TREATMENT PRINCIPLES
Treatment of psoriasis in nonpregnant individuals can be divided into three broad categories: topical
therapy, phototherapy, and systemic therapy. Choice of therapy is based upon the severity of the
disease and its impact on the patient's overall sense of well-being, relevant comorbidities, patient
preference (including cost and convenience), efficacy, and evaluation of individual patient response.
Psoriasis involving limited areas of skin (eg, less than 5 to 10 percent the body surface area) can
often be managed topically. Phototherapy or systemic therapy is usually necessary for adequate
treatment of more extensive disease. Topical therapy and phototherapy is generally preferred over
systemic therapy for the treatment of pregnant women because of concern for safety. (See
"Treatment of psoriasis in adults".)
The treatment paradigm is the same for both pregnant and nonpregnant patients, except that some
medications are avoided in pregnancy and the risk/benefit ratio may be calculated differently
because fetal risk must also be taken into account [8]. We agree with a recommendation from the
Medical Board of the National Psoriasis Foundation that topical treatment with emollients or
1427
moisturizers and a low- or medium-potency topical corticosteroid is the first-line medical intervention
for pregnant women with limited psoriasis [9]. UVB phototherapy (particularly narrowband UVB) is
the preferred treatment for women with more severe symptoms.
When women receiving systemic therapy for psoriasis become pregnant, the decision must be made
whether to continue treatment or to transition to topical therapy or phototherapy. Although
contraindicated therapies (eg, acitretin, methotrexate) must be discontinued, the appropriate action
is less definitive for patients receiving other systemic treatments. Because many women with
psoriasis improve during pregnancy, women may be able to switch to phototherapy during the
prenatal period. Biologic tumor necrosis factor (TNF) inhibitors and cyclosporine are occasionally
used during pregnancy for women with severe disease who cannot transition to topical therapy or
phototherapy. In these situations, the potential risks and benefits of therapy must be considered
carefully. (See 'Third-line therapy' below and 'Contraindicated therapies' below.)
In our discussion of treatment, we list the previously used US Food and Drug Administration (FDA)
letter (A, B, C, D, and X) categories assigned to help evaluate pregnancy risk. The FDA will no longer
be using this labeling and has begun to introduce narrative descriptions of the data available for the
use of new drugs during pregnancy [10].
Treatment of nonpregnant individuals is reviewed separately. (See "Treatment of psoriasis in adults"

and "Treatment of psoriatic arthritis" and "Treatment selection for moderate to severe plaque
psoriasis in special populations".)
First-line therapy — Many women with limited psoriasis (nondebilitating psoriasis that involves less
than 5 to 10 percent of the body surface area) can be managed sufficiently with topical therapy.
Emollients, moisturizers, and low- to medium-potency topical corticosteroids are the preferred topical
therapies for this population based upon safety considerations (table 1) [9].
Emollients and moisturizers — The simplest topical therapies are emollients or moisturizers,
which may control bothersome scale. Use of these agents is well tolerated, lacking significant
adverse effects.
Topical corticosteroids — For limited psoriasis, intermittent topical corticosteroids may control
disease with no or minimal maternal or fetal risk [11,12]. Most topical corticosteroids are classified
by the FDA as pregnancy category C (table 2). (See "Treatment of psoriasis in adults", section on
'Corticosteroids'.)
A systematic review did not find sufficient evidence to link topical corticosteroid use to increased
risk for congenital abnormalities, preterm delivery, or stillbirth [13]. However, there may be an
association between use of potent topical corticosteroids and low birthweight [13]. In particular, a
1428
retrospective study found a correlation between low birth weight and high levels of potent or very
potent topical corticosteroid use [14]. (See "Topical corticosteroids: Use and adverse effects", section
on 'Use during pregnancy or lactation'.)
Therefore, for pregnant women who will be treated with topical corticosteroids for psoriasis, the use
of low- or medium-potency topical corticosteroids is preferred (table 1) [9]. We reserve the use of
high-potency topical corticosteroids for patients who fail treatment with lower-potency topical
corticosteroids.
Of note, the development of striae (stretch marks) is common in pregnancy and use of topical
corticosteroids may increase risk for striae in sites of application. (See "Topical corticosteroids: Use
and adverse effects", section on 'Adverse effects'.)
Second-line therapy — When topical therapy with emollients, moisturizers, or topical corticosteroids
is insufficient or impractical due to resistant disease or extensive skin involvement, narrowband UVB
phototherapy is often useful for treatment.
UVB phototherapy — Phototherapy can be used to treat localized psoriasis or the entire cutaneous
surface area. Narrowband ultraviolet B phototherapy at wavelength 311 nm appears to be a safe and
often effective treatment of psoriasis in pregnant women [11,12]. The major disadvantage of this
approach is the need to travel to a clinic three days per week for treatment. Broadband UVB (290 to
320 nm) is a slightly less effective alternative that can be used if narrowband UVB is not available.
Localized disease can be treated with a laser device that emits UVB (eg, 308 nm excimer laser) [12].
(See "Treatment of psoriasis in adults", section on 'Ultraviolet light' and "UVB therapy (broadband and
narrowband)".)
Patients receiving phototherapy generally require adjuvant therapy with emollients, moisturizers, or
low- to medium-potency topical corticosteroids for symptomatic relief.
Common adverse effects of UVB phototherapy include erythema, skin dryness, and pruritus.
Exacerbation of melasma, a photosensitive skin disorder commonly associated with pregnancy, also
is a potential risk of phototherapy [9]. Melasma is characterized by the development of
hyperpigmentation on sun-exposed skin (picture 2) (see "Melasma: Management"). To minimize risk
of melasma, shielding of the face during phototherapy is advised [2]. Additional adverse effects
associated with phototherapy are reviewed separately. (See "UVB therapy (broadband and
narrowband)", section on 'Short- and long-term adverse effects' and "Psoralen plus ultraviolet A
(PUVA) photochemotherapy", section on 'Adverse effects'.)
Maternal folate deficiency has been associated with an increased risk for fetal neural tube defects.
Concerns regarding the effect of UV light exposure decreasing serum folate levels are discussed
1429
separately. (See "Treatment of psoriasis in adults", section on 'Folate deficiency'.)
Third-line therapy — Most pregnant women with psoriasis can be managed effectively with the
therapies described above. Patients who cannot be managed effectively with the topical
moisturizers, topical corticosteroids, or phototherapy may require systemic therapy to achieve
sufficient improvement in symptoms. Biologic tumor necrosis factor (TNF) inhibitors and
cyclosporine can be effective for these patients. However, data on safety in pregnant women are
limited and the need for systemic treatment should be considered carefully.
Anti-TNF biologic agents — Although data on the use of anti-TNF biologic agents in pregnancy
are limited, there is a growing body of literature demonstrating that the biologic TNF-inhibitors used
for psoriasis may be used safely during pregnancy. Transfer of certolizumab pegol, a pegylated, Fc-
free anti-TNF biologic agent used for psoriasis, across the placenta is minimal and less than other
anti-TNF biologic agents. Limited data support low risk for immunosuppression in the newborn and
teratogenicity for this agent [15,16]. (See "Treatment of psoriasis in adults", section on 'Biologic
agents' and "Safety of rheumatic disease medication use during pregnancy and lactation".)
Adalimumab, etanercept, and infliximab are classified by the FDA as category B (table 2). However,
because adalimumab, etanercept, and infliximab can cross the placenta and can be detected in
infants for up to several months or longer after birth [17,18], there is concern for the possibility of
postpartum effects on infants born to treated women. Although the best approach is unconfirmed,
discontinuation of these drugs prior to the end of gestation and postponement of live vaccine
administration to infants has been suggested. For infliximab, drug discontinuation is suggested at 30
weeks gestation (based upon the knowledge that transmission across the placenta primarily occurs
in the third trimester) and avoidance of live vaccine administration to infants born to treated women
is suggested until the age of seven months [19,20]. Similar precautions may be appropriate for
adalimumab and etanercept. An infant exposed to infliximab in utero died from disseminated
Bacillus Calmette-Guérin (BCG) infection after receipt of the BCG vaccine at the age of three months
[21].
The manufacturers of all the biologic medications for psoriasis and psoriatic arthritis manage
ongoing registries of drug-exposed pregnant women and encourage enrollment of all such cases.
The safety of these drugs in pregnant women is discussed in detail separately. (See "Safety of
rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis
factor inhibitors' and "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on
'Anti-tumor necrosis factor agents'.)
Cyclosporine — Cyclosporine is a calcineurin inhibitor and FDA pregnancy category C (table 2). It
can be very effective in treating severe cutaneous psoriasis.
1430
Teratogenicity data in humans are derived primarily from organ transplant recipients. The risk of
teratogenicity among the offspring of women treated with cyclosporine appears to be low, but
premature labor and infants who are small for gestational age have been reported. Such findings
may be related to the underlying medical condition rather than to the drug, and could also be related
to both the medical condition and the drug. Another concern is that, in some studies, newborns
whose mothers consumed cyclosporine had a decrease in T and B cells [12]; however, it is not clear
that this change had any clinical significance. The use of cyclosporine in pregnancy is discussed in
detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation",
section on 'Cyclosporine' and "Treatment of psoriasis in adults", section on 'Systemic calcineurin
inhibitors'.)
CONTRAINDICATED THERAPIES
Several therapies useful for the treatment of psoriasis in nonpregnant individuals are contraindicated
in pregnant women because of teratogenicity. These include topical tazarotene, methotrexate, and
acitretin.
Tazarotene — Tazarotene is a retinoid approved for the topical treatment of psoriasis. Tazarotene is
FDA pregnancy category X (table 2) and should not be given to pregnant women [22,23].
Less than 1 percent of the dose is absorbed on psoriatic skin [24]. However, tazarotene is avoided
during pregnancy based on good data that another retinoid (oral isotretinoin) is associated with a
significant increase in major congenital malformations. First trimester oral isotretinoin exposure is
strongly associated with embryopathy, including craniofacial, cardiac, thymic, and central nervous
system malformations. (See "Treatment of psoriasis in adults", section on 'Tazarotene' and "Oral
isotretinoin therapy for acne vulgaris", section on 'Teratogenicity'.)
Methotrexate — Methotrexate is a folate antagonist and FDA pregnancy category X (table 2). It
should not be used for treatment of psoriasis in a pregnant or lactating woman because it is
teratogenic and may interfere with cellular metabolism in a nursing infant [23]. Conception should be
avoided for three months after the last dose because the drug can persist in the liver for several
months. This drug is discussed in detail separately. (See "Safety of rheumatic disease medication
use during pregnancy and lactation", section on 'Methotrexate' and "Treatment of psoriasis in adults",
section on 'Methotrexate'.)
Acitretin — Acitretin is FDA pregnancy category X (table 2), given that there is good evidence that
retinoids significantly increase the incidence of severe congenital anomalies in experimental animals
and humans [25]. It should not be used for treatment of psoriasis in a pregnant or lactating woman.
1431
(See "Treatment of psoriasis in adults", section on 'Retinoids' and "Oral isotretinoin therapy for acne
vulgaris", section on 'Teratogenicity'.)
Acitretin can be metabolized to etretinate in the body, and etretinate has been identified in body fat
as long as 52 months after stopping acitretin [26]. For this reason, experts recommend that
pregnancy be avoided for three years after the last dose of acitretin.
OTHER PSORIASIS THERAPIES
Several other psoriasis therapies, while not deemed contraindicated for women with psoriasis, are
less favorable options for the treatment of pregnant women due to safety concerns or lesser
efficacy.
Topical calcineurin inhibitors — Topical calcineurin inhibitors (eg, tacrolimus, pimecrolimus) are
classified as FDA pregnancy category C (table 2). These drugs are not particularly effective in
psoriasis; however, they are occasionally used when topical corticosteroids must be avoided.
Based on experimental animal studies and human case reports, these drugs do not appear to
increase the risk of congenital anomalies. Treatment with oral tacrolimus may be associated with
increased risk for low birth weight and premature delivery [9]; however, it is unclear whether similar
effects occur with the low systemic absorption associated with topical administration. (See "Safety
of rheumatic disease medication use during pregnancy and lactation".)
Coal tar — Coal tar is FDA pregnancy category C (table 2). Safety data for coal tar in pregnancy are
limited. Although there is concern for potential mutagenic properties of coal tar based upon animal
studies, a case series including 23 women who used coal tar products during pregnancy did not
detect an increase in congenital anomalies [27]. Topical coal tar can be considered for use in the
second and third trimesters of pregnancy [11,12]. As a precaution, coal tar is often avoided in the first
trimester of pregnancy. (See "Treatment of psoriasis in adults", section on 'Tar'.)
Calcipotriol — Calcipotriol (calcipotriene) and calcitriol, vitamin D derivatives, are FDA pregnancy
category C (table 2). Studies in rats and rabbits have not reported an increased risk of congenital
anomalies [25]. Hypercalcemia has been reported with excessive topical use [28], and excessive
vitamin D intake can lead to skeletal abnormalities in offspring [25]; however, this is unlikely with
limited topical use [12,22,23]. (See "Treatment of psoriasis in adults", section on 'Topical vitamin D
analogs'.)
Anthralin — The risks of anthralin therapy during pregnancy are unknown. Therefore, use of anthralin
in pregnant women is not recommended [9].
1432
PUVA phototherapy — Use of systemic psoralen and ultraviolet A phototherapy (PUVA) during
pregnancy is more controversial than use of UVB phototherapy. Some experts suggest it can be used
if the psoralen is applied topically [12]. PUVA phototherapy is designated as a pregnancy category C
intervention [9]. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light' and "Psoralen
plus ultraviolet A (PUVA) photochemotherapy".)
Sulfasalazine — Sulfasalazine is FDA pregnancy category B (table 2). Case series have found no
increase in the incidence of adverse pregnancy outcomes with sulfasalazine exposure during
pregnancy. Since sulfasalazine binds albumin, there is a theoretic risk that sulfasalazine will displace
bilirubin from albumin and thereby increase the risk of kernicterus; however, there is no evidence that
clinically significant displacement of bilirubin occurs. Although the safety profile of sulfasalazine is
reassuring, it is minimally effective for treatment of psoriasis. (See "Safety of rheumatic disease
medication use during pregnancy and lactation", section on 'Sulfasalazine'.)
Systemic glucocorticoids — Systemic glucocorticoids are not recommended for the treatment of
psoriasis because of the potential for severe flaring of psoriasis upon drug withdrawal. An exception
is pustular psoriasis of pregnancy (impetigo herpetiformis), for which systemic glucocorticoids are a
mainstay of therapy. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)
Ustekinumab — Ustekinumab, a monoclonal antibody that targets interleukin (IL)-12 and IL-23, is
also classified by the FDA as category B (table 2). Data on the safety of ustekinumab in pregnancy
are primarily limited to animal studies. Individual cases of uncomplicated delivery of a healthy infant
[29-33] and spontaneous abortion [34] have been reported in patients treated with ustekinumab
during pregnancy. Pending further study, anti-TNF biologic therapy is preferred over ustekinumab for
psoriasis in the pregnant population. (See "Treatment of psoriasis in adults", section on
'Ustekinumab'.)
Other biologic agents and apremilast — There are insufficient data regarding fetal exposure to
ixekizumab, secukinumab, and brodalumab, the newer IL-17 inhibitors approved for the treatment of
moderate to severe psoriasis. An analysis of the manufacturer's global safety database for
secukinumab through June 2017 identified no safety signals with regard to spontaneous abortions
or congenital malformations [35].
There are insufficient data regarding the IL-23 inhibitors guselkumab, tildrakizumab, and
risankizumab. Similarly, there are insufficient data regarding apremilast, an oral phosphodiesterase
type 4 inhibitor. A moderate level of caution should be employed with use of these medications in the
setting of pregnancy.
Fumaric acid — Fumaric acid esters are used to treat psoriasis in Europe. Although animal studies do
not show any teratogenicity, there are very limited data in humans. Therefore, the use of fumaric acid
1433
esters is not recommended in a pregnant woman [36].
● The effect of maternal psoriasis on pregnancy outcomes remains uncertain. Choosing drug
therapies that pose the least risk to the fetus is the major issue in managing the pregnancies of
affected women. (See 'Special considerations' above and 'Treatment principles' above.)
● Ideally, women should plan pregnancy when they are in remission and off medication or taking
the minimum effective dose of medications that have the best fetal safety profiles. However,
postponing pregnancy until a period of remission often is unrealistic. The selection of
treatments with good fetal safety profiles is particularly important for these patients. (See
'Special considerations' above.)
● Psoriasis improves during pregnancy in 40 to 60 percent of women, worsens in 10 to 20 percent,

and remains stable in the remainder. In women who improve, the degree of improvement can be
dramatic. In the postpartum period, psoriasis severity remains the same or worsens in most
women. (See 'Special considerations' above.)
● For women with limited psoriasis (ie, nondebilitating psoriasis that involves less than 5 to 10
percent of the body surface area), we suggest topical rather than systemic therapy (Grade 2C).
Emollients and moisturizers are useful for reducing bothersome scale. Our first-line medical
treatment is a low- to medium-potency topical corticosteroid (table 1). (See 'First-line therapy'
above.)
● For women with psoriasis that cannot be managed adequately with topical therapy (ie, resistant
or extensive disease), we suggest narrowband ultraviolet B (UVB) phototherapy rather than
systemic therapies because of the safety and efficacy of phototherapy in pregnancy (Grade 2C).
Because psoriasis often improves during pregnancy, women who required systemic treatment
prior to pregnancy may be able to transition to phototherapy. (See 'UVB phototherapy' above.)
● Topical tazarotene, methotrexate, and acitretin are contraindicated during pregnancy. (See
'Contraindicated therapies' above.)
1434
1435
GRAPHICS
Plaque psoriasis
psoriasis.
1436
Plaque psoriasis
A large, infiltrated, erythematous plaque with well-demarcated margins in a patient with plaque psoriasis.
1437
Plaque psoriasis
Well-demarcated, raised, erythematous plaques with a silvery-white, scaly surface are

characteristic of plaque psoriasis.
1438
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12

States)

emollient
1439

Kenalog ¶, Triderm


solution

spray

Gel Desonate 0.05

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

Body, Derma-
Smoothe/FS Scalp
1440

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1441
Drug ratings in pregnancy (US Food and Drug Administration)
Category Interpretation
A Controlled human studies show no risk
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first trimester with no evidence of
risk in later trimesters. The possibility of fetal harm appears remote.
B No evidence of risk in studies
Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant
women or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not
confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.
C Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects or other) and
there are no controlled studies in women or studies in women and animals are not available. Drugs should be given
only if the potential benefits justify the potential risk to the fetus.
D Positive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite
the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be
used or are ineffective).
X Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on
human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible
benefit. The drug is contraindicated in women who are or may become pregnant.
In 2015, the US Food and Drug Administration (FDA) began overseeing the phase-out of pregnancy risk categories (A, B, C, D, and X)
from prescription drug labeling and began requiring information from available human and animal studies of (1) known or potential
maternal or fetal adverse reactions and (2) dose adjustments needed during pregnancy and the postpartum period. Additional
information is available at the FDA website: Pregnancy and Lactation Labeling Final Rule.
Reproduced with permission from: Lexicomp Online. Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
1442
Melasma
A mottled hyperpigmented patch is present on the cheek.
1443
Comorbid disease in psoriasis

Author: Neil Korman, MD, PhD
INTRODUCTION
Although psoriasis is classically associated with the development of inflammatory plaques on the
skin, increasing evidence supports the recognition of psoriasis as a multisystem chronic
inflammatory disorder with multiple associated comorbidities. Examples of extracutaneous
disorders that have been linked to psoriasis include:
● Psoriatic arthritis
● Obesity
● Metabolic syndrome
● Cardiovascular, cerebrovascular, and peripheral vascular disease
● Malignancy
● Autoimmune diseases
● Chronic kidney disease
● Nonalcoholic fatty liver disease
● Cardiac arrhythmia
● Chronic obstructive pulmonary disease
● Obstructive sleep apnea
● Bone disease
● Parkinsonism
● Psychosocial effects
● Psychiatric disorders
● Alcohol abuse
● Smoking
1444
● Migraine
The relationship between psoriasis and other disease states will be reviewed here. The pathogenesis,
diagnosis, and treatment of psoriasis are discussed separately. (See "Psoriasis: Epidemiology,
clinical manifestations, and diagnosis" and "Guttate psoriasis" and "Treatment of psoriasis in
adults".)
PSORIATIC ARTHRITIS
Psoriatic arthritis is an inflammatory seronegative spondyloarthropathy that occurs in association

with psoriasis. Estimates of the proportion of patients with psoriasis who develop psoriatic arthritis
range from 7 to 42 percent [1].
Psoriatic arthritis is characterized by stiffness, pain, swelling, and tenderness of the joints and their
surrounding ligaments and tendons (dactylitis and enthesitis). The course of psoriatic arthritis is
variable and unpredictable ranging from mild and nondestructive joint involvement to a severe,
debilitating, erosive arthropathy.
In the majority of patients, cutaneous manifestations of psoriasis precede joint disease [2]. The
severity of the skin disease usually does not correlate with the severity of arthritis. Psoriatic arthritis
is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of psoriatic
arthritis" and "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and
diagnosis".)
OBESITY
Multiple studies have demonstrated an increased prevalence of obesity among patients with
psoriasis [3-8]. Obesity is typically defined as a body mass index (BMI) ≥30 kg/m2. (See "Obesity in
adults: Prevalence, screening, and evaluation", section on 'Body mass index'.)
Evidence — The findings of a systematic review and meta-analysis of observational studies

published between 1980 and 2012 support an increased prevalence of obesity in patients with
psoriasis [8]. The pooled odds ratio [OR] for obesity for patients with psoriasis compared with a
control group without psoriasis was 1.66 (95% CI 1.46-1.89). Additional support for a link between
psoriasis and obesity stems from a review of more than 10,000 patients with moderate to severe
psoriasis enrolled in clinical trials of biologic therapies [4]. The average BMI for patients in the trials
reviewed was 30.6 kg/m2.
1445
Studies have also identified a correlation between obesity and the severity of psoriasis [3,5,9]. In the
systematic review and meta-analysis described above, the risk for obesity was more pronounced in
patients with severe psoriasis (pooled OR 2.23, 95% CI 1.63-3.05) than patients with mild psoriasis
(pooled OR 1.46, 95% CI 1.17-1.82) [8]. In particular, a study of 4065 individuals with psoriasis and
40,650 controls that was included in the meta-analysis illustrated a progressive relationship between
disease severity and obesity. Among patients with mild (≤2 percent body surface area [BSA]),
moderate (3 to 10 percent BSA), and severe psoriasis (>10 percent BSA), the prevalence of obesity
compared with controls increased by 14, 34, and 66 percent, respectively [9].
Children are not exempt from the increased risk for obesity observed in the setting of psoriasis. In an
international cross-sectional study of 409 children with psoriasis, children with psoriasis were
significantly more likely to be obese (BMI ≥95th percentile) than controls (OR 4.29, 95% CI 1.96-9.39)
[10]. Similar to the general population of patients with psoriasis, a correlation between disease
severity and obesity was observed. Children with severe psoriasis had a greater increase in risk for
obesity than children with mild disease (OR 4.92, 95% CI 2.20-10.99 versus 3.60, 95% CI 1.56-8.30).
Additional study is necessary to confirm findings of a systematic review and network meta-analysis
that suggest an association between treatment with tumor necrosis factor (TNF) inhibitors and
weight gain in patients with psoriasis [11].
Rationale — More than one factor may contribute to the association between obesity and psoriasis.
Although the negative psychosocial impact of psoriasis was initially considered the sole reason for
excess weight in patients with psoriasis [3], newer data suggest that obesity may increase risk for
this disease. As an example, increased adiposity and weight gain were identified as strong risk
factors for psoriasis in an analysis of data collected from almost 80,000 women in the Nurses'
Health Study II [12]. Compared with women with a BMI of 21.0 to 22.9 kg/m2 at age 18, the
multivariate relative risk for the development of psoriasis for subjects with a BMI ≥30 kg/m2 at the
same age was 1.73 (95% CI, 1.24-2.41), and only 0.76 (95% CI, 0.65-0.90) for women with a BMI <21
kg/m2. In addition, a retrospective study of 27 overweight or obese children with psoriasis found that
93 percent were overweight or obese prior to the onset of psoriasis [13].
A pathophysiologic explanation for the link between obesity and psoriasis has not been definitively
established. Growing evidence supports the designation of psoriasis as a systemic inflammatory
disease [14], and the status of obesity as a proinflammatory state may be a relevant factor. TNF-
alpha, a major proinflammatory cytokine involved in the pathogenesis of psoriasis [15], is found at
increased levels in obesity and is produced by adipose tissue [16]. Additional cytokines and bioactive
products produced by adipose tissue (also known as adipokines or adipocytokines), such as
interleukin (IL)-6, leptin, resistin, adiponectin, and others [17] might also stimulate psoriasis.
1446
Implications — Data on the effects of weight loss on disease severity in psoriasis are limited. The
first randomized trial designed to explore the effect of weight loss on the severity of psoriasis (n =
60) found a statistically nonsignificant trend towards greater improvement in psoriasis (as assessed
by Psoriasis Area Severity Index [PASI] score) in overweight or obese psoriasis patients who were
placed on a low-energy diet compared with a similar group of patients who continued to eat ordinary
healthy foods [18]. The median baseline PASI score for all patients (5.4) correlated with mild to
moderate psoriasis, and during the 16-week trial, patients allocated to the low-energy diet lost a
mean of 15.8 kg compared with a mean loss of 0.4 kg in the control group. By study end, PASI scores
were reduced by a mean of 2.3 in the low-energy diet group compared with only 0.3 in the control
group. In addition, improvement in the Dermatology Quality of Life Index (a secondary outcome
measure aimed at assessing the change in the impact of psoriasis on patient quality of life) was
significantly greater in the low-energy diet group.
Improvement in psoriasis following gastric bypass surgery has been documented in case reports
and a retrospective study [16,19-21]. The mechanism of this is unclear, but may be related to
alterations in the production of proinflammatory and antiinflammatory adipokines, increased
production of glucagon-like peptide-1 (GLP-1, a gut-derived hormone), or weight-loss related changes
in cutaneous microflora that result in the elimination of an antigenic stimulant [16,22]. However,
worsening of psoriasis has also been reported to occur after weight loss and weight loss surgery
[23-25]. Further study is necessary to explore the effect of weight loss on psoriasis.
Obesity may impact the efficacy of some psoriasis treatments [26]. A cohort study of approximately
2400 patients receiving systemic therapy for psoriasis (including conventional and biologic agents)
found that compared with individuals with a BMI of 20 to 24 kg/m2, obese subjects (BMI ≥30 kg/m2)
were less likely to achieve 75 percent improvement in disease severity (odds ratio 0.62, 95% CI 0.49-
0.79 at 16 weeks) regardless of the type of therapy [27]. In addition, in a randomized trial of 61 obese
patients with moderate to severe psoriasis, weight loss improved the response to cyclosporine (2.5
mg/kg per day) [28]. The weight-based dosing regimen for ustekinumab, a newer treatment option
for psoriasis, is used to mitigate the reduction in drug efficacy observed when the standard dose is
utilized in obese patients [26].
METABOLIC SYNDROME
Metabolic syndrome is a constellation of risk factors associated with increased risk for type 2
diabetes mellitus and cardiovascular disease. The criteria used to identify this syndrome vary. One of
the most widely used definitions of the metabolic syndrome is derived from the National Cholesterol
Education Adult Treatment Panel (NCEP ATP III). According to a 2005 update of the NCEP ATP III
1447
criteria, the presence of three or more of the following elements constitutes a diagnosis of metabolic
syndrome [29]:
● Elevated waist circumference (men ≥102 cm, women ≥88 cm)

● Elevated blood pressure (≥130 mm Hg systolic or ≥85 mm Hg diastolic) or receiving drug
treatment for elevated blood pressure
● Elevated fasting glucose (≥100 mg/dL) or receiving drug treatment for elevated blood glucose
● Elevated triglycerides (≥150 mg/dL) or receiving drug treatment for elevated triglycerides
● Reduced high density lipoprotein levels (<40 mg/dL in men and <50 mg/dL in women or
individuals receiving drug treatment for low HDL cholesterol).
The metabolic syndrome is reviewed in greater detail separately. (See "Metabolic syndrome (insulin
resistance syndrome or syndrome X)".)
Evidence — Multiple epidemiologic studies support an association between psoriasis and the
metabolic syndrome or components of the metabolic syndrome [5,12,30-40]. A systematic review
and meta-analysis of 14 observational studies that evaluated the association between psoriasis and
metabolic syndrome in adults found that patients with psoriasis were more likely to have metabolic
syndrome than individuals in the general population (odds ratio 1.42, 95% CI 1.28-1.65) [39].
Children may also be affected by the relationship between psoriasis and metabolic syndrome.
Population-based studies have found increased rates of components of the metabolic syndrome
(hyperlipidemia, hypertension, and diabetes) in children with psoriasis [41,42].
Not all studies have supported an association between psoriasis and metabolic syndrome. A Korean
study of 490 patients with psoriasis and 682 controls that was not included in the meta-analysis
failed to find a statistically significant difference in the prevalence of metabolic syndrome between
the two groups [43].
Rationale — In theory, both psoriasis and obesity may contribute to metabolic syndrome via the
effects of proinflammatory cytokines and adipokines associated with these disorders on glucose
regulation, lipid status, and endothelial function [17]. However, an exact mechanism for the
interaction between psoriasis and metabolic syndrome remains uncertain.
Implications — Metabolic syndrome is well accepted as a risk factor for the development of type 2
diabetes and cardiovascular disease [29]. Thus, psoriasis may serve as a marker for increased risk
for the morbidity and mortality associated with these diseases.
The effect of treatment on the metabolic syndrome on psoriasis is uncertain. The findings of a series
of three patients with mild plaque-type psoriasis suggest a possible benefit [44]. In these patients,
psoriasis improved by at least 50 percent following the institution of interventions to treat the
1448
metabolic syndrome, such as dietary changes, pharmacotherapy for hyperlipidemia and
hyperglycemia, and weight loss. In addition, beneficial effects of psoriasis treatment on HDL
composition and function were observed in a small uncontrolled study [45].
HYPERTENSION AND DIABETES
In addition to a relationship between psoriasis and elevated blood glucose and blood pressure in the
context of metabolic syndrome as reviewed above, observational studies have detected independent
relationships between psoriasis and hypertension and diabetes [5,31,46-49].
Evidence — An association between hypertension and psoriasis is supported by a systematic review

and meta-analysis of 24 observational studies that found that hypertension was more prevalent in
patients with psoriasis than in control populations (odds ratio [OR] 1.58, 95% CI 1.42-1.76) [50]. A
systematic review and meta-analysis that evaluated observational study data on the risk for diabetes
also found an elevated prevalence of diabetes in the psoriasis population (OR 1.59, 95% CI 1.38-1.83)
[51]. A trend towards a stronger association between severe psoriasis and hypertension or diabetes
than between mild psoriasis and hypertension or diabetes was observed in these studies.
Examples of individual studies that support a relationship between psoriasis and these diseases
include:
● A Danish cross-sectional, population-based twin study that included over 33,000 twins found a
significant association between psoriasis and type 2 diabetes (OR 1.53, 95% CI 1.03-2.27) and
between psoriasis and increasing body mass index (OR 1.81, 95% CI 1.28-2.55 in individuals
with a body mass index ≥35) [37].
● In a prospective cohort study of approximately 78,000 women in the Nurses' Health Study II
(among which 1813 reported a diagnosis of psoriasis), women with psoriasis were more likely to
develop diabetes or hypertension than women without psoriasis (multivariate relative risks 1.63,
95% CI 1.25-2.12 and 1.17, 95% CI 1.06-1.30, respectively) [31].
● A population-based cohort study of approximately 108,000 adults with psoriasis and 431,000
adults without psoriasis in the United Kingdom found that psoriasis was an independent risk
factor for type 2 diabetes [47]. The study also found that patients with severe psoriasis and
diabetes were more likely than controls with diabetes to receive systemic diabetic therapy
(particularly oral hypoglycemic agents). The reason for this latter observation remains to be
determined.
● A case-control study of 835 patients with both psoriasis and hypertension and 2418 matched
controls with hypertension found that patients with psoriasis were more likely to require
1449
intensive treatment for hypertension than controls [46]. As an example, psoriasis patients were
16.5 times more likely than controls to require treatment with three antihypertensive agents
(95% CI, 11.01-24.84). In addition, a separate population-based study of 1322 patients with
psoriasis and 11,997 matched controls found a positive dose-response relationship between
uncontrolled hypertension and psoriasis severity [52].
Rationale — The pathophysiologic mechanisms for the relationship between psoriasis and diabetes
and psoriasis and hypertension are unclear. As postulated for metabolic syndrome, the chronic
inflammatory state in psoriasis may be a significant contributing factor. Additional theories on the
relationship between psoriasis and hypertension include effects related to angiotensin II production
in visceral fat as well as the impact that increased reactive oxygen species and increased serum
endothelin-1 may have on endothelial function in patients with psoriasis [46,53].
Implications — The consequences of hypertension and diabetes are reviewed in detail separately.
(See "Overview of hypertension in adults", section on 'Complications of hypertension' and
"Cardiovascular risks of hypertension" and "Overview of general medical care in nonpregnant adults
with diabetes mellitus", section on 'Diabetes-related complications'.)
Psoriasis may be a marker of a modest increase in risk for vascular complications of diabetes. A
retrospective cohort study of 6164 diabetics with psoriasis and 6164 matched diabetics without
psoriasis found that diabetics with psoriasis were more likely to develop microvascular
complications (hazard ratio [HR] 1.14, 95% CI 1.06-1.23) and macrovascular complications (HR 1.13,
95% CI 1.05-1.22) of diabetes than diabetics without psoriasis [54]. Additional study is necessary to
confirm these findings.
ATHEROSCLEROTIC DISEASE
Psoriasis is associated with increased risk for the development of atherosclerotic vascular disease
including cardiovascular, cerebrovascular, and peripheral vascular disease.
Evidence — Most data on atherosclerosis in patients with psoriasis focus on cardiac disease. Several
studies, including studies from North America, Europe, and China have detected an elevated risk for
myocardial infarction (MI) in this population [7,55-58].
The seminal study that identified psoriasis as an independent risk factor for MI was a retrospective
cohort study of more than 130,000 adults with psoriasis and over 550,000 controls in the United
Kingdom [55]. The incidence of MI per 1000 person-years was 3.58 (95% CI 3.52-3.65) for control
patients, 4.04 (95% CI 3.88-4.21) for patients with mild psoriasis (defined as not requiring systemic
therapy), and 5.13 (95% CI 4.22-6.17) for patients with severe psoriasis (defined as requiring
1450
systemic therapy). The increase in risk for MI detected in patients with psoriasis remained even after
adjusting for major cardiovascular risk factors, such as age, sex, smoking, prior MI, diabetes,
hypertension, hyperlipidemia, and BMI. Younger patients exhibited the greatest increase in risk. For
example, for a 30-year-old patient with mild or severe psoriasis, the adjusted relative risks (RR) for MI
were 1.29 (95% CI 1.14-1.46) and 3.10 (95% CI 1.98-4.86), respectively. In contrast, for a 60-year old
patient with mild or severe psoriasis, the respective adjusted RR assessments were 1.08 (95% CI
1.03-1.13) and 1.36 (95% CI 1.13-1.64).
In addition to cardiac disease, other manifestations of atherosclerotic disease, including stroke and
peripheral vascular disease, occur at increased frequency in patients with psoriasis [56,58-62]. A
meta-analysis of seven cohort studies that combined data on MI and stroke found an increased risk
for these events in patients with psoriasis [59]. Examples of individual studies that support an
increased risk for non-MI atherosclerotic events include:
● A population-based cohort study utilizing patient records from the United Kingdom found an
increase in strokes among patients with severe psoriasis (defined as psoriasis treated with
systemic therapy) and a very modest increase in strokes in patients with mild psoriasis (defined
as psoriasis not requiring systemic therapy) [60]. The hazard ratios (HR) were 1.43 (95% CI 1.1-
1.9) and 1.06 (95% CI 1.0-1.1), respectively.
● A United States study of 3236 patients with psoriasis and 2500 controls found an increased
prevalence of ischemic vascular disease (odds ratio [OR] 1.78, 95% CI 1.51-2.11),
cerebrovascular disease (OR 1.70, 95% CI 1.33-2.17), and peripheral vascular disease (OR 1.98,
95% CI 1.32-2.82) among patients with psoriasis [61]. Psoriasis was also a marker of increased
risk for mortality (OR 1.86, 95% CI 1.56-2.21).
● A retrospective analysis of data from approximately 1600 patients with moderate to severe
psoriasis who were enrolled in therapeutic trials found a 28 percent increase in risk for coronary
heart disease and a 12 percent increase in risk for stroke among patients with psoriasis
compared with the general population [56].
Of note, some authors have challenged the designation of psoriasis as a risk factor for
cardiovascular disease [63-65]. In a Dutch cohort study of approximately 15,800 patients with
psoriasis and 27,600 controls, the difference in risk for hospitalization due to ischemic heart disease
was not statistically significant (1.10, 95% CI 0.99-1.23) [64].
An association between cardiovascular disease and psoriasis is detected most consistently among
patients with severe psoriasis. A 2013 systematic review and meta-analysis in which classification
as severe psoriasis was based upon surrogate markers (eg, requirement for systemic treatment or
hospital admission) found support for an increased risk for MI, cardiovascular mortality, and stroke
1451
among patients with severe psoriasis [58]. In contrast to severe psoriasis, studies evaluating the
relationship between milder psoriasis and cardiovascular disease have yielded less consistent
findings [58,66]. Longer duration of disease may be an additional risk factor for adverse
cardiovascular events [67].
Rationale — The rationale for a correlation between psoriasis and atherosclerotic disease is not well
understood. Although the increased prevalence of risk factors for cardiovascular disease (obesity,
hypertension, diabetes, hyperlipidemia, metabolic syndrome, and cigarette smoking) in the psoriatic
population likely contributes to the elevated risk for atherosclerosis, the role of chronic inflammation
in the pathogenesis of both disorders may also be a key factor [68].
Implications — Atherosclerotic disease is a major cause of morbidity and mortality, and psoriasis
may portend an increased risk for death due to cardiovascular disease [58,69]. In a systematic
review and meta-analysis that pooled the results of four studies, all-cause cardiovascular mortality
was significantly greater in patients with severe psoriasis than in the general population
(standardized mortality ratio 1.37 95% 1.17-1.60) [58]. A fifth study that reported a hazard ratio from
multivariate analysis offered additional support; the cohort study of approximately 3600 patients in
the United Kingdom with severe psoriasis (defined as psoriasis treated with systemic therapy) and
14,330 control patients without a history of psoriasis, found that patients with severe psoriasis were
more likely than controls to die from cardiac or cerebrovascular disease (HR 1.57, 95% CI 1.26-1.96)
[69].
Data are limited on the effects of systemic therapies for psoriasis on the risk for cardiovascular
disease in individuals with psoriasis [70]. Treatment with methotrexate may be of benefit [71,72]. In a
retrospective cohort study, treatment of psoriasis with methotrexate was associated with a reduced
risk for cardiovascular disease, cerebrovascular disease, and atherosclerosis [71]. However, a
separate retrospective study did not find a significant difference in rates of ischemic heart disease
hospitalizations in patients taking methotrexate versus patients taking other nonbiologic
antipsoriatic drugs [73].
Treatment with tumor necrosis factor (TNF)-alpha inhibitors also may reduce the risk of
cardiovascular events [70,74]. A reduction in the risk for MI was detected in a retrospective study (n =
8845) that compared the rate of MI in patients who had received at least two consecutive months of
treatment with a TNF-alpha inhibitor, patients who were treated with either oral agents or
phototherapy, and patients who were treated with only topical therapy [75]. After adjustments for risk
factors for MI, patients who had been treated with a TNF-alpha inhibitor were significantly less likely
to have an MI than patients treated with topical therapy (HR 0.50, 95% CI 0.32-0.79). A reduction in
risk for MI was also seen among patients who received oral therapy (including cyclosporine,
1452
acitretin, and methotrexate) or phototherapy when they were compared with the topical therapy
group (HR 0.54, 95% 0.38-0.77).
Moreover, a retrospective cohort study of 2400 patients with severe psoriasis found that patients
who had received treatment with a biologic agent or methotrexate had a reduced risk for
cardiovascular events compared with patients who received other treatment [76]. When compared
with patients treated with other therapies, the age and sex adjusted hazard ratio for death,
myocardial infarction, and stroke was 0.28 (95% CI 0.12-0.64) for patients treated with a biologic
agent and 0.65 (95% CI 0.42-1.00) for patients treated with methotrexate. More than 80 percent of
patients treated with a biologic agent in this study received a TNF-alpha inhibitor.
Additional support for a beneficial effect of TNF-alpha inhibitors on cardiovascular risk stems from
studies in rheumatoid arthritis that have demonstrated reduced rates of serious adverse
cardiovascular events among patients treated with TNF-alpha inhibitors [77,78]. In addition, reduced
levels of C-reactive protein (a marker for inflammation and risk for cardiovascular disease) have
been detected in patients with psoriasis during etanercept therapy [79]. Further study is necessary to
confirm the impact of anti-TNF therapies on cardiovascular disease in patients with psoriasis.
Concern regarding a risk for cardiovascular disease in patients treated with ustekinumab, an IL-
12/23 inhibitor used for the treatment of psoriasis, led to a meta-analysis of controlled trials that did
not find a statistically significant increase in risk for major adverse cardiac events among
ustekinumab-treated patients [80]. In addition, a review of pooled data from four phase 2 and phase 3
randomized trials with up to five years of follow-up did not find an increased risk for major adverse
cardiovascular events in patients treated with ustekinumab for psoriasis [81]. Ustekinumab and
cardiovascular risk is discussed in greater detail separately. (See "Treatment of psoriasis in adults",
section on 'Ustekinumab'.)
Radiologic support for a benefit of biologic therapy on coronary artery disease stems from a
prospective, observer-blinded study that used coronary computed tomography (CT) to assess
coronary artery disease progression in patients with moderate to severe psoriasis [82]. In the study,
28 patients treated with biologic agents (adalimumab, etanercept, infliximab, and/or ustekinumab)
and 28 controls treated only with topical therapy underwent coronary artery calcium (CAC) CT and
contrast-enhanced coronary CT angiography at baseline and after approximately one year.
Compared with patients treated with biologic agents, patients in the control group exhibited
increased progression of CAC. In addition, progression of luminal narrowing in diseased segments
occurred in the control group but not in the treatment group.
Benefit of TNF-alpha inhibitors was also detected in a prospective cohort study of 319 patients with
psoriasis or psoriatic arthritis in whom carotid total plaque area was assessed with ultrasound at
1453
baseline and after two to three years [83]. This study found an association between receipt of TNF-
alpha inhibitor therapy and reduced progression of carotid plaques in men. A similar effect was not
found in women. A second phase of the study that used fluorodeoxyglucose-positron emission
tomography/computed tomography (FDG-PET/CT) to assess aortic vascular inflammation in
psoriatic arthritis patients receiving a TNF-alpha inhibitor (n = 21) and psoriatic arthritis patients not
receiving a biologic agent (n = 13) found improvement in signs of vascular inflammation only in the
TNF-alpha inhibitor group.
MALIGNANCY
Multiple studies have found an increased risk for malignancy in patients with psoriasis [84-92]. A
systematic review and meta-analysis of cohort and case-control studies that assessed cancer
incidence or mortality in patients with and without psoriasis supports increased risk for cancer and
death from cancer among individuals with psoriasis [93]. Increased risk for cancer was found both
among patients with severe psoriasis (1.22, 95% CI 1.08-1.39 based upon analysis of nine studies)
and psoriasis of any severity (1.18, 95% CI 1.06-1.31 based upon analysis of seven studies). Specific
types of cancer that exhibited increased risk for development among patients with psoriasis (any
severity) included oral cavity cancer, squamous cell carcinoma, esophageal cancer, liver cancer,
laryngeal cancer, keratinocyte cancer, kidney cancer, pancreatic cancer, lymphoma, colorectal cancer,
non-Hodgkin lymphoma, and colon cancer. In addition, mortality from cancer was greater among
individuals with psoriasis than individuals without psoriasis, with a relative risk of 1.18 (95% CI 1.06-
1.31) for any psoriasis severity and 1.22 (95% CI 1.08-1.39) for severe psoriasis. High heterogeneity
among studies and dependence on surrogate markers to classify psoriasis severity were some of the
limitations of this study.
Rationale — Multiple factors may contribute to an increased rate of malignancy in patients with
psoriasis, including the effects of immunosuppressive or immunomodulatory therapies and the
presence of a chronic inflammatory state [94]. In patients with cutaneous T cell lymphoma,
misdiagnosis of early stages of this disorder as psoriasis may be an additional factor.
Cutaneous malignancy — Knowledge of the carcinogenic effects of ultraviolet light led to inquiries
regarding the risk for cutaneous malignancy after phototherapy for psoriasis. With the exception of
psoralen plus ultraviolet A (PUVA) treatments, which have been linked to increased risk for skin
cancer (particularly cutaneous squamous cell carcinoma) [95-97], a definitive relationship between
phototherapy and skin cancer has not been established. (See "Treatment of psoriasis in adults",
section on 'Ultraviolet light' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on
'Skin cancer'.)
1454
Increased rates of nonmelanoma skin cancer have been detected among patients with rheumatoid
arthritis treated with biologic drugs (primarily anti-TNF drugs) [98], raising concern over whether a
similar risk exists in patients with psoriasis treated with these agents. However, a meta-analysis of
20 randomized placebo-controlled trials that included more than 6800 psoriatic patients treated with
TNF antagonists failed to show an increased risk for any type of cancer [99].
AUTOIMMUNE DISEASES
Compared with the general population, autoimmune disease may be more likely to occur in
individuals with psoriasis. In a retrospective cohort study that included approximately 23,000
patients with psoriasis, an increased risk for multiple autoimmune diseases was detected, with the
greatest risk increase observed for alopecia areata (odds ratio 2.2, 95% CI 2.0-3.0), followed by celiac
disease, systemic sclerosis, Crohn's disease, vitiligo, and other disorders [100].
An association with Crohn's disease was also illustrated in a study in which 13 of 136 patients with
Crohn's disease (10 percent) and only 3 of 136 controls (2 percent) had psoriasis [101]. Moreover, the
patients with Crohn's disease were more likely to have a first degree relative with psoriasis (10 versus
3 percent). The shared location of susceptibility loci for these disorders on chromosome 16q may be
a relevant factor in the relationship between these diseases [101,102]. In addition to Crohn's disease,
ulcerative colitis has been detected at increased frequency in patients with psoriasis [103,104]. A
relationship between multiple sclerosis and psoriasis is uncertain [100,105,106].
CHRONIC KIDNEY DISEASE
Patients with psoriasis may have an increased risk for chronic kidney disease. The first population-
based cohort study to compare the risk of moderate to advanced chronic kidney disease in adults
with and without psoriasis found an elevated risk for chronic kidney disease in patients with severe
psoriasis [107]. Patients in this United Kingdom study were classified as having severe psoriasis if
records revealed a history of treatments typically prescribed for patients with severe disease; the
remaining patients were classified as having mild disease. After adjustment for sex, age,
cardiovascular disease, diabetes, hypertension, hyperlipidemia, use of nonsteroidal antiinflammatory
drugs, and body mass index, psoriasis was an independent risk factor for moderate to advanced
chronic kidney disease among patients with severe psoriasis (adjusted hazard ratio [HR] 1.93, 95% CI
1.79-2.08). In contrast, a statistically significant difference in risk was not evident in the mild
psoriasis population (adjusted HR 0.99, 95% CI 0.97-1.02). Age appeared to influence the change in
risk for chronic kidney disease; the relative risk for chronic kidney disease was greater among
1455
younger individuals than older individuals when compared with individuals without psoriasis in the
respective age groups.
Although other studies utilizing different criteria to assess for kidney disease support an association
between psoriasis and kidney disease [69,108], not all studies have reached this conclusion
[109,110]. As an example, a retrospective study of 753 patients with psoriasis from an academic
medical center did not find an increased risk for renal failure in patients with psoriasis [109].
NONALCOHOLIC FATTY LIVER DISEASE
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions ranging from fatty liver,
which is relatively benign, to nonalcoholic steatohepatitis, which may lead to fibrosis, cirrhosis, and
rarely hepatocellular carcinoma. NAFLD is frequently associated with the metabolic syndrome. (See
"Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and
"Management of nonalcoholic fatty liver disease in adults", section on 'Disease course'.)
An increased risk for liver disease, particularly NAFLD and cirrhosis, has been detected in patients
with psoriasis [111-114]. A cohort study of patients with psoriasis, psoriatic arthritis, or rheumatoid
arthritis that included approximately 197,000 patients with psoriasis and approximately 12,000
patients with psoriatic arthritis and their matched controls found elevated risk for liver disease in
both of these populations [113]. The occurrence of NAFLD was greatest among patients with
psoriasis or psoriatic arthritis who were prescribed systemic therapy. In an Italian study of 130
patients with chronic plaque psoriasis and 260 matched controls, NAFLD was significantly more
common among the patients with psoriasis (47 versus 28 percent) [111]. In addition, the severity of
psoriasis was significantly greater among patients with both psoriasis and NAFLD than among
patients with psoriasis alone.
Psoriasis may also be associated with greater severity of NAFLD. A study in which NAFLD was
detected in 59 percent of 142 patients with psoriasis found that patients with psoriasis and NAFLD
were more likely to have severe liver fibrosis than patients with NAFLD who did not have psoriasis
[112].
The association of psoriasis with liver disease may be important from a therapeutic standpoint,
since treatment of psoriasis may involve the use of hepatotoxic drugs, such as methotrexate [115].
Compared with patients with rheumatoid arthritis, liver toxicity due to methotrexate therapy occurs
more frequently in patients with psoriasis [116].
CARDIAC ARRHYTHMIA
1456
Patients with psoriasis may have increased risk for cardiac arrhythmias, a factor that may contribute
to increased risk for cardiovascular morbidity and mortality among psoriasis patients. In a
population-based cohort study based upon data from the Taiwan National Health Insurance
Research Database, the incidences of arrhythmias were 15.41 per 1000 person-years among
patients with psoriasis and 11.06 per 1000 person-years among patients without psoriasis (adjusted
hazard ratio [HR] 1.34, 95% CI 1.29-1.39) [117]. Slightly greater risk for arrhythmia was detected
among psoriasis patients with psoriatic arthritis (adjusted HR 1.46, 95% CI 1.22-1.74) than among
psoriasis patients without psoriatic arthritis (adjusted HR 1.33, 95% CI 1.28-1.39). Chronic
inflammation in psoriasis is postulated to contribute to an increased risk for arrhythmia; however, a
mechanism for this observation remains to be confirmed.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Increased rates of chronic obstructive pulmonary disease (COPD) have been detected in patients
with psoriasis. In an Israeli case-control study of 12,500 adults with psoriasis and approximately
24,000 controls, COPD was slightly more prevalent among patients with psoriasis (6 versus 4
percent; adjusted odds ratio 1.27, 95% CI 1.13-1.42) [118]. A smaller population-based study in
Taiwan also found an increased risk for COPD in patients with psoriasis [119]. Similar to psoriasis,
chronic inflammation is involved in the pathogenesis of COPD [120].
OBSTRUCTIVE SLEEP APNEA
Obstructive sleep apnea (OSA) is an increasingly prevalent disorder that may occur in association
with psoriasis [121-124]. Further work is needed to clarify the relationship between psoriasis and
obstructive sleep apnea.
BONE DISEASE
A study of patient data obtained from 2006 to 2012 in the Nationwide Emergency Department
Sample in the United States found that patients with a diagnosis of psoriasis were more likely to
have a diagnosis of osteopenia, osteoporosis, osteomalacia, ankylosing spondylitis, and pathologic
fractures than patients without psoriasis [125]. Additional study is necessary to confirm these
findings.
PARKINSONISM
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Parkinsonism is a neurologic syndrome characterized by tremor, bradykinesia, rigidity, and postural
instability [126]. A retrospective study of data from a health insurance database in Taiwan found a
higher risk for parkinsonism among 4885 patients with psoriasis than among 24,425 controls
(adjusted hazard ratio 1.74, 95% CI 1.35-2.20). Whether chronic inflammation in psoriasis can
contribute to neurologic damage resulting in the development of parkinsonism is unclear. Additional
studies are necessary to explore the relationship between psoriasis and parkinsonism. (See "Etiology
and pathogenesis of Parkinson disease" and "Clinical manifestations of Parkinson disease".)
PSYCHOSOCIAL EFFECTS
Psoriasis can have detrimental effects on the quality of life of adults and children [127-135]. Elevated
rates of various psychopathologies, including poor self-esteem, sexual dysfunction, anxiety,
depression, and suicidal ideation have been reported in patients with psoriasis [127,135-140]. The
significant impact of psoriasis on quality of life was evident in a study of 317 patients that found that
psoriasis was associated with degrees of physical and mental impairment that were similar to
cancer, arthritis, hypertension, heart disease, diabetes, and depression [141].
Occupational success may also be inhibited by psoriasis. Lower rates of employment and decreased
work productivity have been linked to psoriasis [142-144].
Psychiatric disorders — One study that examined the relationship between mental health and
psoriasis compared 3147 adolescents and adults with psoriasis to matched controls. After
controlling for age and gender, psoriasis was associated with increased rates of depression (odds
ratio [OR] 1.49; 95% CI 1.20-1.86); neurotic, stress-related, or somatoform disorders (OR 1.41; 95% CI
1.22-1.62); and personality and behavioral disorders (OR 1.58; 95% CI 1.05-2.39) [145].
Multiple other studies have corroborated the finding of increased rates of depression among
individuals with psoriasis [132,137-139,146]. A cohort study of over 50,000 women from the Nurses’
Health study found higher rates of clinical depression in women with psoriasis and women with both
psoriasis and psoriatic arthritis than in women without psoriasis [138]. In addition, a population-
based study that included over 12,000 United States citizens and controlled for comorbidities found
an association between psoriasis and major depression (OR 2.09, 95% CI 1.41-3.11) [137].
Severe manifestations of depression may occur; in a study of 217 patients with psoriasis,
approximately 10 percent of patients reported a desire to be dead and 5 percent reported active
suicidal ideation [147]. Because the clinical severity of skin disease does not always correlate with
the emotional toll of psoriasis [127,130,148], clinicians should remain cognizant that even patients
with mild psoriasis may experience significant emotional distress related to the disease.
1458
Psychological distress may impair the response to psoriasis therapies. For example, in a cohort of
psoriasis patients treated with PUVA, pathologic or high-level worry was a significant predictor of
time required to achieve disease clearance [149].
ALCOHOL ABUSE
Data on the prevalence of alcohol use and abuse among patients with psoriasis are limited.
Epidemiologic studies have found increased consumption of alcohol and an increased prevalence of
alcohol misuse among individuals with psoriasis [139,150,151].
Additional studies suggest that alcohol consumption may contribute to the development of
psoriasis. A Finnish study demonstrated that alcohol consumption prior to the onset of skin disease
was greater in men with psoriasis (n = 144) than in 285 unmatched male controls who had other skin
diseases [152]. In addition, an analysis of data from over 82,000 women in the Nurses' Health Study
found that when compared with women who did not drink alcohol, women who consumed 2.3 or
more drinks per week were more likely to develop psoriasis (relative risk 1.72, 95% CI 1.15-2.57)
[153].
The mechanism through which alcohol consumption might contribute to psoriasis is unknown.
Potential contributors include alcohol-related alterations in immune competence, proinflammatory
cytokine production, epidermal proliferation and differentiation, and susceptibility to infections [154].
Excess alcohol consumption has been linked to more severe disease [155], and may have inhibitory
effects on the response to treatment [154]. Additional study is necessary to evaluate the relevance of
alcohol ingestion in psoriasis.
SMOKING
Smoking increases the risk of hypertension, peripheral vascular disease, stroke, myocardial
infarction and death. A meta-analysis of prevalence studies of smoking with psoriasis revealed a
strong association with both current smoking (pooled odds ratio 1.78, 95% CI 1.52-2.06) and former
smoking (pooled odds ratio 1.62, 95% CI 1.33-1.99) [156]. Patients with a history of smoking were
also more likely to develop new onset psoriasis (odds ratio 1.39, 95% CI 1.27-1.52). Moreover, current
smokers were almost twice as likely to develop psoriasis as non-smokers (odds ratio 1.93, 95% CI
1.64-2.28), and there was a possible dose-effect of smoking intensity and duration on psoriasis
incidence. These studies demonstrating both an increased prevalence and incidence of smoking in
patients with psoriasis, along with numerous adverse cardiovascular risks of smoking, support the
concept that strong recommendations for smoking cessation should be given to psoriasis patients.
1459
MIGRAINE
There may be an association between psoriasis and migraine [135,157]. A Danish nationwide study
found a disease severity-dependent increase in risk for migraine among patients with psoriasis [157].
Adjusted incidence rate ratios for migraine in patients with mild and severe psoriasis were 1.37 (95%
CI 1.30-1.45) and 1.55 (95% CI 1.29-1.86), respectively. The study also found increased risk for
migraine among patients with psoriatic arthritis, demonstrating an adjusted incidence rate ratio for
migraine in patients with psoriatic arthritis of 1.92 (95% CI 1.65-2.22). In contrast, a Taiwanese
population-based study of 1685 adults with psoriasis and 5055 control subjects without psoriasis
did not find an association between migraine and psoriasis [158].
EVALUATION AND MANAGEMENT
The recognition of psoriasis as a systemic inflammatory disease associated with increased risk for
multiple other disorders and mortality supports the implementation of a comprehensive approach to
the management of patients who present with this disease [159-161]. In an attempt to optimize the
evaluation and management of patients with psoriasis, some academic medical centers have
developed multidisciplinary clinical programs for patients with psoriasis in which professionals such
as rheumatologists, cardiologists, primary care clinicians, psychiatrists, psychologists, nutritionists,
and others work together in a structured manner to manage these patients.
Studies of the clinical value and cost-effectiveness of multidisciplinary clinical programs will be
useful for determining the clinical value and cost-effectiveness of this approach. Moreover,
additional studies that assess the impact of treatment of comorbid diseases on psoriasis and the
effects of treatment of psoriasis on its comorbidities are needed.
Patient assessment — In general, patients who present with psoriasis should be assessed at the
time of diagnosis and periodically thereafter for risk factors, signs, and symptoms of psoriasis
comorbidities. Based upon the results of the clinical assessment, further investigation should be
performed as indicated.
The 2008 American Journal of Cardiology Editor's Consensus on Psoriasis and Coronary Artery
Disease recommended that patients with moderate to severe psoriasis be informed of a potential
increased risk for coronary artery disease (CAD) [162]. In addition, the panel recommended
implementation of the following measures for patients with moderate to severe psoriasis and
consideration of these measures for patients with milder disease:
● Assessment of the personal and family history of CAD
1460
● Annual assessment of blood pressure
● Screening of lipid profiles and fasting blood glucose
● Treatment of risk factors for CAD
A 2008 consensus statement from the National Psoriasis foundation also addressed
recommendations for the assessment of psoriasis comorbidities [163]. In addition to supporting the
standard recommendations for identifying and reducing cardiovascular risk (eg, smoking cessation,
weight loss, and physical activity), the consensus panel recommended the following (see "Overview
of primary prevention of coronary heart disease and stroke"):
● Interventions to recognize and control depression.
● Moderation of alcohol intake.
● Vigilance for signs of lymphoma, cutaneous malignancies, and solid tumors (age-appropriate
screening, annual skin examinations on patients on immunosuppressants or with a history of
PUVA treatment, vigilance for plaques that appear atypical for psoriasis).
● Routine monitoring for the development of psoriatic arthritis. (See "Clinical manifestations and
diagnosis of psoriatic arthritis", section on 'Classification criteria'.)
Referrals to specialists such as cardiology, gastroenterology, hepatology, nephrology, psychiatry, and

pulmonary medicine can be beneficial based upon the presence of signs or symptoms of particular
comorbidities.
● Increasing evidence supports the designation of psoriasis as a multisystem inflammatory

disorder with multiple comorbidities. Examples of disorders associated with psoriasis include
obesity, metabolic syndrome, hypertension, diabetes, atherosclerosis, malignancy, hepatic and
pulmonary disorders, and psychiatric disease. (See 'Introduction' above.)
● The chronic inflammatory nature of psoriasis may contribute to the observed association
between psoriasis and obesity, metabolic syndrome, and atherosclerotic disease. Further
1461
studies are necessary to define the nature of the relationship between psoriasis and these
diseases. (See 'Obesity' above and 'Metabolic syndrome' above.)
● The psychosocial impact of psoriasis is not always proportional to the severity of skin disease.
Patients with mild psoriasis may experience significant impairment of quality of life related to
this disease. (See 'Psychosocial effects' above.)
● Recognition of the link between psoriasis and other diseases may facilitate early diagnosis and
treatment of psoriasis comorbidities. The assessment for risk factors, signs, and symptoms of
potential comorbid diseases is an important component of patient management. (See
'Evaluation and management' above.)
1462
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Patient education: Psoriasis (Beyond the Basics)

PSORIASIS OVERVIEW
Psoriasis is a chronic skin disorder that causes areas of thickened, inflamed, red skin, often covered
with silvery scales. Children and adolescents can develop psoriasis, but it occurs primarily in adults.
Women and men are equally affected. Psoriasis is not an infection, and it is not contagious.
The severity of psoriasis is determined by how much of the body's surface is covered and how much
it affects a person's quality of life. Psoriasis is not curable, although many treatments are available to
reduce the symptoms and appearance of the disease.
PSORIASIS CAUSES
Researchers have not identified the exact cause of psoriasis. However, the disease develops due to a
combination of immune, genetic, and environmental factors.
Immune system — The immune system plays an important role in the skin changes that occur in
psoriasis. Understanding the normal process of skin development is helpful for understanding why
skin changes occur in people with psoriasis.
1463
The skin is made up of several layers (figure 1). The top layer is the epidermis, a layer of cells that
divide and eventually die, covering the surface of the skin with a layer of dead cells called the
stratum corneum. The middle layer is the dermis; this is the layer where collagen and blood vessels
are found. The inner layer is the subcutaneous layer, a layer of fat underneath the skin. Every day, as
cells in the epidermis die and become part of the stratum corneum, dead cells at the top of the
stratum corneum also are shed. This balance prevents the dead skin layer from becoming too thick.
In skin affected by psoriasis, immune cells enter the skin through blood vessels and cause the
epidermis to grow very rapidly and to stop shedding properly (figure 2). This causes thickening of the
skin as well as the scaly build-up composed of dead skin cells that is seen on areas affected by
psoriasis. Dilated blood vessels in the dermis that feed the rapidly growing epidermis cause the red
color of the skin.
Genetics — Genetic factors play a role in determining whether someone develops psoriasis. About 40
percent of people with psoriasis or psoriatic arthritis (a type of arthritis closely related to psoriasis)
have family members with the disorder (see "Patient education: Psoriatic arthritis (Beyond the
Basics)"). Several genes have been identified that make people more susceptible to psoriasis, but
there is no genetic test that can definitely tell whether an individual will develop the disease.
Environment and behavior — Certain environmental and behavioral factors seem to be linked to
psoriasis. Bacterial and viral infections, alcohol consumption, and certain medications (including
beta blockers, lithium, and antimalarial drugs) may affect a person's risk of developing psoriasis or
worsen symptoms. Smoking appears to increase the risk and severity of psoriasis, particularly for
psoriasis of the palms and soles.
PSORIASIS SYMPTOMS
Symptoms of psoriasis include:
● Areas of skin that are dry or red, usually covered with silvery-white scales, and sometimes with
raised edges
● Rashes on the scalp, genitals, or in the skin folds
● Itching and skin pain
● Joint pain, swelling, or stiffness
● Nail abnormalities, such as pitted, discolored, or crumbly nails
TYPES OF PSORIASIS
1464
There are several common types of psoriasis:
Plaque psoriasis — Plaque psoriasis is the most common form of psoriasis. Plaque psoriasis tends
to affect young and middle aged adults, but can occur at any age. The individual skin plaques are
usually between 0.4 and 4 inches (1 to 10 cm) wide but may be larger. Some of the most common
areas for plaques are the scalp, elbows, knees, and back (picture 1 and picture 2). The severity of
plaque psoriasis varies widely. Plaque psoriasis may occur in just a few small areas or may cover a
large portion of the body.
Guttate psoriasis — This type of psoriasis is sometimes linked to a recent streptococcal infection,
usually pharyngitis (eg, strep throat). It often affects children or young adults with no past history of
psoriasis, and causes a sudden eruption of small scaly papules on the trunk of the body (picture 3).
Pustular psoriasis — Pustular psoriasis can be a severe, and occasionally life-threatening, form of
psoriasis. It develops quickly, with multiple small pustules that may join into larger areas (picture 4).
Symptoms can include fever and abnormal blood levels of white blood cells and calcium. Pustular
psoriasis can also cause pus-filled blisters on the palms of the hands and soles of the feet. These
blisters can crack, causing painful breaks in the skin, and can be disabling.
Inverse psoriasis — This type of psoriasis affects less visible body areas, such as the groin, armpits,
buttocks, genitals, and the area under the breasts (picture 5). Sometimes this is mistakenly
diagnosed as a fungal or bacterial infection.
Nail psoriasis — Some people with psoriasis develop nail problems, including tiny pits over the
surface of the nails. The pits look as if someone has taken a pin and pricked the nail several times
(picture 6). In addition, nails may develop a tan-brown color (also known as "oil spots") or may
separate from the nail bed (also known as "onycholysis") (picture 7). In more severe cases, people
have thick, crumbling nails.
Treatment of nail psoriasis is difficult and may include injections of steroids into the nail bed or oral
medications such as methotrexate, cyclosporine, or immunomodulatory drugs. (See 'Psoriasis
treatment' below.)
Psoriatic arthritis — Up to one-third of people with psoriasis also have psoriatic arthritis, a condition
that causes joint pain and swelling. Skin signs usually develop first, although about 15 percent of
patients develop arthritis (joint swelling and stiffness) before symptoms of psoriasis. People with
psoriatic arthritis often have severe nail problems. (See "Patient education: Psoriatic arthritis
(Beyond the Basics)".)
Other associated conditions — There is a higher than normal frequency of depression in people with
psoriasis. Psoriasis also has been associated with obesity and an increased risk of heart disease.
1465
PSORIASIS DISEASE COURSE
Psoriasis is usually a lifelong condition and is not currently curable, although the severity of the
disease can improve or worsen over time and can be controlled with treatment.
In people with certain forms of the disease, itching or pain and stiffness is severe and disabling.
Some people with visible psoriasis lesions have feelings of embarrassment about their appearance.
Stress, anxiety, loneliness, and low self-esteem can occur as a result.
People with psoriasis have higher rates of depression compared with those without the condition.
People who have depression often benefit from working with a psychologist, clinical social worker, or
other therapist to discuss their illness and identify possible ways to cope. A number of organizations,
such as the National Psoriasis Foundation (www.psoriasis.org), are available to provide support to
people with psoriasis and their families. (See 'Where to get more information' below.)
PSORIASIS DIAGNOSIS
Psoriasis can be diagnosed by examining the skin. Occasionally, a skin biopsy or scraping may be
taken to rule out other disorders. There is no blood test that can definitively diagnose psoriasis.
PSORIASIS TREATMENT
Psoriasis is not curable but many treatments are available that can reduce the bothersome
symptoms and appearance of the disease. Treatment depends upon the severity of the disease, the
cost and convenience of the treatment, and a person's response to the treatment. A combination of
therapies is often recommended.
Referral to a dermatologist (a doctor who specializes in skin conditions) may be needed if the
diagnosis of psoriasis is uncertain, if the initial treatment does not improve symptoms, or if the
disease is widespread or severe. People with psoriatic arthritis may need to see a rheumatologist (a
doctor who specializes in joint conditions).
Medicines applied to the skin — Many medications are available that can be rubbed onto the skin to
treat psoriasis. Because psoriasis cannot be cured, continued use of medication is required to
maintain improvement. For the best results, patients must use treatments as directed.
Emollients — Keeping skin soft and moist can minimize itching and tenderness. Over-the-counter
moisturizers such as petroleum jelly or thick creams may be recommended; these should be applied
1466
immediately after bathing or showering.
Topical corticosteroids — Corticosteroids (sometimes called "steroids" but distinct from body
building steroids) are applied to the skin to help to reduce inflammation. This is often done twice per
day at the beginning of treatment. As a patient's psoriasis improves, a doctor may recommend
decreasing the frequency of treatment.
These cortisone-type creams and ointments are available in a variety of strengths (potencies); the
least potent are available without a prescription (eg, hydrocortisone 1% cream) and are usually only
effective in sensitive skin areas like the face and body folds. More potent formulations require a
prescription. Other forms, such as solutions, gels, shampoo, lotion, foam, and spray, are available.
Some people with psoriasis prefer these forms of medication over creams or ointments.
Side effects can include thinning of the skin and stretch marks (particularly when applied to normal
skin). These effects are most likely to occur when topical corticosteroids are used for long periods of
time. It is important to use these medications properly to reduce the risk for these side effects. A
patient who notices these effects should contact his or her doctor.
Calcipotriene or calcitriol — Calcipotriene (sample brand names: Dovonex, Sorilux) and calcitriol
(sample brand name: Vectical) are related to vitamin D and work by slowing the growth of skin cells
in the epidermis. These medicines can be used instead of or in addition to topical corticosteroids.
They are usually applied twice a day when used alone. The side effects are usually minimal, with skin
irritation being the most common problem. These drugs do not cause thinning of the skin.
Other preparations (Taclonex, Enstilar) combine calcipotriene with a corticosteroid (betamethasone)

in a once daily treatment. Although effective, combination products can be expensive.
Tar — Tar is a substance distilled from coal that has been used to treat psoriasis for many years.
It is not completely clear how tar works, although it appears to inhibit the inflammation that leads to
psoriasis. Tar preparations are available in shampoos, creams, oils, and lotions without a
prescription, and are usually applied to the skin or scalp once or twice a day. Tar products do not
cause serious side effects, although they can stain skin, hair, and clothing. Tar products are often
used along with corticosteroids or with ultraviolet light treatments. (See 'Ultraviolet light' below.)
Tazarotene — Tazarotene (sample brand name: Tazorac) is a skin treatment derived from vitamin
A that is available in a cream or gel. It is usually applied once per day, in the evening. It may also be
applied for 20 minutes and then washed off if skin irritation develops. Improvement should be seen
within two months of treatment.
Calcineurin inhibitors — Topical calcineurin inhibitors, including tacrolimus (brand name:

Protopic) and pimecrolimus (Elidel) creams, can be used to treat psoriasis, especially on the face and
1467
skin folds, such as in the armpits or under the breasts.
Anthralin — Anthralin is a treatment for psoriasis that has been used for psoriasis since the early
20th century. It is now used less commonly than many other medications because the treatment can
cause temporary red-brown stains on skin and permanent stains on clothing. Because anthralin can
be irritating, it is usually applied to the skin for only 10 to 60 minutes per day. Anthralin may be less
effective than topical corticosteroid, topical calcipotriene, and topical calcitriol therapy.
Ultraviolet light — Exposure to ultraviolet light is another way to treat psoriasis. During the summer
months, people with psoriasis often notice that their symptoms improve. Ultraviolet light treatment
(from a dermatologist) may be recommended to treat psoriasis. However, it is important to discuss
the potential risks and benefits of ultraviolet light therapy before beginning treatment.
Before receiving ultraviolet light therapy, you may be asked to bathe and gently scrub areas affected
by psoriasis, and then apply mineral oil to these areas; the oil allows the light to penetrate the skin
more easily.
Although ultraviolet light therapy is effective for treating psoriasis, office treatment can be
inconvenient and expensive, despite insurance coverage. Some dermatologists may recommend
brief sun exposure or home light treatment (or use of a tanning bed if other options are not feasible)
as alternatives to office treatment. Sometimes, an oral medication may be prescribed to sensitize the
skin to the light treatment; when this is done, care must be taken to prevent severe burns from
occurring.
Risks — Long-term ultraviolet light therapy may increase the risk for skin cancer. Ultraviolet light
therapy is not recommended for people with a history of melanoma or other skin cancers. (See
"Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)".)
Some clinicians also use lasers to treat psoriasis. The laser allows higher doses of ultraviolet B
(UVB) radiation to be directed to the lesions while sparing normal skin; as a result, skin may heal with
fewer treatments than with traditional ultraviolet light therapy. Laser treatment is most suitable for
people who have small areas of psoriasis.
Oral medications
Methotrexate — Methotrexate treats psoriasis by suppressing the immune response that triggers
the disease. This drug is often used to treat moderate to severe psoriasis and/or psoriatic arthritis. It
is usually taken once per week, and it may be taken in oral (pill) form or as an injection.
Methotrexate can be used for long-term treatment of psoriasis, although it is important to have your
liver monitored during treatment; methotrexate can affect liver function in some people. Patients
1468
should avoid drinking alcohol while on methotrexate because alcohol also hurts the liver.
Improvement in psoriasis may not be seen until three months of methotrexate treatment are
completed.
While taking methotrexate, many providers recommend taking folic acid 1 mg daily or leucovorin
(also known as folinic acid) 5 mg weekly to reduce the risk of certain methotrexate side effects, such
as upset stomach and a sore mouth.
Severe side effects can occur with methotrexate – including damage to the lungs, liver and bone
marrow, and even death – so careful monitoring is essential. Serious interactions may occur with
certain medications, particularly sulfa-type antibiotics. Methotrexate is not safe to take during
pregnancy.
Retinoids — Retinoids are derived from vitamin A. An oral form called acitretin (brand name:
Soriatane) may be recommended to people with severe forms of psoriasis. Improvement may be
noticeable within one month, although the full effect of retinoids may take up to three to six months.
Side effects of retinoids include cracking and drying of the lips and skin, nosebleeds, trouble seeing
in the dark, hair loss, joint pain, and depression. Acitretin may cause increased levels of triglycerides
and liver enzymes in the blood; blood testing is usually recommended to monitor for these changes.
Acitretin can cause severe birth defects and is only slowly removed from the body, so women should
not get pregnant while taking acitretin or within three years after stopping the medication. Thus, for
practical reasons, this medication is typically not prescribed to women who could get pregnant.
Apremilast — Apremilast (brand name: Otezla) is a newer oral medication for psoriasis and
psoriatic arthritis that works by reducing inflammation. Apremilast is usually taken twice daily.
People with severe kidney problems typically take apremilast only once daily.
Improvement in psoriasis may begin within the first few weeks of apremilast treatment. The most
common side effects of apremilast are diarrhea, nausea, upper respiratory tract infection, and
headache. In addition, people taking apremilast should contact their health care providers if they
notice the emergence or worsening of depression, suicidal thoughts, or other mood changes while
taking this medication.
Other drugs — Several medications that suppress the immune system can be used to treat severe
psoriasis for a short period of time. These include cyclosporine, hydroxyurea, and azathioprine.
Injectable medications — Several injectable medications, known as "biologics," target the overactive
immune system and may be beneficial in the treatment of psoriasis. Medications include etanercept
(Enbrel), infliximab (sample brand name: Remicade), adalimumab (brand name: Humira),
ustekinumab (brand name: Stelara), secukinumab (brand name: Cosentyx), ixekizumab (brand name:
1469
Taltz), brodalumab (brand name: Siliq), guselkumab (brand name: Tremfya), tildrakizumab (brand
name: Ilumya), certolizumab pegol (brand name: Cimzia), and risankizumab (brand name: Skyrizi).
Biologics can be highly effective for the treatment of psoriasis, with improvement in skin symptoms
that usually begins within a few weeks of starting treatment. Because of their cost and potential side
effects, biologics are generally reserved for people with moderate to severe psoriasis that has not
responded to other treatments.
Like methotrexate and cyclosporine, biologics affect the immune system and should not be used in
people with serious infections. Screening for tuberculosis (TB) is necessary before starting therapy
since the risk of developing active TB infection is increased. If there is evidence of prior infection
with tuberculosis, treatment to prevent reactivation of the infection is recommended (see "Patient
education: Tuberculosis (Beyond the Basics)"). Testing for hepatitis B is also recommended.
Dietary changes — The role of dietary interventions in treating psoriasis has been unclear. Experts
recommend that people with psoriasis who are overweight or obese reduce the number of calories
they consume in order to try to lose weight. They also recommend a gluten-free diet for people with
psoriasis who have been diagnosed with celiac disease or confirmed to have gluten sensitivity based
on blood tests. Beyond this, there is no specific approach that has been proven to improve psoriasis
symptoms; however, eating a nutritious, balanced diet (high in fruits, vegetables, and whole grains;
and low in unhealthy fats and added sugar) has many other health benefits.
WHERE TO GET MORE INFORMATION
Your health care provider is the best source of information for questions and concerns related to
your medical problem.
This article will be updated as needed on our website (www.uptodate.com/patients). Related topics
for patients, as well as selected articles written for health care professionals, are also available.
Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials.
Patient education: Psoriasis (The Basics)

Patient education: Psoriatic arthritis in adults (The Basics)
1470
Patient education: Psoriatic arthritis in children (The Basics)
Patient education: Topical corticosteroid medicines (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are best for patients who want in-depth information and are
comfortable with some medical jargon.
Patient education: Psoriatic arthritis (Beyond the Basics)

Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)
Patient education: Tuberculosis (Beyond the Basics)
Professional level information — Professional level articles are designed to keep doctors and other
health professionals up-to-date on the latest medical findings. These articles are thorough, long, and
complex, and they contain multiple references to the research on which they are based. Professional
level articles are best for people who are comfortable with a lot of medical terminology and who
want to read the same materials their doctors are reading.
Approach to the patient with a scalp disorder

Approach to the patient with anal pruritus
Clinical manifestations and diagnosis of psoriatic arthritis
Psoriasis: Epidemiology, clinical manifestations, and diagnosis
Management of psoriasis in pregnancy
Pathogenesis of psoriatic arthritis
Treatment of psoriasis in adults
Treatment of psoriatic arthritis
Overview of biologic agents and kinase inhibitors in the rheumatic diseases
The following organizations also provide reliable health information.
● National Library of Medicine
(https://medlineplus.gov/psoriasis.html)
● National Institute on Arthritis and Musculoskeletal and Skin Diseases
(www.niams.nih.gov/Health_Info/default.asp)
● American Academy of Dermatology
(www.aad.org/public/diseases/scaly-skin/psoriasis)
● American Academy of Allergy, Asthma and Immunology

1471
(www.aaaai.org)
● National Psoriasis Foundation
1-800-723-9166
(www.psoriasis.org/home/)
[1-6]
1472
GRAPHICS
Normal skin
1473
Skin changes in psoriasis
The skin is made up of different layers. In psoriasis, the top layer of skin (called the epidermis)
thickens, and blood vessels in the second layer (called the dermis) widen. The skin also becomes
inflamed.
1474
Plaque psoriasis
Plaque-type psoriasis causes the skin to form red, raised, scaly areas.
Reproduced with permission from: www.skinsight.com. Copyright VisualDx. All rights reserved.
1475
Plaque psoriasis
Plaque-type psoriasis causes the skin to form red, raised, scaly areas.
1476
Guttate psoriasis
Guttate psoriasis causes many small, red, scaly bumps to appear on the body.
1477
Pustular psoriasis
Skin redness and numerous pustules occur in pustular psoriasis.
1478
Inverse psoriasis
Inverse psoriasis of the axilla (armpit) is characterized by erythema without visible scaling.
Courtesy of James C Shaw, MD.
1479
Nail psoriasis
People with psoriasis sometimes develop pits on their nails, like the ones shown here.
1480
Nail psoriasis
The nails of people with psoriasis sometimes develop tan-brown color changes, like those
shown here.
1481
Pustular psoriasis: Pathogenesis, clinical manifestations, and

diagnosis
Author: Robert E Kalb, MD
INTRODUCTION
Psoriasis is a common skin disorder characterized by the development of erythematous, scaling plaques
on the skin and a wide spectrum of clinical presentations. The most common presentation of psoriasis is
chronic plaque psoriasis, which manifests as well-defined inflammatory, red, scaling plaques on the skin.
Pustular psoriasis is a less common subtype of psoriasis that presents as an acute, subacute, or chronic
pustular eruption. Pustular psoriasis primarily affects adults, but can also occur in children.
Pustular psoriasis develops independently or in association with preexisting psoriasis and may occur in a
generalized or localized distribution. Generalized pustular psoriasis (GPP) presents as an acute or
subacute, widely distributed eruption of pustules arising on inflamed, erythematous skin (picture 1A-C).
Localized forms of pustular psoriasis primarily affect the palms, soles, or extremity digits.
Some cases of generalized or localized pustular psoriasis may actually represent a new genetic
autoinflammatory disease based on mutations in the interleukin (IL)-36 receptor antagonist. Other
specific genetic abnormalities have also been identified in patients with pustular psoriasis. (See
'Genetics' below.)
The epidemiology, pathogenesis, and clinical manifestations of pustular psoriasis will be reviewed here.
Other forms of psoriasis and the management of pustular psoriasis are reviewed separately. (See
"Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Guttate psoriasis" and "Pustular
psoriasis: Management".)
CLASSIFICATION
1482
The clinical presentations of pustular psoriasis traditionally have been classified into generalized and
localized forms.
The major clinical variants of generalized pustular psoriasis (GPP) include acute GPP (also known as
generalized pustular psoriasis of von Zumbusch) and generalized annular pustular psoriasis (also known
as subacute GPP) [1]. Acute GPP is characterized by the abrupt onset of numerous pustules, widespread
erythema, and systemic symptoms. The terms "pustular psoriasis of pregnancy" and "impetigo
herpetiformis" are used to refer to acute GPP that occurs during pregnancy. Generalized annular pustular
psoriasis is a less acute presentation of GPP in which patients develop widespread annular or figurate
erythematous plaques studded by pustules. (See "Dermatoses of pregnancy", section on 'Pustular
psoriasis of pregnancy'.)
Descriptions of localized forms of pustular psoriasis include acrodermatitis continua of Hallopeau, a

chronic pustular condition that primarily involves the digits, and palmoplantar pustulosis, a chronic
condition in which the pustular eruption is primarily limited to the palms and soles. It is controversial
whether palmoplantar pustulosis is a variant of psoriasis or an independent entity [2,3]. Alternative terms
used to refer to palmoplantar pustulosis include palmoplantar pustular psoriasis, pustulosis
palmoplantaris, and pustulosis palmaris et plantaris. (See 'Localized pustular psoriasis' below and
"Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis".)
Some authors have used the term "localized GPP" to describe an additional clinical presentation of
psoriasis with pustules in patients with chronic plaque psoriasis [4]. This term describes the development
of pustules within existing psoriatic plaques in the absence of systemic symptoms, as can often occur
during a period of increased disease activity. We categorize these patients as having psoriasis with
pustulosis, rather than a subtype of GPP [1].
GENERALIZED PUSTULAR PSORIASIS
Epidemiology — Although psoriasis is a relatively common condition for which worldwide estimates of
prevalence have ranged between 0.91 to 8.5 percent [5], chronic plaque psoriasis accounts for the vast
majority of psoriasis cases. The exact prevalence of generalized pustular psoriasis (GPP) is unknown, but
the condition appears to be rare.
GPP develops in individuals from all racial backgrounds. There does not appear to be a strong sex
predilection for non-pregnancy-associated GPP [6], although a female preponderance has been reported
in Korea [7]. GPP occurs most frequently in middle-aged adults, and in published reports the average age
of affected patients typically ranges between 40 and 60 years [1,8-10]. GPP may also occur in infants and
children [11-13]. Annular pustular psoriasis is the most common presentation of pustular psoriasis in
children [14,15]. A male preponderance has been reported in pediatric pustular psoriasis [12].
1483
Many patients with GPP have a preceding history of another form of psoriasis, though estimates of the
proportion of patients with preceding psoriasis vary [1,6,9,16]. In a Malaysian retrospective study, 78
percent of 95 patients with acute GPP had a preceding history of psoriasis [1], most of whom had a
history of chronic plaque-type disease. In contrast, a Japanese review of hospital records from patients
treated for GPP in community center hospitals found a history of plaque psoriasis in only 31 percent of
208 patients with acute GPP [16]. Multiple years often elapse after the development of psoriasis prior to
the onset of GPP [1,6,9,16]. Patients without a history of psoriasis are more likely to harbor an IL36RN
mutation [17]. (See 'Genetics' below.)
Pathogenesis — Although the pathogenesis of GPP is not fully understood, studies evaluating the role of
genetics in GPP have yielded new insights into the pathogenesis of this condition. Potential triggers are
also recognized, including roles for drugs, infections, and pregnancy in the induction of GPP.
Genetics — GPP is traditionally classified as a variant of psoriasis; however, evidence suggests that
genetic factors distinct from those associated with chronic plaque psoriasis contribute to GPP. In
particular, mutations in the IL36RN gene that encodes the interleukin-36 receptor antagonist (IL-36Ra), an
antiinflammatory cytokine in the IL-1 family that inhibits proinflammatory signal pathways by preventing
the binding of IL-36 to its receptor, have been detected in some patients with GPP.
A homozygous mutation in IL36RN was first associated with GPP based upon the findings of a linkage
analysis study in nine Tunisian families with autosomal recessive GPP [18]. The authors of this study
proposed the term "deficiency of interleukin-36-receptor antagonist" (DITRA) to refer to the disease
resulting from IL-36Ra deficiency [18].
Since the initial study, additional mutations in IL36RN have been identified in patients with GPP and
childhood pustular eruptions with clinical and histologic features of GPP; moreover, IL36RN mutations
have been detected in patients with sporadic GPP [19-23]. However, not all patients with GPP appear to
harbor IL36RN mutations [21,24,25]. In a study in which IL36RN mutations were sought in 84 unrelated
patients with sporadic GPP, homozygous or compound heterozygous IL36RN mutations were observed in
only seven patients (8 percent) [21]. Homozygous or compound heterozygous IL36RN mutations were
detected in 7 of 19 patients with GPP (39 percent) in another report [24].
There are data that suggest that the link between IL36RN mutations and GPP is stronger in patients with
GPP that develops independently of other forms of psoriasis than in patients with preexisting psoriatic
disease [26]. As an example, a Japanese study of patients with GPP found IL36RN mutations in only 2 of
20 patients with a history of psoriasis compared with 9 of 11 patients without a preceding history of this
disease [17].
Growing understanding of the molecular basis of GPP associated with IL36RN mutations may aid in
therapeutic decisions for patients with this type of GPP. Case reports documenting successful treatment
of GPP in patients with IL36RN mutations with anakinra, an IL-1 receptor antagonist, support the
1484
importance of this pathway [27,28]. In addition, preliminary findings of clinical trials suggest that
treatment with IL-1 antagonists (picture 2) [29] and anti-IL-36R antibodies [30] can improve GPP.
IL36RN mutations are not exclusive to GPP. Mutations in the gene have been detected in patients with
palmoplantar pustulosis, acrodermatitis continua of Hallopeau, or acute generalized exanthematous
pustulosis [21,25,31-34]. It has been suggested that pustular eruptions occurring in the setting of IL36RN
mutations, whether diagnosed as GPP or acute generalized exanthematous pustulosis (AGEP), should be
considered a distinct genetic disease [23,35]. This is also supported by the fact that GPP and AGEP share
common immunohistochemical pathway features [36].
Knowledge of other genetic contributions to GPP is increasing. Mutations in caspase recruitment domain
family member 14 (CARD14) have been associated with pustular psoriasis in children and adults who lack
IL36RN mutations [37,38]. A gain-of-function impact may lead to enhanced IL36G gene transcription via
nuclear factor KB activity [39,40]. Pustular psoriasis has also been associated with mutations in the
adapter protein family 1 (AP1S3). This may lead to disruption of toll-like receptor function and increased
expression of IL36A [41,42].
Ideally, identification of specific genetic mutations will lead to targeted immune therapy [43,44]. (See
"Pustular psoriasis: Management", section on 'IL36RN mutations'.)
Precipitating factors — Case reports and case series suggest that the withdrawal or administration of
certain medications can stimulate the development of GPP. As examples, the onset of GPP has occurred
subsequent to withdrawal of systemic glucocorticoids, cyclosporine, ustekinumab, and potent topical
corticosteroid therapy [1,9,45-47]. The association with systemic glucocorticoids is commonly reported;
in a retrospective study of 102 patients with adult-onset GPP (including 95 with acute GPP), systemic
glucocorticoids were considered a precipitating factor for 44 percent of patients [1].
The development or worsening of GPP during treatment with biologic tumor necrosis factor-alpha
inhibitors and ustekinumab also has been reported [48-53], although these agents have also been
reported to be effective for patients with pustular psoriasis [54-56]. These paradoxical flares may be
related to a cytokine imbalance and unopposed interferon-alpha activation [57,58].
Other medications that have been cited as potential inducers of GPP include amoxicillin [31], terbinafine
[59], codeine [60], ceftriaxone [61], oxacillin [62], rituximab [58], pegylated interferon-alpha-2b [63], and the
bacillus Calmette-Guérin vaccine [64]. Differentiating GPP from drug-induced AGEP can be difficult. (See
Infections may be precipitating factors for GPP [1,6,16,65,66]. In the retrospective study of 102 patients
with adult-onset GPP, 16 (16 percent) had documentation of a preceding upper respiratory tract infection
[1]. Moreover, of the 39 patients with acute GPP tested for anti-streptolysin antibodies, 15 (38 percent)
had positive tests. Other infections that have been associated with the precipitation of GPP include
cytomegalovirus [67,68], varicella zoster virus [69], and Epstein-Barr virus [70].
1485
A common thread for patients who harbor an IL36RN mutation is that many precipitating factors may lead
to uncontrolled IL-36 signaling and enhanced production of other interleukins giving rise to the
phenotypic expression of pustular skin lesions [33,71].
The reason for the rare occurrence of pustular psoriasis in pregnancy (impetigo herpetiformis) is unclear
[72], though hormonal changes related to pregnancy have been proposed as potential contributing
factors [73]. Most affected women do not have a preceding history of psoriasis. Pustular psoriasis in
pregnancy is reviewed separately. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of
pregnancy'.)
Clinical manifestations — The two major clinical presentations of GPP are acute GPP (generalized
pustular psoriasis of von Zumbusch) and generalized annular pustular psoriasis. The clinical
manifestations of pustular psoriasis in pregnancy, which may be considered a subtype of acute GPP, are
reviewed separately [1,72]. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)
● Acute (von Zumbusch-type) GPP – Acute GPP is characterized by the abrupt development of
widespread, painful erythematous patches or thin plaques that rapidly become studded with
numerous pinhead-sized sterile pustules (picture 1A-C). Frequently, the coalescence of pustules
results in larger purulent collections often referred to as "lakes of pus." The pustules resolve within
several days, leaving erythema and extensive scaling. Erythroderma may occur [65].
Recurrent episodes of pustulation during which new crops of pustules emerge is a classic feature of
acute GPP. Episodes are accompanied by fever, chills, and malaise, and patients appear systemically
ill. Other extracutaneous symptoms that may occur in acute GPP include arthralgias, lower extremity
edema, jaundice, and ocular abnormalities (eg, conjunctivitis, iritis, or uveitis) [1,9,74].
Mucosal involvement, manifesting as oral pustules or geographic tongue, can accompany the
cutaneous findings of GPP [1,6,74]. Intraoral involvement may suggest a higher chance of an IL36RN
mutation [35]. Patients may also exhibit cheilitis and nail involvement [1,65,74].
● Generalized annular pustular psoriasis – Generalized annular pustular psoriasis presents as a

recurring, subacute eruption characterized by the development of annular or figurate erythematous
plaques with peripheral pustules and scale [15]. The plaques expand centrifugally over the course of
hours to days [4]. Skin pain or fever also may be present [1].
Similar to acute GPP, pustules from generalized annular GPP resolve with residual scale.
Occasionally, pustules may be evident only on histologic examination [15].
Clinical course — The clinical course of GPP is usually unstable and prolonged without treatment, with
periods of disease quiescence and recurrence over the course of years. Flares may occur upon
reexposure to a precipitating factor or for unknown reasons [1]. Patients usually require continued
therapy to avoid resurgence of flares. (See "Pustular psoriasis: Management".)
1486
Complications of acute GPP may be life-threatening. Potential complications include sepsis; serious
renal, hepatic (neutrophilic cholangitis) or respiratory (neutrophilic pneumonitis, acute respiratory
distress syndrome) abnormalities; and death [1,9,75-77].
Histopathology — Classic pathology findings of GPP include [8,78]:
● Psoriasiform changes in the epidermis (parakeratosis and elongation of the rete ridges)
● Numerous neutrophils migrating from the papillary capillaries into the epidermis
● Spongiform pustules of Kogoj (aggregates of neutrophils between degenerated and flattened

keratinocytes within the upper malpighian layer of the epidermis, forming a subcorneal
macropustule) (picture 3A-B)
● Perivascular lymphocyte-predominant infiltrate in the upper dermis
The spongiform pustule of Kogoj is a characteristic histologic feature of psoriasis that is most prominent
in the pustular variant (picture 3A-B) [8].
Laboratory abnormalities — Laboratory abnormalities are common in patients with acute GPP. Frequent
laboratory findings include [1,9,75]:
● Leukocytosis (up to 30,000 cells/microliter)

● Elevated erythrocyte sedimentation rate (ESR)
● Hypocalcemia and other electrolyte imbalances
● Lymphopenia
● Elevated liver enzymes
● Hypoalbuminemia
● Elevated anti-streptolysin antibody
An elevated ESR and leukocytosis are among the most common laboratory abnormalities in acute GPP. In
a review of 102 patients with GPP in Malaysia (including 95 with acute GPP), an elevated ESR or
leukocytosis was detected in 100 percent and 70 percent of the patients with acute GPP, respectively [1].
Electrolyte abnormalities may occur as a consequence of the skin barrier disruption that results from the
widespread desquamation that follows pustulation in acute GPP. Laboratory abnormalities such as
leukocytosis and elevated liver enzymes also have also been reported in patients with the generalized
annular pustular psoriasis variant of GPP [1,15].
Diagnosis — A diagnosis of GPP should be suspected in patients who present with widespread pustules
arising on erythematous skin. The diagnosis is made based upon recognition of a constellation of clinical
and histologic features. Serologic studies that demonstrate laboratory findings consistent with GPP offer
further support for the diagnosis. This approach is reflected in the diagnostic criteria proposed by some
authors.
1487
Our typical initial workup for patients with suspected GPP consists of the following:
● Patient history and review of symptoms
● Total body skin examination
● Skin biopsy for hematoxylin and eosin staining
● Basic serologic studies
In cases in which there is suspicion for cutaneous or systemic infection, we add cultures of skin or blood
to the clinical investigation.
History and physical examination — The patient history is helpful for identifying GPP. Because many
patients with GPP have a preceding history of psoriasis, confirmation of previous psoriasis provides
support for the diagnosis. Moreover, a history of associated symptoms of fever and malaise, and a
clinical course characterized by rapid disease onset and relapsing episodes support a diagnosis of acute
GPP. (See 'Epidemiology' above and 'Clinical manifestations' above.)
In addition to inquiries about the medical history, the course of disease, and associated symptoms, a
thorough drug history is an essential part of the work-up for patients with suspected GPP. The withdrawal
or initiation of certain drugs has been linked to GPP. Systemic glucocorticoid therapy is a commonly cited
predisposing factor for GPP [1]. Of note, drugs may also induce acute generalized exanthematous
pustulosis, a widespread pustular eruption that clinically resembles acute GPP. (See 'Precipitating factors'
above and 'Differential diagnosis' below.)
A full examination of the skin and oral mucosa should be performed to evaluate the extent of
involvement. Recognition of concomitant lesions consistent with other forms of psoriasis can support
the diagnosis, although the absence of this does not rule out GPP. Occasionally, examination of the oral
mucosa reveals geographic tongue or pustules. (See 'Clinical manifestations' above.)
Skin biopsy — We usually perform a skin biopsy in patients with suspected GPP to aid in
distinguishing GPP from other widespread pustular eruptions, such as acute generalized exanthematous
pustulosis (AGEP), secondarily infected spongiotic dermatitis, and Sneddon-Wilkinson disease. (See
A 4 mm punch biopsy that ideally includes an entire intact pustule (eg, a 4 mm punch biopsy of a 2 mm
pustule) usually provides a sufficient specimen for histopathologic examination. We usually take two to
three punch biopsies from different sites (preferably above the waist) in an attempt to increase the
likelihood of detecting features that are helpful for diagnosis.
A diagnosis of GPP is strongly supported by the detection of psoriasiform changes, epidermal

neutrophils, and spongiform pustules of Kogoj. AGEP can be particularly difficult to distinguish from GPP,
particularly in patients with IL36RN mutations. Eosinophils and necrotic keratinocytes are among the
1488
histologic findings that suggest a diagnosis of AGEP rather than GPP [8,31,35,71,79]. (See "Skin biopsy
techniques", section on 'Punch biopsy' and 'Histopathology' above and "Acute generalized exanthematous
pustulosis (AGEP)", section on 'Diagnosis'.)
Laboratory tests — No serologic tests provide a definitive diagnosis of GPP. Laboratory studies are
obtained to evaluate for abnormalities consistent with the diagnosis (eg, leukocytosis and lymphopenia)
as well as to evaluate for complications of the disease. (See 'Laboratory abnormalities' above.)
Our initial laboratory work-up for patients with suspected GPP includes:
● Complete blood count with differential (to evaluate for leukocytosis and lymphopenia)
● Comprehensive metabolic panel (to evaluate for hypocalcemia, other electrolyte abnormalities, and
hypoalbuminemia and to evaluate liver and renal function)
Pustules caused by pustular psoriasis are sterile in the absence of secondary infection. If there is
uncertainty regarding the diagnosis or concern for secondary infection we usually culture the contents of
a pustule. Blood cultures should be obtained if there is suspicion of systemic infection.
Genetic testing for IL36RN mutations can be performed in patients with GPP; however, it is not commonly
performed and commercial availability is limited. At this time, routine testing of all patients with GPP for
IL36RN mutations is not indicated.
Testing for IL36RN mutations may become more relevant as data on new therapeutic options for patients
with GPP associated with IL36RN mutations (eg, IL-1 antagonists [27-30]) evolve. Testing may prove to be
of greatest value in patients who exhibit features suggestive of an IL36RN mutation. Patients without a
history of psoriasis or who have intraoral involvement may be more likely to harbor the mutation
[17,35,80]. In addition, children with the mutation are more likely to have certain clinical features,
including flexural or perianal erosions or confluent lakes of pus [81]. (See "Pustular psoriasis:
Management", section on 'IL36RN mutations'.)
Differential diagnosis — Multiple disorders may present with clinical features that resemble pustular
psoriasis. Examples of other disorders that present with widespread pustules and erythematous plaques
are reviewed below. In most cases, the clinical history, physical examination, and biopsy results are
useful for differentiating these diseases.
● Acute generalized exanthematous pustulosis – Differentiating acute generalized exanthematous

pustulosis (AGEP) from acute GPP can be difficult because the clinical manifestations of the two
conditions are similar (picture 4) [8,59,82,83]. Patients have been described having AGEP and GPP on
separate occasions depending on the stimulating factor. It may not be possible to distinguish
between AGEP and GPP in patients who harbor an IL36RN mutation, as various stimuli may produce
similar clinical pictures in these patients. It has been suggested that the disease taxonomy of these
1489
pustular eruptions should be based on their genetic profiling rather than the current classification
[31,35,36,71,79].
Clinical signs that favor AGEP include an abrupt onset, short duration (usually less than two weeks
after discontinuation of the offending drug), polymorphous lesions, an association with recently
started drugs, rapid improvement after drug withdrawal, absence of arthritis, and no personal or
family history of psoriasis. Skin biopsy findings that favor AGEP include the presence of eosinophils
and necrotic keratinocytes as well as a mixed neutrophil-rich infiltrate in the dermis and the absence
of tortuous blood vessels [8]. Additionally, significant psoriasiform changes of the epidermis are
common in chronic lesions of GPP but absent in AGEP. Patch testing may also aid in differentiating
these entities. (See "Acute generalized exanthematous pustulosis (AGEP)".)
● Dermatitis with secondary infection – Patients with widespread dermatitis such as atopic dermatitis
may present with extensive pustules indicating a secondary infection (picture 5). A skin biopsy
revealing spongiotic dermatitis and bacterial cultures of pustules can differentiate these conditions
from GPP. Knowledge of the patient's history of skin disease prior to the onset of pustules is also
helpful. (See "Treatment of atopic dermatitis (eczema)", section on 'Management of infection'.)
● Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is a rare chronic pustular

dermatosis that presents with annular erythematous plaques with superficial sterile, pea-sized,
flaccid pustules (picture 6A-B). The disease often occurs in middle-aged women. Skin involvement of
subcorneal pustular dermatosis is most likely to affect the trunk, intertriginous areas, and flexor
aspects of the extremities [84]. Subcorneal pustular dermatosis may occur in association with
various conditions, including pyoderma gangrenosum, monoclonal IgA gammopathy, and multiple
myeloma [84]. Histologic examination reveals subcorneal pustules, but unlike GPP, subcorneal
pustular dermatosis does not exhibit spongiform pustules (picture 7). (See "Neutrophilic
dermatoses", section on 'Subcorneal pustular dermatosis'.)
● IgA pemphigus – IgA pemphigus is a rare autoimmune blistering disorder that most commonly
occurs in middle-aged or elderly adults. Two forms of IgA pemphigus have been described: the
subcorneal pustular dermatosis-type IgA pemphigus and the intraepidermal neutrophilic type of IgA
pemphigus. Both types present as an annular or circinate eruption of pustules, erythematous
plaques, and crusts that primarily involves the trunk and proximal extremities. Subcorneal or
intraepidermal pustules are seen on histopathologic examination. The disorder is distinguished from
other diseases by the detection of intercellular IgA deposits in the epidermis on direct
immunofluorescence. Rarely, other forms of pemphigus may present with pustules [85-87]. (See
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'IgA pemphigus'.)
● Tinea corporis – Similar to annular pustular psoriasis, extensive tinea corporis may present with
annular, erythematous plaques with peripheral scale and pustules (picture 8). Systemic symptoms
are absent. A potassium hydroxide preparation or skin biopsy revealing fungal hyphae confirms this
1490
diagnosis [88,89]. (See "Dermatophyte (tinea) infections", section on 'Tinea corporis' and "Office-
based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)
LOCALIZED PUSTULAR PSORIASIS
Localized pustular psoriasis primarily involves the hands and feet. The two major clinical presentations
are acrodermatitis continua of Hallopeau, which begins on the distal digits and palmoplantar pustulosis,
which primarily involves the palms and soles.
Acrodermatitis continua of Hallopeau — Acrodermatitis continua of Hallopeau (ACH, also known as

acropustulosis, pustular acrodermatitis, acrodermatitis perstans, and dermatitis repens) is a rare form of
localized pustular psoriasis [90-92]. ACH presents as a chronic, relapsing, inflammatory eruption with
sterile pustules that primarily involves the distal fingers or toes, nail folds, and nail beds. ACH most
frequently occurs in middle-aged women [90].
The etiology and pathogenesis of ACH are not well understood. The onset of the disorder may be
preceded by trauma or infection of a digit [90]. Mutations in the IL36RN gene, similar to those identified in
generalized pustular psoriasis (GPP), have been detected in patients with ACH, suggesting that some
cases of ACH may be a clinical phenotype of deficiency of the IL-36-receptor antagonist (DITRA) [32,34].
The significance of the finding for the general population of patients with ACH remains to be determined.
(See 'Genetics' above.)
The initial clinical manifestations of ACH usually are restricted to the distal areas of one or two digits.
Involvement of the fingers is more common than involvement of the toes [90]. As in GPP, individual
pustules may coalesce to form larger purulent collections. Pustules eventually rupture, leaving shiny
erythema and hyperkeratosis.
Over time, ACH may progress to involve other digits and may extend proximally to the hand, forearm, or
foot (picture 9). Chronic involvement of the nail bed and matrix can lead to onychodystrophy and
anonychia [93]. Atrophy of the distal phalanx and underlying osteolysis also can develop. Infrequently,
progression to generalized pustular psoriasis occurs [94].
The diagnosis of ACH is made via recognition of consistent clinical and histologic findings. A Gram stain
and culture should be performed to rule out pustules secondary to bacterial infection [90]. A potassium
hydroxide preparation should also be performed as part of the diagnostic work-up to rule out cutaneous
candidiasis and dermatophytosis. Additional acral disorders to consider in the differential diagnosis are
herpetic whitlow and dyshidrotic eczema. (See "Office-based dermatologic diagnostic procedures",
section on 'Potassium hydroxide preparation'.)
The histologic findings of involved skin in ACH resemble pustular psoriasis. Spongiform pustules are
present in the upper epidermis and the dermis demonstrates a lymphohistiocytic infiltrate and focal
1491
edema. Thinning of the epidermis and severe atrophy of the papillary dermis may be evident in areas of
longstanding disease [90].
The treatment of ACH is reviewed separately. (See "Pustular psoriasis: Management", section on
'Localized pustular psoriasis'.)
Palmoplantar pustulosis — There is controversy over whether palmoplantar pustulosis is a variant of

psoriasis or an independent disorder that occurs with increased frequency in patients with psoriasis. The
condition presents with clusters of white to yellow-brown sterile pustules, erythema, and scale on the
palms and soles and appears strongly associated with smoking (picture 10A-B). The associated
symptoms of itching, burning, and pain can be severe and disabling. (See "Palmoplantar pustulosis:
● Pustular psoriasis can be divided into generalized and localized clinical presentations. Generalized
pustular psoriasis (GPP) consists of acute GPP (also known as generalized pustular psoriasis of von
Zumbusch) and generalized annular pustular psoriasis. Acrodermatitis continua of Hallopeau is a
localized form of pustular psoriasis. There is controversy over whether palmoplantar pustulosis is a
subtype of psoriasis or a distinct entity. (See 'Classification' above.)
● GPP most commonly occurs in adults, but may also occur in children. The recognition of mutations
in the gene encoding the IL-36-receptor antagonist (IL36RN) in some patients with GPP has yielded
new insights into the pathogenesis of this condition. (See 'Epidemiology' above and 'Pathogenesis'
above.)
● Certain exposures may contribute to the development of GPP. Medications (particularly systemic
glucocorticoids), infections, and pregnancy have been linked to the onset of GPP. (See 'Precipitating
factors' above.)
● Acute GPP is characterized by the acute development of widespread erythematous plaques and
pustules along with systemic symptoms of fever and malaise. Generalized annular pustular
psoriasis is less acute and is characterized by the development of annular or figurate erythematous
plaques with pustules. (See 'Clinical manifestations' above.)
1492
● The diagnosis of GPP is based upon the recognition of consistent clinical, pathologic, and laboratory
features. A thorough patient history and skin biopsy should be performed. Common laboratory
abnormalities include leukocytosis, an elevated erythrocyte sedimentation rate, lymphopenia,
electrolyte abnormalities (particularly hypocalcemia), hypoalbuminemia, elevated liver enzymes, and
an elevated antistreptolysin antibody level. (See 'Diagnosis' above.)
● GPP can closely resemble acute generalized exanthematous pustulosis (AGEP), a drug-induced
condition. In patients with IL36RN mutations, it may not be possible to differentiate AGEP and GPP.
● Acrodermatitis continua of Hallopeau is a rare localized and chronic form of pustular psoriasis that
primarily involves the extremity digits. Pustules, erythema, scale, and nail dystrophy are
characteristic clinical features. Involvement may lead to nail loss and osteolysis in involved digits.
(See 'Acrodermatitis continua of Hallopeau' above.)
1493
GRAPHICS
1494
Pustular psoriasis
1495
1496
Response of generalized pustular psoriasis to treatment with an IL-1 antagonist
Dramatic response of severe generalized acute pustular psoriasis to treatment with an IL-1 antagonist.
IL: interleukin.
Originally published in: Mansouri B, Richards L, Menter A. Treatment of two patients with generalized pustular psoriasis with the interleukin-1β inhibitor
gevokizumab. Br J Dermatol 2015; 173:239. Reproduced with permission. Image courtesy of XOMA (US), LLC. Copyright © 2014.
1497
Spongiform pustule of Kogoj in generalized pustular psoriasis
The biopsy reveals a central pustule comprised of neutrophils. (Hematoxylin and Eosin original magnification 100x)
1498
Spongiform pustule of Kogoj in generalized pustular psoriasis
Examination under high power reveals neutrophils extending into the epidermis with spongiform pustule formation.
Eosinophils are absent, helping to exclude a diagnosis of acute generalized exanthematous pustulosis. (Hematoxylin
and Eosin original magnification 200x)
1499
Acute generalized exanthematous pustulosis (AGEP)
Confluent nonfollicular pustules superimposed on edematous erythema in a 46-year-old

woman with AGEP. A skin biopsy showed intracorneal pustules with numerous neutrophils
and neutrophilic infiltration of the epidermis and upper dermis.
Copyright © Vincent CB Lin, MD, Dermatlas; http://www.dermatlas.org.
1500
Staphylococcus aureus infection in atopic dermatitis
Pustules and honey-colored crusting are seen on the dorsal hand of this patient with
infected atopic dermatitis.
Courtesy of Joseph Morelli, MD.
1501
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)
Multiple flaccid pustules and crusted plaques are present.
1502
Multiple flaccid pustules and areas of crusting are present on the skin. The largest lesion
has a somewhat annular configuration.
1503
Subcorneal neutrophilic pustule.
1504
Tinea corporis
Annular, erythematous plaque with pustules.
1505
Pustules, erythema, scale, and nail dystrophy involving the distal fingers.
1506
1507
Erythema, scale, pustules, and brown macules on the palms.
1508
Pustular psoriasis: Management

Author: Robert E Kalb, MD
INTRODUCTION
Pustular psoriasis is an uncommon subtype of psoriasis that may present as a generalized pustular skin
eruption (generalized pustular psoriasis [GPP]) or a localized pustular skin eruption (acrodermatitis
continua of Hallopeau and palmoplantar pustulosis) (picture 1A-C). The goals of treatment of GPP are to
improve skin manifestations, to alleviate associated systemic symptoms, and to minimize risk for life-
threatening systemic complications. Treatment of localized pustular psoriasis is indicated to minimize
the development of bothersome or disabling symptoms.
The treatment of GPP and localized pustular psoriasis will be reviewed here. The clinical features of
pustular psoriasis, the management of pustular psoriasis in pregnant women (impetigo herpetiformis),
and the management of other forms of psoriasis are reviewed separately. (See "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis" and "Dermatoses of pregnancy" and "Treatment of
psoriasis in adults" and "Psoriasis in children: Management of chronic plaque psoriasis" and "Guttate
psoriasis".)
GENERALIZED PUSTULAR PSORIASIS
Disease overview — Generalized pustular psoriasis (GPP) is characterized by the development of a

widespread eruption of pustules and erythematous plaques (picture 1A-C). A preceding history of
psoriasis may or may not be present. The acute variant (also known as generalized pustular psoriasis of
von Zumbusch) is characterized by the sudden onset of a pustular eruption accompanied by fever and
malaise. Laboratory abnormalities, such as leukocytosis, an elevated erythrocyte sedimentation rate,
hypocalcemia and other electrolyte abnormalities, hypoalbuminemia, and elevated liver enzymes, are
common. In addition, serious complications, including sepsis and hepatic, respiratory, or renal
1509
dysfunction, can occur [1-4]. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis", section on 'Generalized pustular psoriasis'.)
GPP may also present as a less acute disorder in which patients develop widespread, annular or figurate,
erythematous plaques with peripheral pustules and scale (generalized annular pustular psoriasis) [4,5].
Pain and fever may accompany these cutaneous manifestations. Generalized annular pustular psoriasis
is a common presentation of pustular psoriasis in children. (See "Pustular psoriasis: Pathogenesis,
clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'Epidemiology'.)
There is no cure for GPP, and recurrences are common [4]. Thus, long-term treatment is often required to
minimize recurrences of disease.
Approach to therapy — Determining the optimal approach to treatment is complicated by the lack of high-
quality data on the efficacy of treatments for GPP. Data on treatment primarily consist of retrospective
studies, case reports, and expert opinion. Interpretation of the available data is further compromised by
the lack of a validated grading system for the severity of GPP and the absence of a standardized method
of assessing the response to treatment. The approach described in this topic reflects our preferred
approach based upon review of the literature and clinical experience; other approaches also may be
reasonable.
The treatment approach reviewed below focuses on nonpregnant adults with GPP. The treatment of GPP
in pregnant women and children is reviewed separately. (See "Dermatoses of pregnancy", section on
'Pustular psoriasis of pregnancy' and 'Children' below.)
Increasing knowledge about the pathogenesis of GPP associated with IL36RN mutations may lead to new
therapeutic options for this form of GPP. (See 'IL36RN mutations' below and "Pustular psoriasis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetics'.)
Important interventions — Our approach to treatment consists of the following key steps:
● Determine need for hospitalization and supportive care – Patients with acute GPP usually appear
systemically ill, and admission to the hospital often is necessary to ensure adequate supportive care.
The decision to hospitalize a patient is made based upon global consideration of the severity of
illness, vital sign stability, fluid and electrolyte status, and concern for systemic infection.
Supportive skin care measures may help to soothe skin symptoms in patients with GPP. Use of
moisturizers, wet wraps, and/or oatmeal baths can be beneficial in patients with this disease [1].
● Identify and discontinue the causative drug (in drug-induced cases) – The withdrawal or
administration of a variety of drugs has been linked to the development of GPP. In general, the
causative agent should be discontinued, provided this can be done safely.
1510
Systemic glucocorticoids are commonly cited contributors [4]. However, there is insufficient
evidence to confirm the best way to discontinue systemic glucocorticoids in patients with
glucocorticoid-induced GPP. Options include maintaining the glucocorticoid dose until disease
control is achieved with other therapies and continuing to taper the systemic glucocorticoid during
the initiation of GPP therapy. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis", section on 'Precipitating factors'.)
Patients in whom GPP was precipitated by an antipsoriatic drug may be best managed with an agent
with a different mechanism of action. For example, the tumor necrosis factor (TNF)-alpha inhibitor
infliximab would be a less favorable choice for a patient with adalimumab-induced GPP.
● Initiate treatment to control skin disease – Medical treatment options for GPP consist of systemic
therapies, topical therapies, and phototherapy. We typically use systemic treatment for the initial
management of adults because phototherapy tends to have a delayed onset of action and topical
therapies are impractical for widespread disease. In addition to limiting factors, such as drug
availability and patient-specific contraindications, the selection of an initial systemic therapy is
based upon the acuity and severity of disease. Topical therapies primarily serve as adjuncts to
systemic therapy in adults with GPP. (See 'First-line pharmacologic therapy for adults' below and
'Adjunctive therapy' below.)
● Manage extracutaneous complications – Extracutaneous complications, such as sepsis or internal

organ dysfunction, should be managed appropriately. (See "Pustular psoriasis: Pathogenesis, clinical
manifestations, and diagnosis", section on 'Clinical course'.)
First-line pharmacologic therapy for adults — Our preferred first-line treatments for nonpregnant adults
include established therapies (acitretin, methotrexate, cyclosporine, infliximab) and newer treatment
options (secukinumab, ixekizumab, brodalumab, and guselkumab). The approach to treatment selection
differs for patients with tolerable, nondisabling disease and patients with severe, acute disease. (See
'Tolerable, nondisabling disease' below and 'Severe, acute disease' below.)
Tolerable, nondisabling disease — Acitretin and methotrexate are the preferred initial treatments for
adults with relatively stable GPP. Advantages of these drugs include that they are relatively well tolerated,
available in oral form, and can be used for long-term maintenance treatment. A disadvantage is their
relatively slow onset of action; thus, an alternative approach is indicated for patients with more severe
disease. (See 'Severe, acute disease' below.)
Data are insufficient to compare the efficacy of acitretin and methotrexate. Selection between these
drugs is based upon patient-specific factors, such as ability to tolerate side effects and contraindications.
As an example, the requirement that women abstain from pregnancy for three years after acitretin
treatment gives acitretin a relative contraindication for use in women of childbearing age.
1511
Oral retinoids — Oral retinoids that have been used for GPP include etretinate, acitretin (a
metabolite of etretinate), and isotretinoin. Acitretin is our preferred oral retinoid because clinical
experience with isotretinoin for this indication is more limited, and etretinate was withdrawn from United
States market in 1998.
● Administration and precautions – Our usual starting dose for acitretin is 0.75 to 1 mg/kg per day.
Japanese guidelines have suggested an initial dose of etretinate of 0.5 to 1 mg/kg per day [6].
Improvement (ie, cessation of new pustule formation and initial improvement in other clinical signs)
is usually noted within 7 to 10 days of oral retinoid therapy, and a complete response often requires
two to three months of treatment. After disease control is achieved, the dose of acitretin can be
tapered slowly to the lowest dose necessary to maintain improvement.
Examples of adverse effects of oral retinoids include xerosis, cheilitis, dry mucous membranes,
hypertriglyceridemia, hair loss, liver function test abnormalities, bone changes, and visual changes.
Oral retinoids are teratogenic and pregnancy should be avoided for three years following acitretin
therapy. Therefore, the drug has a relative contraindication for women of childbearing age.
● Efficacy – Evidence to support retinoid use is limited. Some support comes from a Japanese study
that analyzed treatment data from 385 patients with acute GPP obtained through questionnaire
responses from multiple community center hospitals [7]. The study found that among 188 patients
treated with retinoids, treatment was reported as effective in 84 percent. Retinoid treatment regimens
were not standardized; typically, treatment was with etretinate (1 mg/kg per day and tapered as
tolerated). Many patients received retinoids in combination with other therapies. Data from a
retrospective study also suggests benefit of etretinate [8].
In a series of 11 adults with GPP, isotretinoin therapy seemed beneficial for improving pustule
formation in 10 patients, although monotherapy with the drug did not seem to be effective for
clearing all lesions [9]. Isotretinoin also appeared useful in an adolescent female who failed to
respond adequately to topical corticosteroids and methotrexate [10] and in two patients who did not
tolerate acitretin [11].
Methotrexate — Methotrexate may be given subcutaneously or orally and appears to be effective

for GPP.
● Administration and precautions – A typical dose of methotrexate for adults with GPP is 15 mg per
week, with a maximum dose of 25 mg per week. Methotrexate is not given daily. We often use
subcutaneous, rather than oral, methotrexate given that absorption of oral methotrexate may be
reduced at higher doses and bioavailability may be superior with subcutaneous dosing [12-14].
Significant clinical improvement is expected within 8 to 12 weeks.
Myelosuppression is a potential serious adverse effect of methotrexate that warrants careful

administration of treatment and laboratory follow-up. The amount of methotrexate used for the initial
1512
dose varies among experts, with some experts initiating with a small test dose (eg, 5 mg per week)
followed by upward titration of the dose and others initiating at higher doses (eg, 15 mg per week)
[15]. When treating older adult patients or patients with renal insufficiency, the initial dose should not
exceed 10 mg per week.
Additional adverse effects of methotrexate include gastrointestinal distress, hepatotoxicity,

pulmonary toxicity, and teratogenicity. Methotrexate should be combined with folic acid
supplementation (eg, 1 mg of folic acid per day) to decrease hematologic and gastrointestinal
toxicity [16]. (See "Major side effects of low-dose methotrexate".)
Monitoring protocols for methotrexate treatment vary; in general, a complete blood count with
differential and platelets should be performed at baseline and soon after the initiation of
methotrexate and following dose increases. While some clinicians perform hematologic testing
approximately one week after dose initiation or changes, others (including the author) perform tests
after two to four weeks provided the patient is not an older adult individual and does not have renal
insufficiency. Hematologic testing is repeated every two to four weeks during the first few months of
treatment and is subsequently tapered to every one to three months. Periodic laboratory monitoring
of kidney and liver function is also indicated during methotrexate therapy.
● Efficacy – Data on the efficacy of methotrexate are limited. In a multicenter study in Japan in which
community hospitals were sent questionnaires about patients with GPP, efficacy of methotrexate
was documented for 76 percent of 41 patients given this therapy alone or in conjunction with other
therapies [7]. In addition, in a retrospective study of 63 patients hospitalized for GPP at Mayo Clinic
affiliated-hospitals between 1961 and 1989, good responses to methotrexate were reported for three
of eight patients with acute GPP and both of two patients with annular pustular psoriasis [8].
Severe, acute disease — For patients with severe, acute disease that warrants rapid stabilization and
improvement, we select faster acting drugs. The traditional first-line treatments of choice are infliximab
or cyclosporine. Some biologic anti-interleukin (IL)-17 and anti-IL-23 drugs have emerged as alternative
fast-acting therapies; however, experience with these agents is more limited [17-22]. (See 'Alternative first-
line therapies' below.)
Once control of acute disease is achieved, patients may be maintained on fast-acting therapies or
transitioned to acitretin or methotrexate for long-term treatment. Cyclosporine is the exception; risk for
serious side effects with prolonged cyclosporine therapy supports transitioning to other treatments.
Cyclosporine — Oral cyclosporine has a long history of use for psoriasis and can induce rapid
improvement of GPP.
● Administration and precautions – Effective doses of cyclosporine for adults with GPP have ranged
from 2.5 to 5 mg/kg per day [17]. We typically treat severe, acute GPP with 4 to 5 mg/kg (ideal body
weight) per day. Marked improvement often occurs within the first few days of treatment [1,23-25].
1513
Because side effects of cyclosporine are a concern, once disease control is achieved, we attempt to
taper the dose over the course of two to three months and transition to other treatments.
Potential adverse effects of cyclosporine include hypertension, renal toxicity, and increased risk for
infections and malignancy. Laboratory tests as well as blood pressure should be monitored closely
during therapy. Adverse effects of cyclosporine are discussed in greater detail separately. (See
"Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)
● Efficacy – Despite the common use of cyclosporine for severe, acute GPP, data on the efficacy of the
drug are limited. A beneficial effect of cyclosporine is supported by retrospective data obtained from
hospitals in Japan that suggested treatment efficacy in 60 to 70 percent of patients treated with
cyclosporine alone or in conjunction with other therapies [7,26].
Infliximab — Infliximab is a TNF-alpha inhibitor given through intravenous infusion that may lead to
rapid improvement in GPP.
● Administration and precautions – Standard dosing of infliximab for psoriasis is 5 mg/kg at weeks 0,
2, and 6, and every six to eight weeks thereafter. Marked improvement is usually evident within
several days.
Infliximab may be continued for long-term management of GPP after control of acute disease is
achieved. Alternatively, patients can be transitioned to other therapies.
Potential adverse effects of infliximab include infusion reactions and increased risk for infection,
malignancy, heart failure, and demyelinating disease. Patients should be evaluated for latent
tuberculosis and hepatitis B prior to initiating therapy. There are also reports of infliximab inducing
psoriatic eruptions, including GPP [27,28]. The adverse effects of infliximab are reviewed separately.
(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
● Efficacy – The use of infliximab for GPP is based upon case reports and a retrospective study that
suggest efficacy of this treatment [18,29-39]. Among 10 patients in whom flares of acute GPP were
treated with infliximab in a French multicenter retrospective study, clinical remission was achieved
by 8 patients (80 percent). The fast onset of infliximab was evident in the time required to achieve
clearance of pustules; pustules cleared in a median of two days (range, one to eight days) [18].
The possibility that a single dose of infliximab may be sufficient is suggested by a case report
documenting dramatic improvement in acute GPP within 24 hours following a single dose of
infliximab followed by the initiation of methotrexate [29]. Infliximab has also been successfully used
in combination with acitretin for the induction of rapid improvement while awaiting the onset of
action of acitretin [40].
Alternative first-line therapies — Although they lack a long history of use for severe, acute GPP,
antipsoriatic agents targeting the Th17 pathway (an important pathway in the pathogenesis of psoriasis)
1514
have emerged as reasonable alternatives to the traditional approach of cyclosporine or infliximab
therapy. Limited data suggest secukinumab, ixekizumab, brodalumab, and guselkumab can be effective
for GPP; however, optimal treatment regimens are unclear. We use the standard dosing for plaque
psoriasis for GPP. (See "Treatment of psoriasis in adults", section on 'Biologic agents'.)
● Secukinumab – Benefit of secukinumab (an anti-IL-17A monoclonal antibody) for GPP is suggested
in a 52-week, open-label study in which 12 adults with GPP received secukinumab (150 mg once
weekly at baseline; weeks 1, 2, 3, and 4; and then every four weeks, with the option to increase the
dose to 300 mg in patients who showed minimal or no improvement) [20]. Eight patients also
received nonbiologic systemic therapies for psoriasis, but doses of these agents could not be
increased. At week 16 (the primary endpoint), 10 patients (83 percent) received clinical global
impression ratings of "very much improved" or "much improved." One patient showed no
improvement, and a second patient discontinued treatment prior to 16 weeks due to a protocol
deviation. Improvement was rapid, with maximum improvement achieved within three weeks.
Response rates remained high at 52 weeks.
Responses to secukinumab are also documented in case reports, including a patient with acute GPP
who experienced complete resolution of pustulation within one week during treatment with
secukinumab (300 mg given once weekly for three weeks) [41-45].
● Ixekizumab – Ixekizumab (an anti-IL-17A monoclonal antibody) may be beneficial based upon a 52-
week, open-label study in which 78 patients with plaque psoriasis, erythrodermic psoriasis, or GPP
received ixekizumab (160 mg at week 0, then 80 mg every two weeks until week 12, then 80 mg every
four weeks). At week 12, four of the five patients with GPP achieved 75 percent improvement in the
Psoriasis Area and Severity Index (PASI) score, and three patients achieved 90 percent improvement
[46]. This level of response was sustained with continued treatment over 52 weeks [47]. Concomitant
systemic glucocorticoid therapy equivalent to less than or equal to 10 mg per day of prednisone was
permitted.
● Brodalumab – A 52-week, open-label study evaluating the efficacy of the anti-IL-17 receptor A
monoclonal antibody brodalumab (140 mg at day 1, weeks 1 and 2, then every two weeks, with the
option to increase the dose to 210 mg) for GPP and erythrodermic psoriasis found that 11 of 12
patients with GPP achieved a clinical global impression of "improved" or "remission" by week 52 [19].
Improvement was rapid, with 9 of 12 patients achieving this status at week 2. Concomitant treatment
with stable or decreasing doses of systemic methotrexate, vitamin A preparations, or glucocorticoids
was permitted.
● Guselkumab – Guselkumab (a monoclonal antibody directed against the p19 subunit of IL-23)
appeared beneficial in GPP and erythrodermic psoriasis in a 52-week, open-label study [22]. Ten
patients with GPP were treated with 50 mg at weeks 0, 4, and every 8 weeks thereafter. The dose
could be escalated to 100 mg at week 20 based on prespecified criteria, and patients were allowed to
1515
continue topical therapies and methotrexate. Seven of the patients with GPP achieved the primary
study endpoint of treatment success (at least minimal improvement based upon a Clinical Global
Impression rating at week 16), including four who achieved greater than minimal improvement. Two
patients discontinued the study due to lack of response and a diagnosis of cutaneous squamous cell
carcinoma. All eight patients who completed the study had treatment success at 52 weeks.
Second-line therapy for adults — When patients do not respond to or cannot tolerate a first-line therapy,
we typically select one of the other acceptable first-line therapies. (See 'First-line pharmacologic therapy
for adults' above.)
Patients for whom this is not an option may benefit from other approaches to therapy, such as psoralen
plus ultraviolet A (PUVA) photochemotherapy, adalimumab, etanercept, ustekinumab, or combination
therapy.
PUVA photochemotherapy generally is not used as a first-line therapy because of a delayed onset of
action and the frequent clinic visits (eg, often three times per week) necessary for treatment. Limited
evidence for efficacy and reports of drug-induced disease exacerbations contribute to the status of
adalimumab, etanercept, and ustekinumab as second-line, rather than first-line, therapies.
● Psoralen plus ultraviolet A (PUVA) photochemotherapy – PUVA photochemotherapy involves the

administration of photosensitizing psoralen orally or topically prior to exposure to an ultraviolet A
(UVA) light source. Because of a relatively slow onset of action, PUVA photochemotherapy is
typically reserved for patients who have already achieved control of acute disease.
In an uncontrolled prospective study of eight patients with acute GPP, oral PUVA photochemotherapy
(four times weekly) was associated with complete clearing of GPP in all patients within a mean of
13.5±10 treatment sessions [48]. Maintenance therapy (twice weekly PUVA treatments tapered to
discontinuation if tolerated) was given upon complete remission, and seven patients remained in
complete remission during follow-up periods of up to 1.5 years. The frequent clinic visits required for
PUVA photochemotherapy make this a less favorable treatment option for some patients.
● Adalimumab or etanercept – Successful control of GPP during treatment with adalimumab or

etanercept, both TNF-alpha inhibitors, has been reported in small numbers of patients [18,49-54]. In
one retrospective study, two of three GPP flares treated with adalimumab progressed to clinical
remissions, and clearance of pustules occurred within 7 and 28 days [18]. Of note, there are reports
of TNF-alpha inhibitors inducing pustular psoriasis, including GPP [27].
● Ustekinumab – Case reports and case series have documented efficacy of ustekinumab, an anti-IL-
12/23 drug, in acute pustular psoriasis [55-57]. In one report, all four patients responded well to
therapy, including one who harbored an IL36RN mutation. Three of the four patients also received
low-dose acitretin [56]. The onset or worsening of pustular psoriasis following ustekinumab
treatment also has been reported [58-61].
1516
● Combination therapy – Several case reports demonstrate efficacy in recalcitrant GPP when two or
more classes of therapeutic agents are used in combination. Examples include etanercept and
cyclosporine [24], infliximab and methotrexate [36,62], adalimumab and acitretin [63], adalimumab
and methotrexate [64], infliximab and acitretin [40], and cyclosporine and PUVA photochemotherapy
[23]. In addition, children have responded to combination therapy with narrowband ultraviolet B
(UVB) and systemic therapies [65,66] as well as infliximab combined with methotrexate [62].
Adjunctive therapy — Because of the widespread nature of GPP, topical medications are primarily
reserved for adjunctive therapy.
Topical therapy — Topical therapies that have seemed useful for adjunctive therapy in case reports are
similar to those used in chronic plaque psoriasis and include topical corticosteroids [67], combination
therapy with a topical corticosteroid and topical vitamin D analog [68], and topical tacrolimus [69]. Topical
corticosteroids are the topical agents we use most frequently.
The development of GPP in association with use of topical corticosteroids [70-72] and topical vitamin D
analogs [70,73,74] has been reported. We aim to minimize this risk through focusing topical therapy on
small areas of persistent or recalcitrant skin involvement [17,75].
A response of GPP to total body application of topical tacrolimus has been reported [76].
Other therapies — A variety of other therapies have been used for GPP, although concern for side effects
or limited experience precludes a recommendation for the routine use of these therapies.
Although systemic glucocorticoid therapy can lead to rapid improvement in GPP [26], the treatment must
be used with caution because systemic glucocorticoids are implicated as potential inciting factors for
GPP [17]. In addition, there is concern for the serious side effects from long-term glucocorticoid therapy.
Thus, we do not typically use systemic glucocorticoids. In the event that systemic glucocorticoid
treatment is given to obtain initial control of GPP, we suggest also initiating a second therapy in an
attempt to reduce the likelihood of a disease flare during tapering and discontinuation of the systemic
glucocorticoid. However, evidence to support this approach is lacking. The adverse effects of systemic
glucocorticoids are reviewed separately. (See "Major side effects of systemic glucocorticoids".)
Several case reports document the successful use of granulocyte and monocyte apheresis for the
treatment of refractory GPP, including a report of use in a patient harboring the IL36RN mutation [77-84].
Other treatments that have been reported to be effective for GPP in case reports include anakinra
[80,85,86], canakinumab [87], mycophenolate mofetil [88], oral zinc [89], dapsone [90], and apremilast [91].
It remains to be seen whether anakinra is primarily effective for GPP associated with deficiency of the
interleukin-36-receptor antagonist (DITRA). (See 'IL36RN mutations' below.)
In a phase 1 study (n = 7), treatment with an experimental monoclonal antibody against the IL-36 receptor
(BI 655130) appeared effective for GPP both in the presence and absence of an IL36RN mutation [92].
1517
The efficacy of the biologic TNF-alpha inhibitor certolizumab and the IL-23 inhibitor tildrakizumab for
GPP is unclear.
Special populations
Children — Childhood GPP is rare, contributing to a paucity of data on the efficacy and safety of
treatments for GPP in children.
Acute generalized pustular psoriasis — We consider the following agents appropriate initial
treatment choices for children with GPP:
● Tolerable, nondisabling disease
• Acitretin (less than 1 mg/kg per day)

• Methotrexate (0.2 to 0.4 mg/kg per week)
• Etanercept (<63 kg: 0.8 mg/kg once per week; ≥63 kg: 50 mg once per week)
● Severe, acute disease
• Cyclosporine (1 to 3 mg/kg per day)
• Infliximab (5 mg/kg at weeks 0, 2, and 6, then every six to eight weeks if continuation of therapy
is needed)
As in adults, children requiring cyclosporine or infliximab for severe disease may be transitioned to other
therapies after achievement of control of disease [93]. Long-term treatment with cyclosporine is not
recommended due to risk for serious side effects. (See "Pharmacology of cyclosporine and tacrolimus",
section on 'Side effects'.)
No randomized trials have been performed to confirm the efficacy of these agents in the treatment of
acute GPP in children. The selection of an oral retinoid [10,75,94-97], cyclosporine [25,66,98-102],
methotrexate [96,103,104], etanercept [62,105-108], or infliximab [105,108] is primarily based on case
reports or case series that suggest efficacy of these drugs in children with GPP and experience with
these agents for other forms of psoriasis in children. In particular, randomized trials supporting the
efficacy and safety of etanercept for moderate to severe plaque psoriasis in children have contributed to
use of etanercept as a first-line therapy in the pediatric population [109-111]. However, evidence for
efficacy of etanercept in GPP is very limited, and etanercept is not typically used as a first-line therapy in
adults.
Given the contraindication for pregnancy during acitretin treatment and for three years after drug
discontinuation, the use of acitretin in girls must be considered carefully. Successful treatment with
isotretinoin in place of acitretin has been reported in an adolescent female [10]. A slight risk for skeletal
toxicity has been observed in children treated with high doses of oral retinoids for disorders of
keratinization [112].
1518
Additional therapies that may be useful in the treatment of pediatric acute GPP based upon case reports
include narrowband UVB phototherapy in conjunction with systemic therapy [65,66], adalimumab [49],
and the combination of infliximab and methotrexate [62]. Also, an infant with GPP associated with DITRA
has responded to anakinra [113], and an adolescent with DITRA achieved a rapid clinical response and
sustained remission during treatment with secukinumab [43].
Generalized annular pustular psoriasis — Topical corticosteroid therapy may be effective for the
treatment of children with annular pustular psoriasis, which exhibits less severe manifestations than
acute GPP [5]. In addition, topical compresses, wet wraps, or oatmeal baths may be helpful for soothing
the skin lesions [5,114].
Topical therapy for annular pustular psoriasis is less practical when a large proportion of the body
surface is affected. Patients who cannot be managed only with topical therapy can be treated with
systemic agents. Case reports suggest that oral retinoids, oral dapsone, and methotrexate can be
effective for this variant [5].
Pregnant women — The management of pustular psoriasis in pregnancy (impetigo herpetiformis) is

reviewed separately. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)
IL36RN mutations — Growing understanding of the molecular basis of GPP associated with IL36RN
mutations may aid in therapeutic decisions for patients with this type of GPP [115]. Evidence suggests
that some cases of GPP (or acute generalized exanthematous pustulosis [AGEP]) may actually represent
a new genetic autoinflammatory disease based on mutations in the IL36RN gene, which encodes the IL-
36 receptor antagonist. This disease is known as DITRA. (See "Pustular psoriasis: Pathogenesis, clinical
Patients with IL36RN mutations upregulate IL-1 in response to IL-36 stimulation. Case reports
documenting successful treatment of GPP in patients with IL36RN mutations with anakinra, an IL-1
receptor antagonist, support the importance of this pathway [86,113]. In addition, preliminary findings of
clinical trials suggest that treatment with IL-1 antagonists can improve GPP (picture 2) [87,116]. As more
data accumulate, IL-1 blockade may become the treatment of choice for patients who harbor the genetic
mutation.
The beneficial effects of systemic therapy, such as acitretin, TNF-inhibiting drugs, and anti-IL-17/23
antibodies, for GPP appear independent of the presence of the IL36RN mutation [37,56,107,117-119].
Whether agents targeting the IL-36 pathway or IL-1 will be more effective and/or safer for patients with
the mutation remains to be determined.
LOCALIZED PUSTULAR PSORIASIS
1519
The approach to the treatment of pustular psoriasis differs from generalized pustular psoriasis (GPP).
Local treatment generally is used as first-line treatment, with systemic therapies reserved for patients
who fail to respond well to local therapy.
Acrodermatitis continua of Hallopeau — Acrodermatitis continua of Hallopeau (ACH) is a rare, chronic,

localized form of pustular psoriasis that primarily involves one or more extremity digits (picture 3). ACH is
often poorly responsive to therapy. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis", section on 'Acrodermatitis continua of Hallopeau'.)
A variety of local and systemic therapies have been utilized for ACH with variable results. Data on
treatment of this rare disease are primarily limited to case reports. Topical corticosteroids, topical
tacrolimus, topical calcipotriol (alone or in combination with topical corticosteroids or topical tacrolimus),
topical mechlorethamine hydrochloride, topical fluorouracil, psoralens plus ultraviolet A (PUVA)
photochemotherapy, narrowband ultraviolet B (UVB) phototherapy, ultraviolet A1 (UVA1) phototherapy,
and brachytherapy are among the local treatments documented as effective in individual patients with
ACH [120-123]. Systemic therapies have included oral retinoids, methotrexate, cyclosporine, systemic
glucocorticoids, methotrexate and propylthiouracil, infliximab, adalimumab, etanercept, ustekinumab,
tocilizumab, secukinumab, and anakinra [120,124-130]. The efficacies of these interventions have not
been compared, and the best approach to treatment is unclear.
Our initial choice for treatment of ACH is typically a superpotent topical corticosteroid (eg, halobetasol or
clobetasol), which we instruct the patient to apply to the affected areas once to twice daily for two to four
weeks (table 1). Preferably, the patient should apply the medication under an occlusive dressing at night,
particularly during the first week of therapy. Plastic wrap is commonly used as an occlusive dressing.
Alternatively, occlusion can be applied using damp cloth covered by dry cloth.
If a good response to treatment occurs, the frequency of application can be tapered as tolerated to a
frequency as low as once or twice per week. Alternatively, we prescribe a topical vitamin D analog (eg,
topical calcitriol or calcipotriene) in conjunction with the superpotent topical corticosteroid and instruct
the patient to apply the topical corticosteroid followed immediately by the vitamin D analog once to twice
daily for two to four weeks. Once sufficient improvement is achieved, we taper the topical corticosteroid
as tolerated and continue treatment with the vitamin D analog. A commercial product containing both
betamethasone dipropionate and calcipotriene is available.
When patients fail to respond adequately to topical therapy, we proceed to local phototherapy or systemic
therapy, although we usually continue to use topical corticosteroids as adjunctive therapy. PUVA
photochemotherapy, narrowband UVB, and UVA1 therapy have appeared effective for ACH [120,122,123].
We often use acitretin (0.5 to 1 mg/kg per day) as our first-line systemic treatment, with methotrexate and
cyclosporine as alternatives. If a patient fails to improve with these traditional systemic therapies, we
often switch to a biologic tumor necrosis factor (TNF)-alpha inhibitor, an anti-interleukin (IL)-12/23
therapy, or an anti-IL-17 therapy, such as adalimumab, infliximab, ustekinumab, or secukinumab [131-
1520
134]. A case report documents success with a combination of ustekinumab and acitretin in a patient who
failed multiple biologic agents [135].
Palmoplantar pustulosis — Palmoplantar pustulosis is a chronic condition characterized by the

development of yellow to brown pustules, scale, and patchy erythema on the palms or soles. It is
controversial whether palmoplantar pustulosis is a localized variant of pustular psoriasis (palmoplantar
pustular psoriasis) or a separate entity. The treatment of palmoplantar pustulosis is reviewed separately.
(See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis" and "Palmoplantar
pustulosis: Treatment".)
● Generalized pustular psoriasis (GPP) is an uncommon form of psoriasis characterized by the

development of widespread pustules and erythematous plaques on the skin. The goals of treatment
are to improve skin manifestations, alleviate systemic symptoms, and prevent serious or life-
threatening complications of this disease. (See 'Generalized pustular psoriasis' above.)
● Treatment options for adults with GPP include topical therapies, systemic therapies, and
phototherapy. Most patients require systemic therapy. Topical therapies are primarily used as
adjuncts to systemic therapy. (See 'Approach to therapy' above.)
● As part of the initial management of patients with GPP, the need for hospitalization should be
assessed. In addition, the patient's medical history should be reviewed for drugs that may contribute
to the development of GPP. (See 'Approach to therapy' above.)
● The approach to the treatment of GPP is influenced by the acuity and severity of symptoms. For
adult patients with relatively stable disease, we suggest acitretin or methotrexate as initial therapy
(Grade 2C). For adult patients with severe, acute GPP, we suggest initial therapy with fast-acting
therapies, such as cyclosporine, infliximab, or select anti-interleukin (IL)-17/23 therapies (Grade 2C).
(See 'First-line pharmacologic therapy for adults' above.)
● Other therapeutic agents that may be effective in adults with GPP include psoralen plus ultraviolet A
(PUVA) photochemotherapy, adalimumab, etanercept, and ustekinumab. Combination therapy with
more than one treatment can also be attempted. (See 'Second-line therapy for adults' above.)
1521
● Systemic glucocorticoids can induce rapid improvement in GPP but have been identified as potential
inciting factors for this disease. We do not usually use systemic glucocorticoids for the treatment of
GPP. (See 'Other therapies' above.)
● Data on the treatment of acute GPP in children are very limited. Options for first-line therapy include
acitretin, cyclosporine, methotrexate, etanercept, and infliximab. Some children with annular pustular
psoriasis can be managed with topical treatment. (See 'Children' above.)
● Increasing knowledge about the pathogenesis of GPP associated with IL36RN mutations may lead to
new therapeutic options for this form of GPP. (See 'IL36RN mutations' above.)
● Acrodermatitis continua of Hallopeau (ACH) is a rare form of localized pustular psoriasis that
primarily affects the extremity digits and is often refractory to treatment. Data on treatments for ACH
are limited to case reports. We suggest a superpotent topical corticosteroid as initial treatment
(Grade 2C). (See 'Acrodermatitis continua of Hallopeau' above.)
1522
GRAPHICS
1523
Pustular psoriasis
1524
1525
Response of generalized pustular psoriasis to treatment with an IL-1 antagonist
Dramatic response of severe generalized acute pustular psoriasis to treatment with an IL-1 antagonist.
IL: interleukin.
Originally published in: Mansouri B, Richards L, Menter A. Treatment of two patients with generalized pustular psoriasis with the interleukin-1β inhibitor
gevokizumab. Br J Dermatol 2015; 173:239. Reproduced with permission. Image courtesy of XOMA (US), LLC. Copyright © 2014.
1526
Pustules, erythema, scale, and nail dystrophy involving the distal fingers.
1527
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12
Diflucortolone valerate Cream, oily cream, Nerisone (Canada, United 0.1

(not available in United ointment Kingdom, others)
States)
¶ ¶
1528
Triderm


solution

spray

Gel Desonate 0.05

solution

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01


(group 7) ≥2%)
Scalacort
1529

Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available generically in
the United States.
Data from:
1530
Palmoplantar pustulosis: Epidemiology, clinical features, and

diagnosis
Authors: Giovanna Brunasso, MD, Cesare Massone, MD
INTRODUCTION
Palmoplantar pustulosis (PPP) is a chronic inflammatory condition characterized by crops of sterile

pustules on the palms and soles that erupt repeatedly over time (picture 1A-F). Yellow-brown
macules (remnants of resolving pustules), erythema, scale, and fissures are additional frequent
findings. Other terms that have been used to refer to PPP are palmoplantar pustular psoriasis,
pustulosis palmoplantaris, and pustulosis palmaris et plantaris.
Despite the limited area of skin involvement in PPP, the condition can have a significant negative
effect on quality of life. Symptoms of pruritus, burning sensations, or pain are often present. In
severe cases, the discomfort associated with skin involvement can cause difficulty with walking or
other activities of daily living.
The clinical features and diagnosis of PPP will be reviewed here. Other pustular disorders, including
acrodermatitis continua of Hallopeau (an acral variant of pustular psoriasis that primarily involves
the digits) are reviewed separately. (See "Palmoplantar pustulosis: Treatment" and "Approach to the
patient with pustular skin lesions" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and
diagnosis" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on
'Acrodermatitis continua of Hallopeau' and "Neutrophilic dermatoses".)
CLASSIFICATION
1531
The classification of palmoplantar pustulosis (PPP) is controversial. While some authors propose
that PPP is a variant of psoriasis [1,2], others consider the disease a separate condition [3-10].
Authors who consider PPP a subtype of psoriasis have done so based upon the recognition of
similarities between the conditions. As an example, our retrospective study comparing 39 patients
with PPP and 51 patients with palmoplantar plaque psoriasis (a non-pustular form of psoriasis
characterized by erythematous scaly plaques on the palms and soles) did not find statistically
significant differences in age of onset, disease duration, family history of psoriasis, concomitant
arthritis, or smoking habits between the two groups [1]. In addition, erythematous, scaly plaques
similar to those of palmoplantar plaque psoriasis frequently accompanied pustules in PPP.
Other findings that suggest a direct relationship between PPP and psoriasis include the detection of
psoriasis-like plaques on the trunk or extremities of some patients with PPP [11]. Moreover, a family
history of psoriasis has been reported in 10 to 43 percent of patients with PPP [1,7]. A Scottish
retrospective study of 73 patients with PPP found a family history of chronic plaque psoriasis or PPP
in 21 and 3 percent of patients, respectively, a concomitant diagnosis of PPP and chronic plaque
psoriasis in 27 percent, and concurrent psoriatic arthritis in 12 percent. These prevalences are 10 to
15 times higher than in the general population and suggest a close association between the two
diseases [7].
Observations used to negate the designation of PPP as a variant of psoriasis include the strong
association of PPP with smoking (an association much stronger than psoriasis vulgaris), the female
predominance in PPP, the lack of an association between PPP and the psoriasis susceptibility locus
PSORS1 (the major genetic determinant for psoriasis vulgaris) [12], the association of PPP with
metal allergies [8,9,13], and differences in the response of PPP and psoriasis to therapy. Further
study of the pathogenic mechanisms of PPP may help to resolve the controversy over the
relationship between psoriasis and PPP. (See 'Pathogenesis' below.)
EPIDEMIOLOGY
Epidemiologic data on palmoplantar pustulosis (PPP) are limited. In general, PPP appears to be
uncommon in the general population. A 1971 study that used data from outpatient registers from a
Swedish dermatology department found a prevalence of PPP in relation to other skin diseases of
0.37 percent of patients [14]. Patients with signs of psoriasis elsewhere on the body were excluded in
this study. In addition, a review of claims data collected between April 2010 and March 2011 from a
Japanese national database found a prevalence of PPP of 0.12 percent, of which 8.5 percent had a
concomitant diagnosis of psoriasis [6]. In our personal experience in an academic dermatology
practice, PPP seems to present slightly more often.
1532
PPP usually develops in middle-aged adults. The mean age of onset in a retrospective study that
included 39 patients with PPP was 48 years [1]. In the nationwide Japanese study, the highest
prevalences for PPP occurred between the ages of 50 and 69 years [6]. PPP occurs more frequently
in women than in men; observational studies from various parts of the world have found proportions
of female patients ranging from 58 to 94 percent [1,6-10,15].
PATHOGENESIS
The pathogenesis of palmoplantar pustulosis (PPP) is not fully understood. Contributions of

components of both the innate and adaptive immune systems are proposed. Environmental
exposures and genetic susceptibility also may contribute to PPP.
● Mechanism – Studies investigating the mechanisms of PPP have yielded several observations
regarding the development of this disease:
• The acrosyringium appears to be the primary site of vesicle/pustule formation and

inflammation [16], and an abnormality in sweating may contribute to the formation of
vesicles and pustules in PPP [17]. The finding that patients with PPP in Japan increase use
of health care services during the hot season compared with the cold season may also
support a role for sweating as a contributor to PPP [6].
• The inflammatory process that destroys the acrosyringium involves lymphocytes,

neutrophils, eosinophils, and mast cells [18].
• Increased numbers of Langerhans cells have been detected around sweat ducts in PPP
skin, suggesting the possibility of an antigen-driven process [18].
• Specific chemotactic factors may contribute to the development or propagation of the

inflammatory process in PPP:
- Increased expression of interleukin (IL)-8 (a known neutrophil chemoattractant) and IL-

17 related cytokines (eg, IL-17A, IL-17C, IL-17 D, IL-17 F, IL-22, IL-23A, IL-23 receptor)
has been detected in PPP tissue [19,20]; in particular, expression of IL-17 has been
detected within the acrosyringium [18].
- Increased serum levels of tumor necrosis factor-alpha (TNF-alpha), IL-17, IL-22, and
interferon-gamma (IFN-gamma) have been detected in patients with PPP [20].
Additional studies are necessary to elucidate how these factors interact in the development of
PPP.
1533
● Environmental factors – Clinical observations suggest that smoking, stress, infection, and drugs
may contribute to the development or exacerbation of PPP.
• Smoking – There is a strong association between smoking and PPP, suggesting that
smoking has a role in the pathogenesis of this disease. The reported prevalences of current
or previous smoking among patients with PPP range from 42 to 100 percent [1,7,15]. The
mechanism through which smoking could contribute to PPP has not been established.
Proposed mechanisms have included effects of nicotine on sweat gland function or
keratinocyte function (eg, nicotine-induced increase in keratinocyte cornification) [21]. In
addition, differences in nicotine acetylcholine receptor staining patterns in PPP skin
observed in a study of biopsy specimens taken from patients with PPP, healthy smokers,
and healthy non-smokers prompted consideration that an abnormal response to nicotine
could contribute to inflammation [17].
• Stress – The observation that patients with PPP frequently report worsening of symptoms
with stress led to a study investigating skin nerve fibers in involved skin [22]. The study
found increased numbers of contacts between nerves and mast cells and intense
substance P-like immunoreactivity in neutrophils in pustules and the papillary dermis,
suggesting a role for neuro-mediation in the inflammatory process of PPP. In addition, a
study of 21 patients with PPP and 21 age- and sex-matched controls found a higher rate of
moderate to high anxiety among the patients with PPP than in the control population (61
versus 19 percent) [23].
• Infection – Focal infections (eg, acute or chronic tonsillitis, dental infection, chronic
sinusitis) may be associated with PPP. Reports from Japan document episodes of PPP that
follow infection, worsen in the setting of infection, or improve following treatment of
infection [24-26]. Also, differences in immune responses in tonsillar tissue have been
detected in Japanese patients with PPP [27-33].
• Drugs – There are multiple reports of the development of PPP following treatment with
biologic TNF-alpha inhibitors [34-37]. The mechanism behind this occurrence is not
definitively known. Paradoxically, biologic TNF-alpha inhibitors have also been used for the
treatment of PPP. (See "Palmoplantar pustulosis: Treatment", section on 'Severe recalcitrant
disease'.)
• Metal allergy – A role for metal allergy in the development of PPP has been suggested by
some authors based upon observations in small numbers of patients [7-9,13,38,39]. One
report describes an exacerbation of PPP following a strongly positive nickel patch test [9].
However, sufficient data to confirm an association are lacking.
1534
● Genetics – Although PPP does not appear to be associated with the PSORS1 locus that is
strongly associated with psoriasis vulgaris [10,12], other genetic factors common to both
diseases may influence an individual’s risk for the development of PPP. The findings of a study
of 43 patients with PPP and 149 healthy controls suggest that variations of IL19, IL20, and IL24
genes may influence risk for both PPP and psoriasis vulgaris [40]. In addition, missense variants
in the CARD14 gene may be involved in the pathogenesis of PPP as well as psoriasis vulgaris
and generalized pustular psoriasis [10].
The genetic findings of patients affected by PPP with and without concomitant plaque psoriasis
have been compared. A study that used gene expression microarray to compare skin biopsies
from PPP with concomitant plaque psoriasis with skin biopsies from PPP without concomitant
plaque psoriasis found that these entities could not be distinguished based upon gene
expression, suggesting a relationship between these conditions [41]. The same authors found
an increase in IL-17 gene expression without an increase in IL-23 in PPP with and without
concomitant plaque psoriasis, a feature that may contribute to poor responses of PPP to
ustekinumab, an inhibitor of IL-12 and IL-23 [42]. (See "Palmoplantar pustulosis: Treatment",
section on 'Severe recalcitrant disease'.)
The clinical manifestations of palmoplantar pustulosis (PPP) consist of the classic findings on the
palms or soles and associated cutaneous and extracutaneous clinical features.
Cutaneous manifestations — PPP is characterized by the development of recurrent crops of discrete

1 to 10 mm sterile pustules limited to the palms and/or soles (picture 1A-F) [1-3,14,43,44]. The
pustules often coalesce and resolve after several days, leaving brown macules and hyperkeratosis.
Well-demarcated erythema, hyperkeratosis, and desquamation often surround the sites of
pustulation.
Patients with PPP may have involvement of only the palms or only the soles of the feet; however,
involvement of both the palms and soles is most common [1,21]. On the hands, the thenar and
hypothenar eminences and central palm are common sites for pustule development [14,45]. The
instep, the medial and lateral borders of the foot across from the instep, and the sides or back of the
heel are common sites of PPP on the feet. Diffuse involvement of the palms or soles can also occur
(picture 1C, 1G-H). The distribution is usually bilateral, but may also be unilateral, particularly at the
onset of disease [14].
The impact of PPP on quality of life can be significant and should not be underestimated [46].
Patients frequently experience symptoms of itching and burning in the areas of involvement, and
1535
fissures may form, resulting in pain and bleeding. Severe eruptions can inhibit the patient’s ability to
walk or perform other activities that require use of the hands or feet.
Associated clinical findings — Patients with PPP may develop additional clinical findings, including
non-pustular cutaneous eruptions, nail dystrophy, and arthritis.
● Extra-palmoplantar skin involvement – The development of non-pustular psoriasis-like skin

eruptions in other areas, such as the forearms, elbows, dorsal feet, lower legs, knees, or
buttocks, has been described in patients with PPP [11]. These extra-palmoplantar skin lesions
tend to be less pronounced and less well demarcated than classic plaque psoriasis (picture 2).
Other potential findings include scale and erythema on the scalp, and infrequently, solitary
pustules in areas other than the hands and feet [11]. Extra-palmoplantar skin changes may be
more likely to occur in patients with severe PPP than in patients with milder disease [11].
The proportion of patients with extra-palmoplantar skin involvement is difficult to assess

because some studies have intentionally excluded patients with extra-palmoplantar psoriatic
lesions and reported estimates for extra-palmoplantar psoriasis in patients with PPP vary widely,
ranging from 4 to 73 percent [1].
● Nail abnormalities – Nail abnormalities are common in patients with PPP [47,48]. Subungual
pustules, onycholysis, pitting, destruction of the nail, or discoloration of the nail plate may be
seen (picture 3) [47]. In a series of 50 adults with PPP, nail abnormalities were present in 15
patients (30 percent) and subungual pustulation was the most common nail abnormality seen
[47].
● Arthritis – A subset of patients with PPP have concomitant arthritis, arthralgias, or unspecified
forms of arthritis. In our retrospective study of 39 patients with PPP, 10 patients also had
arthritis (26 percent), in accordance to other literature reports [1]. None of these patients had
SAPHO syndrome. (See 'SAPHO syndrome' below.)
Several systemic abnormalities have been linked to palmoplantar pustulosis (PPP).
SAPHO syndrome — PPP is one of the cutaneous manifestations that may occur in patients with
SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, a rare arthropathy
characterized by various presentations of arthropathy and a variety of neutrophilic skin disorders
[49]. The arthropathy of SAPHO syndrome commonly involves the anterior chest wall and may
present with pain, tenderness, and swelling of the sternum and its articulations. (See "Major causes
1536
of musculoskeletal chest pain in adults", section on 'Sternocostoclavicular hyperostosis (SAPHO
syndrome)'.)
Osteoarticular features often precede skin findings, but may appear concomitantly or subsequent to
skin involvement [49]. Other pustular skin disorders that may occur in the setting of SAPHO
syndrome are psoriasis, acne conglobata, acne fulminans, dissecting cellulitis of the scalp, and
hidradenitis suppurativa.
Systemic diseases — The relationship between PPP and systemic diseases is controversial. Limited
data suggest that several systemic abnormalities may occur at increased frequency in patients with
PPP, such as thyroid disease [7,50,51], disturbed calcium homeostasis [52], diabetes [7,52], and
dyslipidemia [1,7]. Further studies are necessary to confirm a relationship between PPP and these
conditions. Increased prevalence of gluten sensitivity was suggested by a Swedish study of 123
patients with PPP [53]; however, a German study did not find an association between PPP and gluten
sensitivity, suggesting geographical or ethnic variability [54].
DISEASE COURSE
Palmoplantar pustulosis often persists for several years or decades, with frequent periods of disease
exacerbation and partial remissions [55]. The disease may significantly impair quality of life
secondary to discomfort and resultant functional disability.
DIAGNOSIS
The diagnosis of palmoplantar pustulosis usually can be made based upon recognition of the clinical
findings of a pustular eruption limited to the palms and/or soles with associated erythema and
hyperkeratosis and a clinical evaluation to rule out other conditions. Performance of a potassium
hydroxide (KOH) preparation (or fungal culture) is particularly important to rule out cutaneous fungal
infection as the cause of symptoms in patients with plantar involvement.
A skin biopsy is not usually necessary, but can be useful for supporting the diagnosis in patients with
atypical presentations or refractory disease. A KOH preparation should be performed prior to a skin
biopsy to prevent an unnecessary biopsy.
History and physical examination — Expected physical findings of PPP are multiple pustules on the
palms and/or soles, often with surrounding erythema and hyperkeratosis. Brown macules at sites of
resolving pustules, fissures, and nail changes also may be present. If vesicles rather than pustules
1537
are the primary finding, the possibility of acute palmoplantar eczema (dyshidrotic eczema) should be
considered. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
In addition to a physical examination of the palms and soles, a full examination of the skin and nails
is indicated. The full skin examination allows the clinician to rule out generalized pustular psoriasis
with palmoplantar involvement, to identify the presence of extra-palmoplantar skin lesions, and to
detect additional skin manifestations that might suggest SAPHO syndrome (eg, acne, dissecting
cellulitis, hidradenitis suppurativa). (See "Pustular psoriasis: Pathogenesis, clinical manifestations,
and diagnosis", section on 'Generalized pustular psoriasis' and "Major causes of musculoskeletal
chest pain in adults", section on 'Sternocostoclavicular hyperostosis (SAPHO syndrome)'.)
The clinical evaluation should also include a review of systems that includes questions about bone
or joint pain to identify symptoms suggestive of concomitant arthritis or SAPHO syndrome. Because
of the potential association of PPP with thyroid abnormalities and gluten sensitivity, we also question
patients about symptoms of thyroid disease or gluten sensitivity (eg, diarrhea, steatorrhea,
flatulence), as well as a personal or family history of these diseases. (See "Diagnosis of and
screening for hypothyroidism in nonpregnant adults", section on 'Clinical features' and "Diagnosis of
hyperthyroidism", section on 'Clinical manifestations' and "Pathogenesis, epidemiology, and clinical
manifestations of celiac disease in adults", section on 'Gastrointestinal manifestations'.)
Potassium hydroxide preparation — We usually perform a KOH preparation in patients who present
with clinical findings suggestive of PPP to rule out the possibility of a dermatophyte infection as the
cause of the eruption. Alternatively, a fungal culture can be performed. (See "Office-based
Bacterial culture — The pustules of PPP are sterile. Bacterial cultures are primarily reserved for
atypical presentations to rule out infection.
Skin biopsy — Skin biopsies often are not necessary for diagnosis. However, in cases in which the
diagnosis is uncertain, biopsies can be helpful for supporting the diagnosis. A 4 mm punch biopsy
that includes at least a portion of a pustule and surrounding erythema is our preferred procedure. In
challenging cases (eg, prior treatment or atypical clinical features), multiple biopsies may be
necessary to identify the histopathologic features of PPP. (See "Skin biopsy techniques", section on
'Punch biopsy'.)
Histopathology — Histologic findings that are consistent with a diagnosis of PPP include
[21,56,57]:
● Epidermal changes (parakeratosis, loss of granular layer, psoriasiform epidermal hyperplasia)
● Spongiosis or epidermal vesicle formation (in early lesions)
1538
● Pustules filled with neutrophils and eosinophils in the upper epidermis
● Accumulation of mast cells and eosinophils below pustules in the upper dermis
● Mixed perivascular and diffuse infiltrate in the dermis (lymphocytes, neutrophils, eosinophils,
mast cells)
Laboratory studies — Laboratory tests are expected to be normal. If there is clinical suspicion for
disorders that may occur at increased frequency in patients with PPP, including thyroid disease,
gluten sensitivity, or diabetes, laboratory evaluation for these disorders should be initiated. (See
'Systemic diseases' above.)
Several other skin disorders that may present with pustules, erythema, and/or scale on the palms or
soles are included in the differential diagnosis of palmoplantar pustulosis (PPP).
● Palmoplantar plaque psoriasis – Palmoplantar plaque psoriasis is plaque psoriasis that

primarily involves the palmoplantar area. Patients present with erythematous, scaly plaques on
the palms and/or soles (picture 4). Fissures are common. The absence of pustules
distinguishes palmoplantar plaque psoriasis from PPP.
● Acute palmoplantar eczema – Acute palmoplantar eczema (dyshidrotic eczema, pompholyx) is

a relapsing vesiculobullous palmoplantar disorder that most commonly presents as an acute,
intensely pruritic eruption of small vesicles to large bullae on the lateral aspects of the fingers,
palms, and/or soles (picture 5A-C). Although pustules are not a primary feature of acute
palmoplantar eczema, pustules can develop as a result of secondary infection. The absence of
hyperkeratotic and well-defined erythematous lesions that tend to crack in acute palmoplantar
eczema facilitates the clinical distinction between PPP and acute palmoplantar eczema. The
histologic findings of PPP can be difficult to distinguish from acute palmoplantar eczema with
pustules because the disorders share multiple histopathologic features [56]. (See "Acute
palmoplantar eczema (dyshidrotic eczema)".)
● Acrodermatitis continua of Hallopeau – Acrodermatitis continua of Hallopeau is a rare, chronic

variant of pustular psoriasis characterized by the presence of sterile pustules involving the nails
and surrounding skin of the fingers or toes (picture 6A-B). Associated paronychia,
onychodystrophy, atrophic skin changes, and osteolysis of the distal phalanges can occur. The
term acropustulosis repens has been used to describe a milder presentation [58]. The primary
involvement of the digits distinguishes this disorder from PPP. (See "Pustular psoriasis:
1539
Pathogenesis, clinical manifestations, and diagnosis", section on 'Acrodermatitis continua of
Hallopeau'.)
● Vesicular/bullous tinea pedis or manuum – Vesicular tinea pedis (foot) or manuum (hand) result
from dermatophyte infection of the palmar, plantar, or interdigital areas. Affected patients
present with vesicles or vesicopustules with associated scale and erythema (picture 7A-B). A
potassium hydroxide (KOH) preparation or fungal culture is useful for diagnosing this condition.
(See "Dermatophyte (tinea) infections", section on 'Tinea pedis'.)
In rare cases, pemphigus vulgaris can present as a vesicular or vesiculopustular eruption on the
palms or soles that may be confused with dyshidrotic eczema or PPP. A patient in whom pemphigus
vulgaris manifesting as vesiculopustules on the palms and soles preceded other manifestations of
pemphigus has been documented in a case report [59]. A biopsy revealing intraepidermal and
suprabasilar acantholytic dyskeratosis and direct immunofluorescence demonstrating
intraepidermal deposits of IgG confirm the diagnosis of pemphigus vulgaris. (See "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus".)
● Palmoplantar pustulosis (PPP) is a pustular skin disorder that usually occurs in adults. Women
are more frequently affected than men. Many patients with PPP smoke or have a previous
history of smoking. (See 'Epidemiology' above.)
● The pathogenesis of PPP is not well understood. Environmental factors (eg, smoking, stress,
infection, and certain drugs) may contribute the disease. (See 'Pathogenesis' above.)
● PPP usually presents as recurrent crops of pustules on the palms and/or soles (picture 1A-F).
Brown macules representing resolving pustules, erythema, and scale are also often present.
Associated symptoms of pruritus, burning sensations, or pain are common. (See 'Clinical
● Extra-palmoplantar findings present in some patients with PPP include psoriasis-like skin
lesions (picture 2), subungual pustulation and other nail abnormalities (picture 3), and arthritis.
PPP may develop in association with SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)
syndrome. Additional studies are necessary to clarify the relationship between PPP and thyroid
disease, gluten sensitivity, and type 2 diabetes. (See 'Associated disorders' above.)
● PPP exhibits a chronic clinical course characterized by exacerbations and partial remissions
over the course of several years or decades. The disease can have a significant negative effect
on quality of life because of the associated symptoms. (See 'Disease course' above.)
1540
● The diagnosis of PPP can often be made through clinical evaluation. A potassium hydroxide
(KOH) preparation is useful for ruling out a superficial dermatophyte infection as the cause of
the symptoms. Biopsy findings can offer support for the diagnosis when then the clinical
evaluation is inconclusive. (See 'Diagnosis' above.)
● PPP should be distinguished from other disorders that may present with pustules, erythema, or
scale on the hands or feet. Examples include palmoplantar plaque psoriasis, acute palmoplantar
eczema (dyshidrotic eczema or pompholyx), acrodermatitis continua of Hallopeau, and vesicular
tinea. (See 'Differential diagnosis' above.)
1541
GRAPHICS

1542
1543
Deep-seated pustules with surrounding erythema and scale involving the entire palmar surface of this
patient with palmoplantar pustulosis. Older lesions typically appear dusky red-brown in color with
crusting.
1544
Pustules, brown macules (remnants of pustules), erythema, and hyperkeratosis on the soles of the feet.
1545
Numerous pustules, brown macules (remnants of pustules), erythema, and hyperkeratosis on the
soles of the feet.
1546
Focal area of pustules, brown macules (remnants of pustules), erythema, and

hyperkeratosis on the sole of the foot.
1547
1548
Erythema, scale, pustules, and brown macules on the palms.
1549
Palmoplantar pustulosis with extra-palmoplantar involvement
Palmoplantar pustulosis involving the hand (A). Psoriasis-like plaque on the upper extremity (B, C).
1550
Nail abnormalities in palmoplantar pustulosis
Nail involvement in palmoplantar pustulosis. Severe nail pitting associated with distal onycholysis
and yellow discoloration resulting in complete nail dystrophy.
1551
Palmoplantar plaque psoriasis
Erythematous, scaly plaques on the palms in a patient with psoriasis.
1552
Dyshidrotic eczema
Vesicles and bullae on the palms and fingers.
1553
Dyshidrotic eczema of moderate severity
In palmar acute dyshidrotic eczema, the vesicles are tense, deep-seated, and multilocular, resulting in
a "tapioca pudding" appearance.
1554
Severe dyshidrotic eczema
Coalescing vesicles involve the entire palmar surface in this patient with severe dyshidrotic eczema.
1555
Pustules involving the nail bed.
1556
Erythema, pustules, and nail dystrophy are present on the distal finger.
1557
Bullous tinea pedis
Vesicles and bullae on the plantar skin of a patient with tinea pedis.
1558
Acute tinea pedis
The medial aspect of the left great toe demonstrates erythematous, papulovesicular lesions
caused by Trichophyton mentagrophytes.
1559
Giovanna Brunasso, MD Speaker's Bureau: Celgene [Plaque psoriasis (Apremilast)]; Almirall [Plaque psoriasis
(Dimetilfumarato)]; Novartis [Plaque psoriasis (Secukinumab)]; AbbVie [Plaque psoriasis (Risankizumab)].
Consultant/Advisory Boards: Janssen Pharmaceutica [Plaque psoriasis (Guselkumab)]. Cesare Massone,
MD Nothing to disclose Kristina Callis Duffin, MD Grant/Research/Clinical Trial Support: Amgen; AbbVie;
Celgene; Eli Lilly and Company; Novartis; Bristol-Myers Squibb; Pfizer; Janssen Pharmaceutica; Stiefel
Laboratories; UCB; Boehringer-Ingelheim [Psoriasis (Etanercept, brodalumab, adalimumab, apremilast,
ixekizumab, baricitinib, secukinumab, abatacept, tofacitinib, ustekinumab, guselkumab, golimumab, infliximab,
risankizumab, mirikizumab, bimekizumab, BI 655130, and calcipotriene)]. Consultant/Advisory Boards: Amgen;
AbbVie; Celgene; Eli Lilly and Company; Novartis; Bristol-Myers Squibb; Pfizer; Janssen Pharmaceutica; UCB;
Boehringer-Ingelheim; Ortho Dermatologics [Psoriasis (Etanercept, brodalumab, adalimumab, apremilast,
ixekizumab, baricitinib, secukinumab, abatacept, tofacitinib, ustekinumab, guselkumab, golimumab, infliximab,
risankizumab, mirikizumab, bimekizumab, BI 655130, and calcipotriene)]. Abena O Ofori, MD Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
1560
Palmoplantar pustulosis: Treatment

Authors: Giovanna Brunasso, MD, Cesare Massone, MD
INTRODUCTION
Palmoplantar pustulosis (PPP) is an uncommon chronic skin disorder characterized by recurrent

eruptions of pustules on the palms and soles (picture 1A-F). Scale, erythema, pruritus, burning
sensations, and pain are common associated features.
Although PPP involves a limited area, the disorder can have a significant negative effect on quality of
life and can interfere with performance of activities of daily living. Patients with PPP on the soles of
the feet may experience difficulty walking, and hand involvement may interfere with other activities.
PPP tends to have a prolonged course consisting of periods of exacerbation and partial remission.
The treatment of the disease is often challenging, as responses to individual treatments are variable
and unpredictable.
The management of PPP will be reviewed here. The clinical manifestations and diagnosis of PPP are
reviewed separately. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis".)
OVERVIEW
High-quality data on the treatment of palmoplantar pustulosis (PPP) are limited, contributing to
uncertainty about the ideal approach to treatment. Although multiple randomized trials have been
performed, most are small and of poor methodological quality [1]. Moreover, the lack of a
standardized method for assessing the response to treatment, as well as the wide variability in
treatment regimens, complicate comparisons of study findings.
1561
Because of the variable and unpredictable response to treatment, our therapeutic approach consists
of first treating with generally well-tolerated therapies that have been reported to be effective for
improving PPP in conjunction with benign general measures to minimize symptoms. Our preferred
first-line therapies are topical corticosteroids, oral retinoids, and photochemotherapy. Patients who
do not respond to these interventions are candidates for other treatments. (See 'First-line therapy'
below and 'Second-line therapy' below.)
GENERAL MEASURES
Regardless of the severity of the disease, we encourage all patients to engage in the following
behavioral changes in an attempt to minimize symptoms and disease exacerbations:
● Skin moisturization – Moisturization of the skin can help to mediate the discomfort associated
with palmoplantar pustulosis (PPP) by helping to minimize formation of cracks and fissures in
skin. We encourage patients to apply a bland, unscented, emollient moisturizer on affected areas
and surrounding skin several times daily as needed.
● Avoidance of irritants – Clinical experience suggests that skin irritation may contribute to
exacerbations of PPP. In particular, we encourage patients to avoid wet work with the hands (eg,
washing items with detergents or soaps) or to use gloves when engaging in such activity.
● Smoking cessation – Although data are insufficient for definitive conclusions on the effect of
smoking cessation on the course of PPP [1], we encourage all of our patients with PPP to stop
smoking based upon knowledge of the strong link between smoking and PPP [2]. The findings of
an uncontrolled prospective study of 63 adult smokers with PPP suggest there may be a benefit
of smoking cessation; statistically significant improvements in the number of pustules and
patient scores for disease severity were noted after three to six months among patients who
stopped smoking, but not among the remainder of the patients [3]. A high dropout rate was
among the limitations of this study. Additional studies are needed to explore the effect of
smoking cessation. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and
diagnosis", section on 'Pathogenesis'.)
FIRST-LINE THERAPY
First-line therapeutic options for palmoplantar pustulosis (PPP) include topical corticosteroids, an
oral retinoid, and photochemotherapy.
1562
Topical corticosteroids are often our initial choice for limited PPP (focal involvement on the palms or
soles) based upon the ease of administration and well-tolerated nature of these agents. However,
when patients present with extensive disease (diffuse palmar or plantar involvement) we usually
begin oral retinoid treatment or photochemotherapy immediately in conjunction with topical
corticosteroid therapy.
Topical corticosteroids — Topical corticosteroid therapy is an accepted first-line therapy for PPP and
is the most widely used treatment [4,5]. The major advantage of topical corticosteroid therapy is that
it is a skin-directed treatment with a low risk for serious adverse effects that can be administered by
the patient. Clinical follow-up to ensure proper use of topical corticosteroids is still required.
● Efficacy – There are few data on the efficacy of topical corticosteroids for PPP. An open-label
right-left trial in which 19 patients with bilateral PPP were randomly assigned to apply
triamcinolone 0.1% cream (a medium potency topical corticosteroid) under a hydrocolloid
dressing to sites of PPP on one side of the body every three days and to apply clobetasol
propionate 0.05% cream (a super high potency topical corticosteroid) twice daily without
occlusion to the contralateral side found that both treatments induced improvement in PPP after
four weeks [6]. However, significantly greater clinical improvement developed in sites treated
with triamcinolone under occlusion than in sites treated with clobetasol without occlusion.
Additionally, complete clearance occurred more frequently in the triamcinolone under occlusion
areas (63 versus 16 percent of treated areas). Responses to both treatments were transient;
symptoms recurred within a few weeks after treatment cessation.
Benefit of topical corticosteroid therapy is also suggested by a retrospective study [4]. Among
49 patients with PPP who were treated with high potency topical corticosteroids (twice daily for
up to four weeks followed by less frequent use of lower potency topical corticosteroids), marked,
moderate, partial, and no improvement were documented in 27, 29, 20, and 24 percent of
patients, respectively.
● Administration – Our preferred regimen for topical corticosteroid therapy is a super high
potency topical corticosteroid applied under occlusion (table 1). We typically instruct patients to
apply the topical corticosteroid under a hydrocolloid dressing. The topical corticosteroid and a
hydrocolloid dressing are reapplied every three days until clearance of active PPP or for a
maximum of four weeks. A response to treatment is usually evident within the first two weeks
[6].
If there are no signs of clinical improvement after four weeks or worsening of symptoms occurs,
we usually begin oral retinoid treatment or photochemotherapy. If the patient has partial
improvement that seems likely to continue to improve with a longer course of topical
1563
corticosteroid therapy, we continue topical corticosteroid monotherapy for up to an additional
four weeks, but decrease the intensity of treatment as tolerated (eg, treatment in place two days
per week). If the response remains insufficient, we transition to other treatments. (See 'Oral
retinoids' below and 'Photochemotherapy' below.)
Alternative methods to perform occlusion (eg, plastic wrap) are an option, but may require more
frequent dressing changes. When plastic wrap occlusion is used, we instruct patients to apply
the plastic wrap over the topical corticosteroid every night for one week, then every other night
for two weeks followed by twice-weekly applications under plastic wrap for up to 13 additional
weeks. Topical corticosteroids are not applied on the intervening occlusion-free days. We often
see partial improvement within the first 10 to 20 days.
Once patients achieve resolution of active disease with topical corticosteroid therapy, we
institute maintenance therapy. Our goal is to reduce the intensity of treatment to application of
the high potency topical corticosteroid without occlusion two days per week.
Cutaneous atrophy is a potential adverse effect of topical corticosteroid therapy, particularly

when high potency topical corticosteroids are used. The potential adverse effects of topical
corticosteroid treatment are reviewed in greater detail separately. (See "Topical corticosteroids:
Use and adverse effects", section on 'Adverse effects'.)
Oral retinoids — Systemic treatment with oral retinoids (eg, acitretin, etretinate) can be effective for
PPP.
● Efficacy – A 2006 systematic review identified several randomized trials that evaluated oral
retinoid therapy for PPP [1]. Pooling of data from four randomized trials that compared
etretinate with placebo demonstrated that 72 percent of 67 patients treated with etretinate
compared with 28 percent of 60 patients given placebo showed some improvement in PPP (rate
ratio 2.54, 95% CI 1.65-3.91). Moreover, 39 versus 17 percent, respectively, achieved good or
excellent responses (rate ratio 2.31, 95% CI 1.20-4.46). The doses used for etretinate therapy in
these trials varied; the duration of treatment ranged from 8 to 16 weeks.
Although etretinate is no longer available in many locations, including the United States,
acitretin, a metabolite of etretinate, appears to be similarly effective for PPP. A randomized trial
that compared etretinate with acitretin in 60 adults with PPP found that both treatments were
similarly effective for improving clinical manifestations of PPP [7]. Patients in both groups were
given 30 mg of the assigned medicine for four weeks followed by upward or downward dose
adjustments according to clinical improvement and tolerance of therapy.
1564
Although alitretinoin, a newer oral retinoid, appeared beneficial for PPP in an uncontrolled study
[8], a phase 2 randomized trial, in which 33 adults with PPP (with or without psoriasis) were
randomly assigned in a 2:1 ratio to alitretinoin (30 mg once daily) or placebo for up to 24 weeks,
did not find alitretinoin more effective than placebo [9]. Additional study is necessary to confirm
the effects of alitretinoin in PPP.
● Administration – Our preferred treatment regimen for PPP in adults is an initial three-month
course of acitretin (50 mg per day). We usually begin with a 25 mg dose of acitretin and increase
the dose by 10 mg per week as tolerated. Reductions in dose to reduce side effects are
sometimes necessary.
Once satisfactory improvement is achieved, we aim to taper the drug to the lowest dose required
to maintain improvement. In two randomized trials, maintenance treatment with etretinate
demonstrated greater efficacy for maintaining remissions than placebo [10,11].
Side effects of oral retinoids can be limiting factors for therapy. Potential adverse effects include
xerosis, cheilitis, dry mucous membranes, hypertriglyceridemia, hair loss, liver function test
abnormalities, bone changes, and visual changes. Oral retinoids are teratogenic and pregnancy
should be avoided for three years following acitretin therapy. Therefore, acitretin has a relative
contraindication for use in women of childbearing age.
Photochemotherapy — Psoralen plus ultraviolet A (PUVA) photochemotherapy, which involves the

oral or topical administration of a psoralen (methoxsalen) prior to exposure of affected areas to
ultraviolet A light, can be effective for PPP. We typically administer oral PUVA rather than topical
PUVA because there is greater support for the efficacy of oral PUVA therapy. Also, in our experience,
topical PUVA can be irritating to the skin and is poorly tolerated by some patients. (See "Psoralen
● Efficacy – The use of oral PUVA for PPP is supported by randomized trials that compared oral
PUVA with placebo [12,13]. In a trial of 22 patients with bilateral PPP, a total of 30 treatment
sessions of PUVA given four times per week on one randomly selected side of the body resulted
in complete clearance of treated areas in 12 patients and great improvement in an additional five
patients, whereas none of the untreated sides achieved these levels of improvement [12]. The
difference in effect between treated and untreated areas was statistically significant. In most
cases, improvement was not seen until 10 to 20 treatments were administered and the mean
number of treatments required for clearance of lesions was 26 (range 18 to 30).
The second trial compared oral PUVA (three times per week), etretinate (0.6 mg/kg per day),
combination therapy with oral PUVA and etretinate, and placebo and no PUVA over a course of
12 weeks [13]. In this open trial, thirty patients with severe bilateral PPP were randomly assigned
1565
to etretinate or placebo therapy, and after two weeks began oral PUVA photochemotherapy on
affected areas of one side of the body. The proportion of the 12 areas that received 12 weeks of
PUVA monotherapy that cleared or exhibited much improvement was significantly greater than
among the 12 affected areas assigned to placebo and no PUVA (75 versus 17 percent). The
results among areas treated with etretinate monotherapy did not differ significantly from oral
PUVA monotherapy, a finding that contrasts with another 12-week trial that favored etretinate
over oral PUVA [14]. Combination therapy with an oral retinoid and PUVA appeared to be the
most effective therapy. (See 'Re-PUVA' below.)
Although favorable responses to topical PUVA have been documented [12], randomized trials
evaluating topical PUVA have not demonstrated superior efficacy over placebo [15,16]. One trial
comparing oral PUVA and topical PUVA did not find a significant difference in efficacy [14].
However, the response rates to oral PUVA reported in this trial were lower than reported in other
studies.
● Administration – We usually aim to administer oral PUVA three times per week and continue
treatment for at least 12 weeks prior to concluding treatment inefficacy. Potential adverse
effects of PUVA include burns, blistering, nausea, pruritus, phototoxicity, hyperpigmentation,
premature aging of skin, and skin cancer. Adverse effects of PUVA are discussed in greater
detail separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on
'Adverse effects'.)
SECOND-LINE THERAPY
Patients who do not respond sufficiently to first-line treatment may benefit from combination therapy
with an oral retinoid and PUVA or from immunosuppressive therapy.
Re-PUVA — The term "Re-PUVA" is often used to refer to combination therapy with an oral retinoid
and oral or topical psoralen plus ultraviolet A (PUVA) photochemotherapy. The small randomized
trials that have investigated the efficacy of this treatment support greater efficacy of Re-PUVA
compared with either an oral retinoid or PUVA alone [1,13,15,17]. As an example, an unblinded trial in
which 20 patients with bilateral palmoplantar pustulosis (PPP) were randomly assigned to treatment
with oral etretinate or no etretinate and given topical PUVA only on the right hand and foot found
complete clearance occurred in 6 of 10 sites treated with etretinate and PUVA, 2 of 10 sites treated
with etretinate alone, 1 of 10 sites treated with PUVA alone, and none of 10 sites that received neither
treatment after 12 weeks [15]. A separate 20-week randomized trial that compared etretinate and oral
PUVA with oral PUVA and placebo in 17 patients with PPP and 3 patients with hyperkeratotic
palmoplantar psoriasis found that combination therapy was associated with a greater likelihood of
1566
response, significantly fewer treatments required for clearance, and a shorter time to response [17].
Oral PUVA was started two weeks after the start of etretinate therapy and was given three times per
week.
We usually begin acitretin therapy (25 to 50 mg per day) two to four weeks before the start of PUVA
therapy when administering Re-PUVA treatment. Once PUVA treatment is started, we reduce the
dose of acitretin to 10 to 20 mg per day. PUVA treatments are given two or three days per week. We
are cautious with the initial dose of PUVA in this population because of concern for retinoid-induced
thinning of the stratum corneum resulting in an increased propensity to burn. Thus, we reduce our
initial PUVA dose by 30 to 50 percent compared with the dose we would use for a patient who is not
on oral retinoid therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on
'Oral PUVA'.)
Immunosuppressants — Immunosuppressive therapy with cyclosporine or methotrexate can be

beneficial for some patients with PPP. The potential for serious adverse effects should be considered
prior to the initiation of these therapies.
● Cyclosporine – A few randomized trials support the use of cyclosporine for PPP. In a trial in
which 40 patients with PPP were randomized to treatment with oral cyclosporine (2.5 mg/kg per
day) or placebo, 17 of 19 patients who completed the four-week treatment phase had at least a
50 percent reduction in the number of pustules compared with 4 of 15 patients in the placebo
group (89 versus 27 percent) [18]. Lower doses of cyclosporine may also be effective. A
randomized trial by the same group in which 58 patients were randomly assigned to oral
cyclosporine (1 mg/kg per day) or placebo for one month found at least a 50 percent reduction
in pustules in 48 percent of 27 patients in the cyclosporine group compared with 19 percent of
31 patients in the placebo group [19].
Uncontrolled studies have also suggested benefit. In a prospective study in which 48 adults with
PPP received oral cyclosporine (3 mg/kg per day) for eight weeks, 17 percent achieved complete
remission (≥90 percent reduction in the Palmoplantar Psoriasis Area and Severity Index
[PPPASI] score), 6 percent had no response, and the remaining patients had partial improvement
[20].
In general, we treat adults with a 3 mg/kg dose of cyclosporine and begin to taper the dose after
10 days of sustained clinical improvement (at least 75 percent improvement from baseline). We
taper the dose of cyclosporine by 25 to 50 mg per week.
Short-term use of the lowest effective dose of cyclosporine is preferred to minimize adverse
effects such as hypertension and renal toxicity. Our typical duration of cyclosporine treatment
1567
lasts 12 to 24 weeks. Close monitoring for side effects is required. (See "Pharmacology of
cyclosporine and tacrolimus", section on 'Side effects'.)
Our personal experience suggests that higher doses of cyclosporine may be effective for some
patients who fail to respond to 3 mg/kg per day; we have successfully used doses of up to 8
mg/kg per day. However, increased risk for side effects is a concern for treatment with higher
doses.
● Methotrexate – Although our personal experience suggests that methotrexate can be useful for
PPP, data to support this assertion are limited. A retrospective study of 114 patients with PPP or
palmoplantar psoriasis found that four of seven patients with PPP who were treated with 15 to
25 mg per week of methotrexate (57 percent) achieved marked improvement in their disease [4].
A separate uncontrolled study in which patients were treated with 25 mg of methotrexate for two
months found complete or almost complete resolution of PPP in 8 of 25 patients (32 percent)
[21]. Most of the responders also had psoriatic skin lesions at other sites.
We typically treat with 7.5 to 20 mg of methotrexate per week given intramuscularly or

subcutaneously. Methotrexate is not given daily. Oral administration of methotrexate (10 to 25
mg per week) is an additional option, though the risk for drug-related gastrointestinal distress
may be higher.
Methods for beginning methotrexate therapy vary. We usually begin methotrexate therapy with a
low dose (eg, 7.5 mg per week) and titrate upward by 2.5 mg per week if a complete blood count
with differential performed one week after initiation (and dose increases) does not reveal
hematologic toxicity and treatment is tolerated. The time course in which we expect to see
improvement is 12 to 16 weeks. Following satisfactory improvement, we aim to taper the dose to
5 to 7.5 mg per week for maintenance therapy.
Monitoring for adverse effects is important during methotrexate therapy, particularly at the start
of therapy and following dose increases. Hematologic toxicity is a potentially life threatening
side effect. Gastrointestinal distress and liver or pulmonary toxicity are additional side effects.
Liver and renal function tests should be monitored periodically. Folic acid supplementation
should be given to patients receiving methotrexate therapy to reduce the risk of some side
effects. (See "Major side effects of low-dose methotrexate" and "Major side effects of low-dose
methotrexate", section on 'Prevention of side effects with folate'.)
SEVERE RECALCITRANT DISEASE
1568
Despite the observation that biologic anti-tumor necrosis factor (anti-TNF) drugs (infliximab,
etanercept, and adalimumab) may induce palmoplantar pustulosis (PPP) [22,23], there is some
evidence that these agents can be effective for treating PPP. A 24-week randomized trial supports
the efficacy of etanercept for PPP [24]. TNF-alpha inhibitors also have been reported as effective for
the treatment of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, a disorder that
may present with PPP [25-30]. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and
diagnosis", section on 'SAPHO syndrome'.)
Treatment with other biologic agents has been attempted for severe or recalcitrant PPP occurring
with or without associated plaque psoriasis. Data suggesting a role for interleukin (IL)-23 production
and the resulting proliferation of T helper type 17 (Th17) cells and Th17 cytokines (eg, IL-17A, IL-17F,
IL-22) in the pathogenesis of PPP has contributed to trials of therapies that inhibit this pathway [31-
33]. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis", section on
'Pathogenesis' and "Pathophysiology of plaque psoriasis", section on 'T helper type 17 cells'.)
The efficacy of ustekinumab, a biologic inhibitor of IL-12 and IL-23, for PPP is uncertain. A 16-week
randomized trial that included 13 patients with PPP and 20 patients with palmoplantar pustular
psoriasis failed to find a statistically significant difference in the response of patients to ustekinumab
(45 mg given at weeks 0 and 4) versus placebo [34]. However, benefit of ustekinumab for PPP or
palmoplantar pustular psoriasis has been reported in an uncontrolled study, case series, and case
reports [35-40].
Two randomized trials suggest benefit of guselkumab, another biologic agent targeting IL-23 [41,42].
In a phase 3 trial, 159 adults with refractory PPP were randomly assigned to guselkumab 100 mg,
guselkumab 200 mg, or placebo given at weeks 0, 4, and 12 and then every 8 weeks thereafter [42].
Patients in the placebo group were rerandomized to guselkumab 100 mg or guselkumab 200 mg
after week 16. At week 16, both the 100 mg and 200 mg guselkumab groups exhibited greater
improvement in the Palmoplantar Psoriasis Area and Severity Index (PPPASI) total score than the
placebo group (least squares mean change of -15.3, -11.7, and -7.6, respectively). In addition, more
patients in the guselkumab 100 mg group had at least 50 percent improvement in the PPPASI total
score (PPPASI-50) at week 16 than in the placebo group (57 versus 34 percent). Although the
proportion of patients achieving this endpoint in the guselkumab 200 mg group (37 percent) was
similar to the placebo group, increasing response to guselkumab was detected over time, and
PPPASI-50 response rates at week 52 were similar in the 100 mg and 200 mg guselkumab groups
(83 and 85 percent, respectively).
Additional study is necessary to clarify the effects of secukinumab, an anti-IL-17A monoclonal

antibody. In the 2PRECISE trial (n = 237), patients with moderate to severe palmoplantar pustular
psoriasis were randomly assigned to 300 mg of secukinumab, 150 mg of secukinumab, or placebo
1569
given at weeks 1, 2, 3, and 4 and then every four weeks. The trial did not achieve the primary
endpoint of superiority of the 300 or 150 mg doses of secukinumab over placebo after 16 weeks (27,
18, and 14 percent achieved 75 percent improvement in the PPPASI score, respectively) [43].
Although benefit of a longer course of treatment was proposed based upon a second phase in which
patients in the secukinumab groups were allowed to continue treatment and nonresponders in the
placebo group were rerandomized to 300 or 150 mg of secukinumab, further study to confirm benefit
is warranted. At week 52, 42 percent of patients in the secukinumab 300 mg group and 35 percent of
patients in the secukinumab 150 mg group achieved at least 75 percent improvement in the PPPASI
score.
The efficacy of other biologic therapies used for psoriasis, such as ixekizumab, brodalumab,
tildrakizumab, and risankizumab, as well as the oral phosphodiesterase 4 inhibitor apremilast and
the Janus kinase inhibitor tofacitinib, is unclear. Improvement of PPP with tofacitinib or apremilast
has been reported in individual patients [44,45]. In a series of four patients treated with brodalumab
(including two who failed to respond to secukinumab) for severe, recalcitrant PPP associated with
plaque psoriasis and/or psoriatic arthritis, three did not respond to treatment and one had a partial
response but discontinued therapy due to oral candidiasis [46].
Further study is necessary to determine efficacy of biologic IL-1 inhibitors (eg, anakinra,
canakinumab) for PPP. Improvement of severe or recalcitrant palmoplantar pustular psoriasis or
acrodermatitis continua of Hallopeau (pustular psoriasis of the digits) during treatment with
anakinra has been documented in case reports [47,48]. Canakinumab was not effective for
palmoplantar pustular psoriasis in a case report [49].
OTHER THERAPIES
Other interventions have been reported to be useful for PPP, including other topical and systemic
drugs, tonsillectomy, a gluten-free diet in patients with associated gluten intolerance, and light-based
or radiation therapy. Data on most of these therapies are limited.
● Other topical drugs – In addition to topical corticosteroids, which represent the mainstay of
topical therapy for PPP, topical therapies such as topical retinoids, tar, anthralin, or calcipotriol
are sometimes used in the clinical setting, though there are few data to support their efficacy. No
randomized trials have evaluated the efficacy of these therapies. We have not had success with
these therapies.
● Oral tetracyclines – Oral tetracyclines are a less commonly used treatment for PPP. Two
randomized crossover trials in which patients were treated with tetracycline or clomocycline
1570
support the efficacy of these drugs over placebo for inducing improvement in PPP [50,51]. We
do not use oral tetracyclines for PPP.
● Colchicine – Although colchicine was associated with marked improvement in 15 of 25 patients

treated for PPP in a retrospective study [4], findings of randomized trials have been
disappointing [52,53]. In addition, rates of adverse effects (diarrhea, headaches, and nausea) in
the randomized trials were high.
● Itraconazole – Two small case series document clinical improvement in PPP (especially new
pustule formation) during treatment with itraconazole [54,55]. Relapses occurred after cessation
of therapy. No randomized trials have evaluated the efficacy of itraconazole therapy.
● Tonsillectomy – Japanese studies linking PPP to tonsillar infections and reports of

improvement in PPP following tonsillectomy suggest that some patients may benefit from this
procedure [56-58]. Improvement of PPP after tonsillectomy has been reported in several
Japanese series [56,59-61].
● Gluten-free diet – Patients with gluten sensitivity and PPP may benefit from gluten-free diet [62].
In a Swedish series, all of nine patients who had elevated anti-gliadin antibodies and/or elevated
tissue transglutaminase antibodies and adhered to a gluten-free diet experienced clearance or
great improvement in PPP [62]. Improvement was slow, occurring over the course of a few
months in patients with moderate PPP and over several years in patients with longstanding
severe PPP.
● Other light-based therapies – Exposure to an excimer light source or a narrowband ultraviolet B

(UVB) light source has been associated with improvement in PPP in uncontrolled studies [63-
65]. An ultraviolet A1 (UVA1) 355 nm laser appeared effective for PPP in an uncontrolled study
[66]. Responses to photodynamic therapy have been documented in case reports [67].
● Radiation therapy – Limited data suggest benefit of superficial radiation therapy [68,69]. A six-
week trial in which 17 patients with PPP were randomly assigned to treatment of PPP on one
side of the body with Grenz ray therapy and a sham treatment on the contralateral side found
greater improvement in PPP on the side of the body exposed to Grenz rays [68]. However, the
response was moderate and no patients achieved disease clearance. In two case reports,
superficial radiation therapy administered with a megavoltage beams technique was associated
with dramatic, rapid improvement of severe, refractory PPP [69].
Other interventions described as beneficial in case reports include oral tofacitinib [70] and high-dose
rate brachytherapy [71].
1571
PATIENT FOLLOW-UP
The purpose of patient follow-up is to assess the response to treatment and to evaluate for adverse
effects. Therefore, the frequency of follow-up should be individualized based upon the severity of
disease and the selected therapeutic regimen. Patients with poorly controlled or severe disease on
systemic therapy will require more frequent follow-up than patients with milder disease.
● Palmoplantar pustulosis (PPP) is a skin disorder that presents with recurrent eruptions of
pustules on the palms or soles (picture 1A-F). PPP is associated with symptoms of pruritus,
burning sensations, or pain in involved areas and can have a significant negative effect on
quality of life. (See 'Introduction' above and "Palmoplantar pustulosis: Epidemiology, clinical
● PPP exhibits a chronic course characterized by exacerbations and partial remissions and can be
difficult to treat. Therapeutic options include topical therapy, systemic therapy, and
photochemotherapy. No treatment is uniformly effective and the response to treatment is
unpredictable. (See 'Overview' above.)
● In an attempt to reduce associated symptoms of PPP, we advise patients to keep skin

moisturized and to avoid irritants that may exacerbate PPP. (See 'General measures' above.)
● There is a strong relationship between smoking and the development of PPP. Although data are
insufficient for conclusions on the effect of smoking cessation on the course of PPP, we
encourage all patients to stop smoking. (See 'General measures' above and "Palmoplantar
pustulosis: Epidemiology, clinical features, and diagnosis", section on 'Pathogenesis'.)
● For patients with PPP that is limited to focal areas of involvement, we suggest a super high
potency topical corticosteroid applied under occlusion for the initial treatment of PPP (Grade
2C). For patients with diffuse eruptions on the palms and/or soles, we suggest initial treatment
with oral acitretin or oral psoralen plus ultraviolet A (PUVA) (Grade 2B). Topical corticosteroid
therapy may be administered concomitantly. (See 'First-line therapy' above.)
● Patients who do not respond to treatment with topical corticosteroids, acitretin, or PUVA may
benefit from other therapies. Combination therapy with acitretin and PUVA and systemic
treatment with cyclosporine or methotrexate are our preferred second-line options for therapy.
(See 'Second-line therapy' above.)
1572
1573
GRAPHICS

1574
1575
Deep-seated pustules with surrounding erythema and scale involving the entire palmar surface of this
patient with palmoplantar pustulosis. Older lesions typically appear dusky red-brown in color with
crusting.
1576
Pustules, brown macules (remnants of pustules), erythema, and hyperkeratosis on the soles of the feet.
1577
Numerous pustules, brown macules (remnants of pustules), erythema, and hyperkeratosis on the
soles of the feet.
1578
Focal area of pustules, brown macules (remnants of pustules), erythema, and

hyperkeratosis on the sole of the foot.
1579
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12

States)

emollient
1580

Kenalog ¶, Triderm


solution

spray

Gel Desonate 0.05

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

Body, Derma-
Smoothe/FS Scalp
1581

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1582
Lichen planus - UpToDate
uptodate.com/contents/lichen-planus/print
INTRODUCTION Lichen planus is an uncommon disorder of unknown

cause that most commonly affects middle-aged adults. Lichen planus may affect the skin
(cutaneous lichen planus), oral cavity (oral lichen planus), genitalia (penile or vulvar lichen planus),
scalp (lichen planopilaris), nails, or esophagus.
The diagnosis and management of lichen planus, with a focus on cutaneous lichen planus, will be
reviewed here. Oral lichen planus, vulvar lichen planus, lichen planopilaris, nail lichen planus, and
lichenoid drug eruption (drug-induced lichen planus) are discussed in greater detail separately. (See
"Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Oral lichen planus:
Management and prognosis" and "Lichen planopilaris" and "Vulvar lichen planus" and "Overview of
nail disorders", section on 'Lichen planus' and "Lichenoid drug eruption (drug-induced lichen
planus)".)
EPIDEMIOLOGY The epidemiology of lichen planus is not well-defined.

Based upon limited data, cutaneous lichen planus is estimated to occur in less than 1 percent of the
population[1].
1583
Cutaneous lichen planus most frequently develops between the ages of 30 and 60 years [1-3].
Childhood cutaneous lichen planus occurs, but is uncommon [4]. There does not appear to be a
strong sex or racial predilection for cutaneous lichen planus [1,2].
Epidemiologic data on other forms of lichen planus are reviewed separately. (See "Oral lichen
planus: Pathogenesis, clinical features, and diagnosis", section on 'Epidemiology' and "Vulvar lichen
planus", section on 'Epidemiology' and "Lichen planopilaris", section on 'Epidemiology' and
"Lichenoid drug eruption (drug-induced lichen planus)", section on 'Epidemiology'.)
ETIOLOGY The etiology of lichen planus is not known. An immune-mediated

mechanism involving activated T cells, particularly CD8+ T cells, directed against basal
keratinocytes has been proposed [5]. Upregulation of intercellular adhesion molecule-1 (ICAM-1) and
cytokines associated with a Th1 immune response, such as interferon (IFN)-gamma, tumor necrosis
factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-6, and IL-8, may also play a role in the pathogenesis of
lichen planus [5-8].
Hepatitis C virus — The association of hepatitis C virus (HCV) with lichen planus
is controversial, and a cause and effect relationship is uncertain. A meta-analysis of primarily case-
control studies conducted in a number of countries found a statistically significant association
between HCV and lichen planus. Compared with control patients, the prevalence of HCV exposure
was greater among patients with lichen planus (OR 5.4, 95% CI 3.5-8.3) [9]. A systematic review also
identified an increase in the proportion of lichen planus patients that were HCV positive compared
with controls (OR 4.80, 95% CI 3.25-7.09) [10]. However, subgroup analysis in both studies revealed
that the strength of this association varied geographically, and was not statistically significant in all
locations. Estimates of the prevalence of HCV infection among patients with oral lichen planus vary
widely; studies have reported prevalence rates from 0 to 62 percent [11].
Clinicians should have a high suspicion for lichen planus in patients with hepatitis C who present
with clinical features suggestive of the diagnosis. The meta-analysis cited above found that patients
with HCV had an increased prevalence of lichen planus compared to controls (OR 2.5, 95% CI, 2.0-
3.1) [9]. In a study from Italy, among 178 adults with HCV antibodies, five (2.8 percent) had oral
lichen planus [12]. There are also reports of the development or exacerbation of lichen planus during
interferon treatment for chronic HCV; the lesions improved when interferon was stopped [13].
Drugs — Clinical manifestations that resemble idiopathic lichen planus can occur as a result
of drug exposure (table 1). Lichenoid drug eruptions (also known as drug-induced lichen planus) are
reviewed separately. (See "Lichenoid drug eruption (drug-induced lichen planus)".)
CLINICAL FEATURES Lichen planus may affect the skin,

mucous membranes (especially the oral mucosa), scalp, nails, and genitalia [1].
1584
Cutaneous lichen planus — The classic presentation of cutaneous
lichen planus is a papulosquamous eruption characterized by the development of flat-topped,
violaceous papules on the skin (picture 1A-D). Often, the clinical manifestations are described as the
four “P’s:”
●Pruritic
●Purple (actually a slight violaceous hue)
●Polygonal
●Papules or plaques
Individual papules are usually a few millimeters in diameter, but may coalesce to form larger plaques
[2]. With close inspection, fine white lines may be visible on the surface of papules or plaques of
cutaneous lichen planus (picture 2). These lines are described by the term “Wickham’s striae” [14].
The extremities, particularly the ankles and the volar surface of the wrists, are common sites for
cutaneous involvement [5]. Involvement of the trunk or generalized involvement also can occur
(picture 3). Rare Blaschkoid (picture 4 and figure 1) [15-17], zosteriform [18-21], and inverse
(intertriginous) [2] distributions of cutaneous lichen planus have been observed.
Patients with lichen planus may exhibit the Koebner reaction (the development of skin lesions in
sites of trauma). The Koebner reaction most often occurs as a result of scratching (picture 5).
The pruritus associated with cutaneous lichen planus often is intense. Asymptomatic eruptions are
rare. Lesions often heal with significant postinflammatory hyperpigmentation.
Cutaneous variants — In addition to the classic presentation of cutaneous lichen

planus, multiple other clinical presentations of cutaneous disease have been described. Shared
histologic findings support the classification of these disorders as variants of cutaneous lichen
planus.
Examples of variants of cutaneous lichen planus include [2]:
●Hypertrophic lichen planus – Hypertrophic lichen planus is characterized by the development of

intensely pruritic, flat-topped plaques (picture 6). The typical site of involvement is the anterior lower
legs. Of note, the occasional development of cutaneous squamous cell carcinoma has been
reported in patients with longstanding hypertrophic lichen planus lesions [22].
●Annular lichen planus – Annular lichen planus is characterized by the development of violaceous
plaques with central clearing (picture 7A-C). Although the penis, scrotum, and intertriginous areas
are common sites of involvement, annular lesions may occur in other areas [23]. Central atrophy
may be present.
1585
●Bullous lichen planus – Patients with bullous lichen planus develop vesicles or bullae within the
sites of existing cutaneous lichen planus lesions. The legs are a common site of lesion development
[2].
●Actinic lichen planus – Actinic lichen planus (also known as lichen planus tropicus) presents with
a photodistributed eruption of hyperpigmented macules, annular papules, or plaques [2]. This variant
is most commonly seen in the Middle East, India, and east Africa [5].
●Lichen planus pigmentosus – Lichen planus pigmentosus presents with gray-brown or dark brown
macules or patches that are most commonly found in sun-exposed or flexural areas [24]. Pruritus is
minimal or absent. The term “lichen planus pigmentosus-inversus” is used to describe patients with
primarily flexural involvement [25].
●Inverse lichen planus – Inverse lichen planus is characterized by erythematous to violaceous

papules and plaques in intertriginous sites, such as the axillae, inguinal creases, inframammary
area, or limb flexures (picture 8) [2]. Associated hyperpigmentation is common. Scale and erosions
may be present.
●Atrophic lichen planus – Atrophic lichen planus presents with violaceous, round or oval, atrophic
plaques. The legs are a common site of involvement [2], and lesions often clinically resemble
extragenital lichen sclerosus. A rare annular atrophic variant of lichen planus characterized by
violaceous papules that enlarge peripherally leaving an atrophic center that demonstrates complete
loss of elastic fibers on pathology has also been reported [26-28].
●Lichen planopilaris (follicular lichen planus) – The scalp is the classic site for lichen planopilaris.
However, follicular involvement manifesting as follicular papules may be observed in other body
sites, particularly in patients with the Graham-Little-Piccardi-Lasseur syndrome. (See "Lichen
planopilaris", section on 'Introduction' and "Lichen planopilaris", section on 'Graham-Little-Piccardi-
Lasseur syndrome'.)
Additional variants include palmoplantar lichen planus (a variant that may demonstrate ulceration)
[29-31] and perforating [32,33] lichen planus.
Overlap syndromes — Lichen planus pemphigoides and lichen planus-lupus

erythematous overlap syndrome are disorders that are characterized by the presence of features of
cutaneous lichen planus and a second disease.
●Lichen planus pemphigoides –Lichen planus pemphigoides presents with overlapping features of
lichen planus and bullous pemphigoid. The onset of lichen planus usually precedes the onset of
bullous lesions [34].
Patients develop bullae in sites of previously normal appearing skin and on top of lesions of lichen
planus [34]. This contrasts with bullous lichen planus, which presents with bullae that are limited to
longstanding lichen planus lesions. Similar to bullous pemphigoid, direct immunofluorescence
1586
studies of lichen planus pemphigoides demonstrate linear deposition of IgG and C3 at the dermal-
epidermal junction. (See "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Direct immunofluorescence'.)
●Lichen planus-lupus erythematosus overlap syndrome –The term lichen planus-lupus

erythematous overlap syndrome refers to a rare condition in which patients develop skin lesions
with clinical, histologic, and/or immunopathologic features of both diseases. Clinically, patients
often present with blue-red atrophic plaques or upper extremity verrucous papules or nodules [35].
Other forms of lichen planus — Other manifestations of lichen

planus may be present in patients with cutaneous lesions.
●Nail lichen planus – When nails are involved, the disease spectrum varies from minor dystrophy to
total nail loss (picture 9A-D). The disease process in lichen planus of the nails primarily occurs in the
nail matrix. (See "Overview of nail disorders", section on 'Lichen planus'.)
●Lichen planopilaris –Lichen planopilaris is the term used to describe lichen planus that occurs on
the scalp. Patients present with areas of hair loss with keratotic follicular papules that, left untreated,
can progress to scarring alopecia (picture 10). Hair regrowth does not occur once follicles are
destroyed. (See "Lichen planopilaris".)
●Oral lichen planus –Lichen planus of the mucous membranes can occur in conjunction with
cutaneous disease or independently. Mucous membrane disease may consist solely of lacelike
Wickham's striae that are particularly evident on the buccal mucosa or can include papular, atrophic,
or erosive lesions (picture 11A-D). Erosive mucous membrane disease is frequently painful and may
lead to secondary complications including superficial candidal infection. Patients frequently report a
persistent loss of appetite due to pain associated with eating. (See "Oral lichen planus:
Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations' and "Vulvar
lichen planus", section on 'Clinical manifestations'.)
●Genital lichen planus –Genital lichen planus in men presents with violaceous papules on the glans
penis (picture 7B, 7D), while in women lesions typically occur on the vulva. The vulvo-vaginal-
gingival syndrome is an erosive form of lichen planus that involves the epithelium of the vulva,
vestibule, vagina, and mouth; it is particularly resistant to treatment [36,37]. Although all three areas
can be affected, the lesions may not be concurrent. The gingival epithelium is usually involved, but
erosions, white plaques, or a whitish and lace-like reticular pattern may occur on the buccal mucosa,
tongue, and palate (picture 12). (See "Vulvar lichen planus".)
●Esophageal lichen planus –Lichen planus may involve the esophagus, presenting with or without
symptoms such as dysphagia or odynophagia [38]. Possible endoscopic findings include
pseudomembranes, friable and inflamed mucosa, submucosal papules, lacy white plaques,
erosions, strictures, and other abnormalities (picture 13). Concomitant oral, genital, or cutaneous
lichen planus is frequently present [38]. The prevalence of esophageal lichen planus is unknown.
1587
●Otic lichen planus – The stratified squamous epithelia of the external auditory canals and tympanic
membranes are potential sites for lichen planus. Common clinical features of otic lichen planus
include erythema, induration, and stenosis of the external auditory canal; thickening of the tympanic
membranes; otorrhea; and hearing loss [39]. Lichen planus of other body sites may or may not be
present. Further study is necessary to determine the prevalence of this disease manifestation.
HISTOPATHOLOGY Lichen planus is associated with a set of

characteristic pathologic findings that are seen in cutaneous lichen planus and to a variable extent
in lichen planus of other body sites. These include (picture 14A-B) [40,41]:
●Hyperkeratosis without parakeratosis
●Vacuolization of the basal layer
●Civatte bodies (apoptotic keratinocytes) in the lower epidermis
●Wedge-shaped hypergranulosis, "saw-tooth" shaped rete ridges
●Small clefts at the dermal-epidermal junction (Max-Joseph spaces)
●Band-like lymphocytic infiltrate at the dermal-epidermal junction
●Eosinophilic colloid bodies (apoptotic keratinocytes) in the papillary dermis
●Pigment incontinence (most prominent in dark-skinned individuals)
The pathologic findings of lichen planus in other body sites and lichenoid drug eruptions are
reviewed separately. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis", section
on 'Biopsy' and "Vulvar lichen planus", section on 'Diagnosis' and "Lichen planopilaris", section on
'Biopsy' and "Overview of nail disorders", section on 'Lichen planus' and "Lichenoid drug eruption
(drug-induced lichen planus)", section on 'Pathology'.)
DIAGNOSIS In many cases, the diagnosis of cutaneous lichen planus can be

made based upon the recognition of consistent clinical findings. In cases in which the diagnosis is
uncertain, a skin biopsy is useful for confirming the diagnosis. The diagnosis of the other forms of
lichen planus is reviewed in greater detail separately. (See "Oral lichen planus: Pathogenesis, clinical
features, and diagnosis", section on 'Diagnosis' and "Vulvar lichen planus", section on 'Diagnosis' and
"Lichen planopilaris", section on 'Diagnosis' and "Lichenoid drug eruption (drug-induced lichen
planus)", section on 'Diagnosis'.)
Clinical evaluation — The clinical evaluation of a patient with suspected

cutaneous lichen planus consists of a patient interview and a physical examination. Patients should
be questioned about medications (drugs that may induce lichen planus (table 1)), pruritus (a
1588
common symptom of cutaneous lichen planus), oral or genital erosions or pain (findings suggestive
of concomitant mucosal lichen planus), and dysphagia or odynophagia (findings suggestive of
esophageal disease). We also typically inquire about risk factors for hepatitis C. (See 'Additional
testing' below.)
The physical examination should include an examination of the entire cutaneous surface, including
the scalp, as well as examination of the oral cavity and external genitalia. Performing a full
examination aids in the assessment of the extent of cutaneous lesions and allows for the
recognition of additional sites of involvement.
Biopsy — A skin biopsy can be used to confirm a diagnosis of cutaneous lichen planus. A
punch biopsy or shave biopsy that reaches the depth of the mid-dermis is usually sufficient. (See
"Skin biopsy techniques", section on 'Punch biopsy' and "Skin biopsy techniques", section on 'Shave
biopsy'.)
Immunofluorescence studies are not routinely needed. Direct immunofluorescence may be

performed in patients with bullous lesions to differentiate the condition from an autoimmune
blistering disease. If performed, direct immunofluorescence often demonstrates colloid bodies in the
papillary dermis that stain for complement and immunoglobulins (especially IgM) and irregular fibrin
deposition along the dermal-epidermal junction [40].
Dermoscopy — Wickham’s striae often can be visualized during dermoscopic

examination of cutaneous lesions of lichen planus [42-44]. (See "Overview of dermoscopy".)
ADDITIONAL TESTING Given the evidence that suggests an

association between lichen planus and hepatitis C virus (HCV) infection, we routinely test for HCV
infection in patients with lichen planus. However, there are conflicting opinions regarding the value
of such testing, and there is disagreement on whether routine testing is essential in all locations.
(See 'Hepatitis C virus' above and "Screening and diagnosis of chronic hepatitis C virus infection",
section on 'Whom to test'.)
In a United States study in which 195 patients with oral lichen planus were prospectively screened
for liver abnormalities, no liver abnormalities or antibodies to hepatitis B or C were detected [45].
This report suggested that routine testing for HCV infection is not necessary. Others have suggested
testing for HCV infection in patients diagnosed with lichen planus, particularly those with risk factors
for HCV infection, due to the risks of morbidity and transmission that exist with HCV infection and
the evidence suggesting an association between lichen planus and HCV [9,10,46,47].
DIFFERENTIAL DIAGNOSIS Key disorders in the

differential diagnosis for classic presentations of cutaneous lichen planus include the following:
1589
●Lichenoid drug eruption – Lichenoid drug eruptions (drug-induced lichen planus) should always be
considered so that the offending agent can be withdrawn when possible (table 1). The cutaneous
manifestations closely resemble idiopathic lichen planus. The patient’s history of drug exposure and
a skin biopsy can aid in distinguishing lichenoid drug eruptions from idiopathic lichen planus.
Lichenoid drug eruptions usually develop insidiously and can affect any area of the body surface
(picture 15A-D). (See "Lichenoid drug eruption (drug-induced lichen planus)".)
●Chronic graft-versus-host disease –Chronic graft-versus-host disease can produce a lichenoid

eruption with clinical and histologic findings similar to lichen planus. The history of preceding
hematopoietic cell transplant is helpful for diagnosis. (See "Clinical manifestations, diagnosis, and
grading of chronic graft-versus-host disease", section on 'Mucocutaneous manifestations'.)
Other papulosquamous and dermatitic disorders, such as psoriasis, atopic dermatitis, lichen simplex
chronicus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, pityriasis rosea,
secondary syphilis, and prurigo nodularis can usually be distinguished from lichen planus through a
careful evaluation for clinical findings that are more consistent with these disorders. Lesions
suspicious for bullous lichen planus should be distinguished from autoimmune blistering diseases
through a biopsy and immunofluorescence studies. Of note, skin involvement in paraneoplastic
pemphigus/paraneoplastic autoimmune multiorgan syndrome (PAMS) often presents as lichenoid
skin lesions. (See "Approach to the patient with cutaneous blisters", section on 'Diagnostic tests' and
"Paraneoplastic pemphigus".)
NATURAL HISTORY The natural history of most cases of

cutaneous lichen planus is to remit within one to two years [48]. Oral, genital, scalp, and nail lichen
planus tend to be more persistent. The clinical course of these types of lichen planus and lichenoid
drug eruptions are viewed in greater detail separately. (See "Oral lichen planus: Management and
prognosis", section on 'Prognosis and follow-up' and "Vulvar lichen planus", section on 'Natural
history' and "Lichen planopilaris", section on 'Clinical course' and "Overview of nail disorders",
section on 'Lichen planus' and "Lichenoid drug eruption (drug-induced lichen planus)", section on
'Clinical course'.)
Comorbid disease — The results of two case-control studies suggest that the
prevalence of dyslipidemia may be greater among patients with lichen planus than among
individuals without this disease [49,50]. Additional studies are necessary to confirm an association
between dyslipidemia and lichen planus and to explore the clinical relevance of this finding. Further
study is also necessary to clarify whether there is an association between oral lichen planus and
thyroid disease [51,52].
TREATMENT There are few data to support evidence-based recommendations

for the treatment of lichen planus [53-55]. Only a few randomized trials have been performed, most
of which were small and subject to methodologic error [56].
1590
The treatment of cutaneous lichen planus is reviewed below. Detailed information on the
management of other forms of lichen planus can be found separately. (See "Oral lichen planus:
Management and prognosis" and "Vulvar lichen planus", section on 'Management' and "Lichen
planopilaris", section on 'Treatment' and "Overview of nail disorders", section on 'Lichen planus' and
"Lichenoid drug eruption (drug-induced lichen planus)", section on 'Treatment'.)
Cutaneous lichen planus — Cutaneous lichen planus usually is a self-

limited disorder. Thus, treatment is focused on accelerating resolution and managing pruritus [1].
(See 'Natural history' above.)
First-line therapy — Topical corticosteroids are commonly used as first-line treatment

for localized cutaneous lichen planus. For patients with generalized disease, in whom monotherapy
with topical corticosteroids is less practical, topical corticosteroids are often used as an adjunct to
systemic therapy or phototherapy. (See 'Second-line therapy' below.)
Topical corticosteroids — Although topical corticosteroids are the mainstay of

treatment for patients with localized cutaneous lichen planus, the efficacy of these agents has not
been evaluated in clinical studies. Recommendations based upon clinical experience and the relative
safety of this mode of treatment support the use of topical corticosteroids as first-line therapy [1,5].
We typically treat localized cutaneous lichen planus on the trunk and extremities with a high potency
or super high potency topical corticosteroid (eg, 0.05% betamethasone dipropionate, 0.05%
diflorasone diacetate) cream or ointment twice daily (table 2). Because topical corticosteroid-
induced cutaneous atrophy is most likely to occur in intertriginous or facial skin, we prefer to use
mid-potency or low-potency corticosteroid creams or ointments when treating these areas. Efficacy
should be assessed after two to three weeks.
Patients should be cautioned about the risk for cutaneous atrophy and should be followed closely
for this side effect. The adverse effects of topical corticosteroid therapy are reviewed separately.
(See "Topical corticosteroids: Use and adverse effects".)
Intralesional corticosteroids — The thick lesions of hypertrophic lichen planus may

be less likely than classic cutaneous lesions to respond well to a topical corticosteroid. Clinical
experience suggests that intralesional corticosteroid therapy can be beneficial for the treatment of
hypertrophic lichen planus [5].
We typically administer triamcinolone acetonide in a concentration of 2.5 to 10 mg/mL. The quantity

administered should blanch or at least infiltrate hypertrophic lesions. Extension of the corticosteroid
into the surrounding normal skin should be minimized. We limit the total dose of triamcinolone to no
more than 40 mg per treatment session. Injections may be repeated after four to six weeks.
1591
Cutaneous atrophy and hypopigmentation may occur as a result of intralesional corticosteroid
therapy. Side effects of this treatment are reviewed separately. (See "Intralesional corticosteroid
injection", section on 'Side effects, complications, and pitfalls'.)
Second-line therapy — Patients with cutaneous lichen planus who cannot be

treated adequately with local corticosteroids (eg, generalized disease or local corticosteroid-
refractory disease) may benefit from other treatments, such as oral glucocorticoids, phototherapy,
and oral acitretin. Only acitretin has been evaluated in a blinded placebo-controlled randomized trial.
The limited availability of data and the potential for lichen planus to spontaneously resolve
contributes to uncertainty about the efficacy of treatments. The risks and benefits of treatment
should be considered carefully prior to treatment.
Systemic glucocorticoids — Oral glucocorticoid therapy may be beneficial for

cutaneous lichen planus based upon clinical experience and a few small uncontrolled studies in
which improvements in the signs or symptoms of cutaneous lichen planus occurred during oral
glucocorticoid therapy [53,57,58]. We consider prescribing a short course of an oral glucocorticoid
when acute control of cutaneous lichen planus is necessary for patients with extensive disease.
Continued, long-term treatment with systemic glucocorticoids is less favorable due to the serious
side effects associated with long-term therapy. (See "Major side effects of systemic
glucocorticoids".)
The optimal dose and duration of systemic glucocorticoid therapy is not known. Our preference is to
begin with 30 to 60 mg daily for four to six weeks followed by a taper of the dose to discontinuation
over the next four to six weeks. Lower doses and shorter courses have also been proposed in the
literature [53].
Phototherapy — Ultraviolet B (UVB) and psoralen plus ultraviolet A (PUVA) phototherapy are
utilized for the treatment of cutaneous lichen planus. Narrowband UVB is the most common
modality used [3,5]. Similar to other treatments for cutaneous lichen planus, data on the efficacy of
phototherapy are limited. Placebo-controlled randomized trials have not been performed. (See "UVB
therapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
Non-placebo-controlled studies evaluating narrowband UVB for cutaneous lichen planus have
generally yielded favorable findings. A small, unblinded, randomized trial of 46 patients with
generalized lichen planus that compared treatment with narrowband UVB (three times per week for
six weeks) to oral prednisone (0.3 mg/kg per day for six weeks) found a significantly better response
in the patients who received phototherapy [59]. Complete responses were attained by 12 of 23
patients in the phototherapy group (52 percent) versus 3 of 23 patients in the prednisone group (13
percent).
Several other studies suggest benefit of UVB phototherapy [60-64]. As an example, a prospective
uncontrolled study of 16 patients with generalized cutaneous lichen planus found that 11 patients
achieved at least a 90 percent reduction in papules after treatment with narrowband UVB (three
times weekly for 40 sessions). Itching tended to improve early in the course of therapy. Additionally,
1592
a retrospective study in which 50 patients with generalized cutaneous lichen planus were treated
with either narrowband UVB (n = 43) or broadband UVB (n = 7) three times per week found
documentation of complete remissions in 70 percent of patients [61]. Among those who achieved a
complete remission, 85 percent remained in remission after a median follow-up period of 34.7
months.
PUVA photochemotherapy, which requires oral or bath administration of 8-methoxypsoralen, also

seems to be efficacious for some patients with cutaneous lichen planus based upon retrospective
studies and case series [65-70]. Although the findings of a retrospective analysis of 28 patients with
generalized lichen planus raised the question of whether PUVA is more likely than narrowband UVB
to induce an initial response [65], the study failed to find a significant difference in the long term
benefit of these treatments. Additional studies are needed to explore the comparative efficacy of
PUVA and narrowband UVB phototherapy.
Given the lack of data confirming superiority of a particular mode of phototherapy, narrowband UVB
therapy (initially given three times per week) is our preferred mode of phototherapy for cutaneous
lichen planus due to the ease with which this treatment can be administered. In contrast to
narrowband UVB, PUVA requires administration of an oral or topical photosensitizer. Additionally,
oral PUVA requires a period of ocular photoprotection following treatment. We taper the frequency of
narrowband UVB treatment once an adequate response is achieved. If no response is observed after
three to four months, we discontinue treatment.
Burning, blistering, and pruritus are potential side effects of phototherapy. Short- and long-term side
effects of phototherapy are reviewed in detail separately. (See "UVB therapy (broadband and
narrowband)", section on 'Short- and long-term adverse effects' and "Psoralen plus ultraviolet A
(PUVA) photochemotherapy", section on 'Adverse effects'.)
Oral retinoids — The best support for the use of acitretin, an oral retinoid, for lichen planus
stems from a placebo-controlled randomized trial of 65 patients with cutaneous lichen planus
[71,72]. At the end of eight weeks, patients treated with 30 mg per day of acitretin (n = 32) were
significantly more likely to have achieved remission or marked improvement than the 33 patients in
the placebo group (64 versus 13 percent achieved this level of response). Improvement during
treatment with acitretin and other oral retinoids has also been documented in small, open-label
studies or case reports [73-75].
Although the randomized trial strongly supports a beneficial effect of acitretin on cutaneous lichen
planus, the potential adverse effects of acitretin account for our categorization of acitretin as a
second-line treatment rather than a first-line treatment for cutaneous lichen planus. Xerosis, hair
loss, hypertriglyceridemia, visual changes, myalgias, pseudotumor cerebri, and skeletal
abnormalities are some examples of retinoid side effects. We primarily reserve the use of acitretin
for patients with disease that cannot be managed with local corticosteroids or phototherapy.
Oral retinoids should be administered by or in consultation with clinicians familiar with the use and
side effects of this therapy (eg, a dermatologist). Acitretin is teratogenic, and is contraindicated for
women who are pregnant or intend to become pregnant. Pregnancy is contraindicated for three
1593
years after discontinuation of acitretin.
Other treatments — Oral antihistamines (eg, hydroxyzine hydrochloride 10 to 50 mg

four times a day, as necessary) may be helpful in controlling pruritus. Other medications that have
been reported to be of benefit in some patients with cutaneous lichen planus include methotrexate
[56], thalidomide [76,77], low molecular weight heparin [78,79], griseofulvin [80], cyclosporine [53],
dapsone [4,81], sulfasalazine [82], metronidazole [83,84], and hydroxychloroquine [85].
Mycophenolate mofetil has been used successfully in the treatment of at least two patients with
extensive generalized lichen planus and one patient with resistant hypertrophic and bullous lichen
planus [86,87]. Further study is necessary to confirm the efficacy of all of these agents.
The results of a small uncontrolled study suggest that apremilast, a phosphodiesterase inhibitor,
may be beneficial for lichen planus [88]. Treatment with apremilast (20 mg twice daily for 12 weeks)
was associated with clinical improvement in all 10 patients, including three patients who achieved at
least a two-grade improvement in the physician global assessment score. Additional studies are
necessary to explore the efficacy and safety of apremilast for lichen planus.
Other types of lichen planus

Genital lichen planus — Topical corticosteroids or topical calcineurin inhibitors
are often used in the treatment of genital lichen planus. The treatment of vulvar lichen planus is
reviewed in detail elsewhere. (See "Vulvar lichen planus".)
Lichen planopilaris — The treatment of lichen planopilaris (LPP) can be difficult.

Topical corticosteroids or intralesional corticosteroids are often used as first-line therapies (table 2)
[89-92]. The treatment of LPP is discussed in greater detail separately. (See "Lichen planopilaris",
section on 'Treatment'.)
Oral lichen planus — Topical corticosteroids are first-line therapy for oral lichen
planus. The treatment of oral lichen planus is reviewed separately. (See "Oral lichen planus:
Nail lichen planus — The treatment of lichen planus involving the nails is reviewed
separately. (See "Overview of nail disorders", section on 'Lichen planus'.)
Lichenoid drug eruption — The management of drug-induced lichen planus is

reviewed separately. (See "Lichenoid drug eruption (drug-induced lichen planus)", section on
'Treatment'.)
1594
provided separately. (See "Society guideline links: Lichen planus".)

●Basics topic (see "Patient education: Lichen planus (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Lichen planus is a mucocutaneous disorder that most commonly affects middle-aged adults.
Clinicians should be aware of the potential for drug-induced forms of lichen planus. (See
'Introduction' above and 'Etiology' above.)
●Studies have suggested an association of lichen planus with hepatitis C virus (HCV), although the
strength of this association varies geographically. Further studies are necessary to determine if HCV
screening should be performed in patients with lichen planus. (See 'Hepatitis C virus' above.)
●Lichen planus may affect the skin, nails, or mucous membranes. Cutaneous lichen planus typically
presents as pruritic, polygonal, violaceous papules and/or plaques with an overlying white, lacelike
pattern (Wickham's striae) (picture 1A-D). Significant post-inflammatory hyperpigmentation is
common. Cutaneous lichen planus may also present with hypertrophic or vesicobullous lesions.
(See 'Clinical features' above.)
●Lichen planopilaris is a form of lichen planus that affects the scalp and can lead to scarring
alopecia. When lichen planus involves the oral cavity, it may present with only lacelike Wickham's
striae or may include papular, atrophic, or erosive lesions. Genital areas can also be affected by
1595
lichen planus. (See 'Clinical features' above and "Lichen planopilaris" and "Oral lichen planus:
Pathogenesis, clinical features, and diagnosis" and "Vulvar lichen planus".)
●Cutaneous lichen planus often spontaneously resolves after one to two years. Oral, genital, scalp,
and nail lichen planus tend to be more chronic. (See 'Natural history' above.)
●We suggest high potency or super high potency topical corticosteroids as initial treatment of
localized cutaneous lichen planus on the trunk or extremities based upon clinical experience and the
relative safety of this therapy (Grade 2C). Intralesional corticosteroids can be useful in patients with
hypertrophic lichen planus. Patients with widespread cutaneous disease may benefit from
phototherapy, acitretin, or a short course of systemic glucocorticoid therapy. (See 'Treatment'
above.)
ACKNOWLEDGMENT The editorial staff at UpToDate, Inc. would

like to acknowledge Dr. Fuad Muakkassa for his contributions to this topic review.
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Lichen planopilaris - UpToDate
uptodate.com/contents/lichen-planopilaris/print
INTRODUCTION Lichen planopilaris (LPP) is an uncommon inflammatory

scalp disorder that is clinically characterized by perifollicular erythema, follicular hyperkeratosis, and
permanent hair loss. LPP is considered a follicular form of lichen planus based upon shared
pathologic features and the frequent coexistence of clinical findings of these disorders. (See "Lichen
planus".)
LPP is divided into three clinical variants:
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●Classic LPP
●Frontal fibrosing alopecia (FFA)
●Graham-Little-Piccardi-Lasseur syndrome (Graham-Little syndrome, GLPLS)
The three variants of LPP are distinguished primarily by the clinical pattern of involvement. Whereas
patchy scalp involvement is a common presentation of classic LPP (picture 1), band-like alopecia
involving the frontal scalp is typical of FFA (picture 2). GLPLS is defined by a triad of features:
cicatricial alopecia on the scalp, noncicatricial alopecia in the axillae and groin, and widespread
lichenoid follicular papules.
The treatment of LPP is challenging due to a paucity of data on the efficacy of therapies and an
inconsistent response to treatment. However, because uncontrolled LPP results in irreversible hair
loss, rapid diagnosis and the prompt institution of treatment are important for the management of
patients with LPP.
The diagnosis and management of LPP will be reviewed here. Lichen planus is discussed separately.
(See "Lichen planus".)
CLASSIFICATION The participants of a 2001 workshop on cicatricial

alopecia sponsored by the North American Hair Research Society proposed a classification scheme
for cicatricial alopecias that is primarily based upon the pathologic features of each disorder [1].
Lichen planopilaris (LPP) was classified as a primary lymphocytic cicatricial alopecia, a member of a
group of inflammatory scalp disorders that demonstrate a lymphocyte-predominant inflammatory
infiltrate, follicular destruction, and permanent hair loss. The classification of the cicatricial
alopecias is reviewed separately. (See "Evaluation and diagnosis of hair loss", section on 'Cicatricial
alopecia'.)
EPIDEMIOLOGY Epidemiologic data on lichen planopilaris (LPP) are

limited. Although it is accepted that LPP is uncommon, the incidence and prevalence of LPP are
unknown. Data from select North American tertiary hair research centers suggest that patients with
LPP account for less than 1 percent to 8 percent of new patients who present to such centers for
evaluation [2,3].
Adults between the ages of 25 and 70 years are the primary population affected by LPP; however,
LPP also is occasionally observed in children [2,4-6]. A retrospective study of 45 patients with
classic LPP found a mean age of onset of 52 years [7].
All three variants of LPP appear to be more common in females than in males [2,4,7,8]. In the
retrospective study of 45 patients with classic LPP mentioned above, the female to male ratio was
4:1 [7]. Other studies have found less dramatic sex differences; in a retrospective study of 25
patients with LPP, the female to male ratio was 1.8:1 [2]. Postmenopausal women are the primary
1598
population affected by the frontal fibrosing alopecia (FFA) variant of LPP [8-11]. In a retrospective
study of 355 patients with FFA (343 women and 12 men), the mean age was 56 years (range 21 to 81
years) [8]. Although Graham-Little-Piccardi-Lasseur syndrome (GLPLS) can occur in males, most of
the reported cases have occurred in Caucasian women between the ages of 30 and 60 years [12].
Data are insufficient for definitive conclusions about racial or ethnic predilections for LPP. The
possibility of a reduced risk in individuals of Asian origin was suggested by data from a tertiary hair
center in Canada [2]. Although Asians (not including East Indians) accounted for 25 percent of the
3500 patients evaluated at the center over five years, only one of the 25 patients with LPP was Asian.
Additional studies are necessary to confirm whether there are racial or ethnic differences in the
prevalence of LPP.
Patients with LPP may have an increased risk for thyroid disease. In a case-control study of 166
patients with LPP and 81 control patients evaluated in a dermatology clinic, thyroid disease was
significantly more frequent among patients with LPP (34 versus 11 percent of patients) [13].
Hypothyroidism was the most common thyroid abnormality in both groups. Further study will be
useful for confirming a relationship between LPP and thyroid disease.
PATHOGENESIS The pathogenesis of lichen planopilaris (LPP) is poorly

understood. Similar to cutaneous lichen planus, LPP is postulated to be an immune-mediated
disorder characterized by an autoreactive, lymphocytic inflammatory process against an unknown
self-antigen. In LPP, follicular antigens may be the target of a cell-mediated cytotoxic immune
reaction.
The permanent loss of hair that characterizes LPP is postulated to emanate from the site in which
inflammation occurs. Unlike alopecia areata, a nonscarring form of hair loss in which inflammation
is most concentrated around the follicular bulb, LPP demonstrates an inflammatory infiltrate
concentrated around the follicular infundibulum and isthmus (figure 1 and picture 3). The follicular
"bulge," a site of pluripotent stem cells involved in regeneration of the lower portion of the hair follicle
during follicular cycling is located within this same region. Damage to the bulge region may account
for the development of permanent alopecia [14].
Endogenous or exogenous agents, such as drugs, viruses, or contact sensitizers have been
proposed as potential triggers for the autoimmune response observed in LPP [4,15,16]. Binding of
components of these agents to keratinocytes could represent an initial trigger for an inflammatory
process. However, a role for specific endogenous or exogenous factors remains unclear.
Other observations that may offer insight into the pathogenesis of LPP include the detection of
reduced expression of peroxisome proliferator-activated receptor (PPAR)-gamma in specimens of
LPP, and the detection of antibodies against the INCENP protein in a patient with Graham-Little-
Piccardi-Lasseur syndrome (GLPLS) [17,18]. PPAR-gamma is a transcription factor that may be
critical for the maintenance of normal pilosebaceous units and INCENP is a component of the
centromere involved in cell mitosis. In addition, the predilection of frontal fibrosing alopecia (FFA) for
postmenopausal women and the apparent response of some cases to antiandrogenic treatment has
1599
raised questions about whether androgens are involved in the pathogenesis of FFA [9,19]. Further
study is necessary to determine the relevance of a retrospective study that found a higher rate of
early menopause among women with FFA than in the general population [8].
A genome-wide association study in two European cohorts of females with FFA and female controls
identified susceptibility loci for FFA, supporting a genetic predisposition to the development of this
condition [20]. The strongest effect on FFA susceptibility was found at 6p21.1 within the major
histocompatibility complex (MHC) region, which upon further analysis was attributed to HLA-
B*07:02 allele. HLA-B*07:02 is postulated to facilitate hair follicle autoantigen presentation, an event
that may contribute to lymphocytic destruction of the follicular bulge. Other susceptibility loci
identified in the study include 2p22.2, 8q24.22, and 15q2.1. The findings suggest a pathogenic role
for risk alleles in MHC class I molecule-mediated antigen processing and T cell homeostasis and
function.
CLINICAL PRESENTATION Classic lichen planopilaris

(LPP), frontal fibrosing alopecia (FFA), and Graham-Little-Piccardi-Lasseur syndrome (GLPLS) have
both overlapping and distinct clinical features. Perifollicular inflammation, follicular hyperkeratosis,
and cicatricial alopecia occur in all three variants. The distribution of involvement is the most
prominent distinguishing clinical feature.
Classic lichen planopilaris — The most common sites for initial

involvement in classic lichen planopilaris (LPP) are the vertex and parietal areas of the scalp. The
earliest clinical signs are perifollicular erythema and follicular hyperkeratosis manifesting as
perifollicular keratotic spines or follicular keratotic plugs. Eventually, patients develop skin-colored or
erythematous patches of alopecia that are a few millimeters to a few centimeters in breadth (picture
4) [21]. Close examination will reveal markedly reduced or absent follicular ostia. Occasionally,
residual islands of normal or inflamed hair-bearing follicles remain within the patches of alopecia.
Perifollicular erythema and follicular hyperkeratosis often remain evident at the periphery of areas of
alopecia in patients with active disease [7]. Tufted hairs similar to those seen in folliculitis decalvans
also may be seen [2].
The extent of scalp involvement varies; patients may present with single or multiple scalp lesions
and involvement may be focal or extensive (picture 5) [2,22]. Small patches of alopecia can slowly
progress and become interconnected, leading to a reticulated pattern of alopecia (picture 1) [23,24].
Associated itching, burning, or scalp tenderness is common. Rarely, linear presentations of LPP on
the face or trunk occur [25,26].
Concomitant features of cutaneous, nail, or mucosal lichen planus are not uncommon in patients
with LPP. It is estimated at the time of presentation, 17 to 28 percent of patients with LPP have
evidence of lichen planus in other body sites [21]. Involvement of other sites may precede or follow
the development of LPP [7].
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Frontal fibrosing alopecia — FFA is characterized by the development
of frontotemporal loss of both terminal and vellus hairs. Hair loss occurs in a band-like distribution
that is usually 1 to 8 cm in diameter (picture 2) [21,27]. Often, a small number of isolated hairs are
spared within the band of alopecia, a finding that has been referred to as the "lonely hair sign" [8,28].
Similar to classic LPP, erythematous and hyperkeratotic follicles are often found at the periphery of
areas of alopecia. Hypopigmentation may also be evident in the affected area [29]. Pruritus or
trichodynia may be present [8].
Involvement of other scalp sites, such as the periauricular, parietal, or occipital areas, may
accompany the classic distribution of FFA (picture 6) [8,9]. In addition, in a retrospective study of 60
women with FFA, diffuse features of LPP on the scalp were found in 8 percent of patients [9]. Men
may have involvement of the sideburns and facial hair [30].
Eyebrow involvement is common in FFA, occurring in 50 to 83 percent of patients [8,9]. Eyebrow

involvement may precede or follow scalp disease. Eyelash involvement also may occur, though it is
less common. In a retrospective study of 355 patients with FFA in Spain, 14 percent had eyelash
involvement [8]. Men with FFA may experience beard involvement [8].
Patients with FFA also may develop hair loss in areas other than the scalp and face. Body, axillary, or
pubic hair loss was documented in 24, 21, and 18 percent of patients in the Spanish retrospective
study, respectively [8].
In addition, involvement of vellus hair follicles on the face manifesting as facial papules or follicular
red dots has been reported [31]. Facial papules were detected in 14 percent of patients in the
Spanish retrospective study [8]. Other reported facial manifestations include diffuse erythema
resulting from a follicular and interfollicular lichenoid infiltrate and the gradual appearance of
pigmented macules [32].
Graham-Little-Piccardi-Lasseur syndrome — GLPLS

has three clinical components [33]:
●Cicatricial (scarring) alopecia of the scalp with features of LPP
●Noncicatricial (nonscarring) alopecia involving axillary and pubic hair
●Lichenoid follicular eruption on the trunk, limbs, face, or eyebrows
Cicatricial alopecia usually precedes the other manifestations of GLPLS [12].
Other presentations — A subtype of LPP that presents with hair loss in a

pattern similar to androgenetic alopecia has been described [34]. Histopathologic examination
reveals predominant involvement of vellus hair follicles. In contrast, classic LPP primarily involves
terminal hair follicles.
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CLINICAL COURSE Lichen planopilaris (LPP) is a chronic disorder
with an unpredictable course [15]. LPP may progress for months to years before stabilizing or may
continue to slowly progress over time. Occasionally, rapid and extensive hair loss occurs [35].
Data on prognostic factors for LPP are limited. The findings of a Spanish retrospective study of 355
patients with frontal fibrosing alopecia (FFA) suggest that patients with eyelash loss, facial papules,
or body hair involvement may be at increased risk for severe FFA [8]. Eyebrow loss as the initial
clinical presentation was associated with an increased likelihood for mild disease. Additional studies
are necessary to confirm these findings.
DIAGNOSIS The diagnosis of lichen planopilaris (LPP) is made based upon

physical examination and scalp biopsy.
Physical examination — The physical examination should include a

thorough examination of the scalp as well as the rest of the skin. The scalp examination may help to
narrow the differential diagnosis by detecting clinical signs that distinguish cicatricial alopecia
(absent follicular ostia) from noncicatricial alopecia (preserved follicular ostia), or by identifying
features characteristically associated with LPP (eg, patchy or frontal alopecia, perifollicular
inflammation, and follicular hyperkeratosis). The examination may also provide clues about disease
activity. (See "Evaluation and diagnosis of hair loss", section on 'Physical examination' and
'Therapeutic approach' below.)
Performance of a full skin examination allows for the detection of cutaneous or mucous membrane
findings of lichen planus, which can occur in patients with LPP. In addition, the skin examination may
reveal findings that suggest Graham-Little-Piccardi-Lasseur syndrome (GLPLS), rather than classic
LPP. (See 'Clinical presentation' above.)
Dermoscopy — Dermoscopy of the scalp (also known as trichoscopy) can yield

additional findings to support the diagnosis. Dermoscopic findings of perifollicular scale, white dots,
and reduced follicular ostia have been linked to LPP [36]. Common dermoscopic findings in frontal
fibrosing alopecia (FFA) include follicular hyperkeratosis and perifollicular erythema [8]. (See
"Overview of dermoscopy".)
Biopsy — A scalp biopsy is required to confirm a diagnosis of LPP.

Procedure — The choice of the biopsy site is critical. Inappropriate biopsy sites are unlikely
to yield diagnostic findings.
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Ideally, the biopsy should be taken from a hair-bearing area with clinical signs of active disease,
such as perifollicular inflammation and follicular hyperkeratosis. Some clinicians have found
dermoscopy useful for identifying an ideal biopsy site [37]. Areas of complete alopecia should be
avoided.
We typically perform two 4 mm punch biopsies in patients who have clinical findings suggestive of
LPP. The receipt of two punch biopsies, rather than a single biopsy, is preferred by many
dermatopathologists, as it allows for evaluation of the hair follicles in both horizontal and vertical
sections. If only one biopsy is performed, the tissue should be sectioned transversely. (See
"Evaluation and diagnosis of hair loss", section on 'Scalp biopsies'.)
Findings — Scalp involvement in classic LPP, frontal fibrosing alopecia (FFA), and GLPLS
demonstrates similar features. Typical pathology findings include (picture 3) [38,39]:
●Follicular plugging and wedge-shaped hypergranulosis involving the follicular epithelium
●Interface dermatitis involving the follicular infundibulum and isthmus (necrotic keratinocytes,
vacuolization of the basal layer, dense band-like lymphocytic infiltrate), often sparing the
interfollicular epithelium
●Perifollicular fibrosis surrounding the infundibulum and isthmus of the hair follicle in developed
lesions
●Loss of sebaceous glands in long-standing disease
●Vertical fibrous tracts replacing follicles in end-stage lesions

for lichen planopilaris (LPP) involving the scalp primarily includes other forms of cicatricial alopecia.
LPP should also be distinguished from alopecia areata, a nonscarring form of patchy alopecia.
The clinical and pathologic findings of active LPP are useful for distinguishing LPP from other
disorders. Inactive, end-stage classic LPP may be difficult or impossible to distinguish from other
inactive cicatricial alopecias.
Disorders commonly in the differential diagnosis of LPP include:
●Discoid lupus erythematosus – Discoid lupus erythematosus is one of the most common causes
of primary cicatricial alopecia. Patients with scalp involvement typically develop atrophic plaques
with follicular plugging and pigmentary alteration (picture 7A-B). Pathologic findings that suggest
discoid lupus erythematosus include a superficial and deep lymphocytic infiltrate and thickening of
the basement membrane. Direct immunofluorescence demonstrates deposition of IgG and IgM
along the basement membrane zone in some cases [38]. (See "Overview of cutaneous lupus
erythematosus", section on 'Discoid lupus erythematosus'.)
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●Pseudopelade of Brocq –Pseudopelade of Brocq is an idiopathic cicatricial alopecia that is
characterized by the presence of small skin-colored patches of alopecia on the scalp. Follicular
hyperkeratosis and erythema are minimal or absent. A biopsy reveals replacement of hair follicles by
bands of fibrous tissue [40]. Some authors have suggested that pseudopelade of Brocq may actually
represent the end stage of other forms of cicatricial alopecia [21].
●Central centrifugal cicatricial alopecia –Central centrifugal cicatricial alopecia is a primary

lymphocytic cicatricial alopecia that is primarily diagnosed in women of African descent. Alopecia
develops on the crown of the scalp and gradually progresses in a centrifugal manner to the parietal
areas (picture 8). Itching or tenderness may be present. Premature desquamation of the inner root
sheath is a key pathologic finding [41].
●Keratosis follicularis spinulosa decalvans –The follicular papules and cicatricial alopecia of
keratosis follicularis spinulosa decalvans (KFSD) should be distinguished from Graham-Little-
Piccardi-Lasseur syndrome (GLPLS). KFSD is a rare genetic disorder that initially presents in infancy
with follicular papules with keratotic spines on the scalp (picture 9A-B). Involvement of eyebrows,
eyelashes, and other hair-bearing areas may develop. Photophobia is a common finding that
supports the diagnosis of KFSD.
●Alopecia areata –Alopecia areata is a nonscarring form of alopecia that most commonly presents
with the acute development of round patches of alopecia on the scalp (picture 10A-B). Follicular
ostia remain within the areas of alopecia, consistent with a nonscarring process. Unlike LPP, which
demonstrates a lymphocytic inflammatory infiltrate centered around the follicular infundibulum and
isthmus, the lymphocytic infiltrate in alopecia areata is concentrated around the follicular bulb. (See
Frontal fibrosing alopecia (FFA) must be distinguished from androgenetic alopecia, which presents
with alopecia involving the frontal and vertex area of the scalp. The nonscarring nature of
androgenetic alopecia and the retention of vellus hairs in this condition are useful for distinguishing
androgenetic alopecia from FFA. Of note, the two disorders may be present simultaneously [8]. (See
diagnosis", section on 'Clinical manifestations' and "Androgenetic alopecia in men: Pathogenesis,
FFA also should be distinguished from traction alopecia, a form of transient or permanent hair loss
that results from chronic tension on hair follicles, such as can occur with hairstyles in which the hair
is tightly braided or otherwise pulled (picture 11). The frontal and temporal hairlines are common
sites of involvement, a feature that may contribute to confusion with FFA [42]. The patient history,
physical examination, and biopsy are useful for distinguishing between these disorders.
Perifollicular erythema and hyperkeratosis are not typical features of traction alopecia. Biopsies
from patients with traction alopecia reveal an increased number of catagen and telogen follicles in
early disease and scarring in late stage disease characterized by permanent hair loss [41].
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TREATMENT Although lichen planopilaris (LPP) is not a life-threatening
disorder, the associated symptoms and concern regarding the cosmetic effects of hair loss prompt
many patients to pursue treatment. As with other cicatricial alopecias, treatment is unlikely to induce
significant hair regrowth in areas of existing alopecia. Thus, the goals of treatment are to improve
patient symptoms and to arrest progression of the disease.
Patient selection — Treatment is most beneficial for patients with active LPP
because end-stage lesions are unlikely to respond to treatment. Patients often simultaneously
exhibit areas of active and inactive disease.
Active LPP on the scalp is suggested by the following findings:
●Perifollicular erythema and hyperkeratosis
●Progressive hair loss
●Symptoms (eg, itching, burning, or tenderness)
●Scalp biopsy demonstrating an inflammatory process consistent with LPP
Once a patient is considered a candidate for treatment, the expectations for treatment should be
thoroughly reviewed with him or her prior to initiating treatment. Because hair loss can cause
significant psychologic distress, an empathetic approach to communicating this information is
needed.
In general, we communicate the following concepts:
●There is no cure for LPP.
●The course of LPP is unpredictable; the condition may continue to slowly progress over time or
may become self-limited.
●Treatment is unlikely to induce hair regrowth in areas of existing alopecia.
●The primary goals of treatment are to prevent additional loss of hair and alleviate symptoms.
●The response to treatment is variable and multiple therapeutic trials may be needed to find the
most effective treatment.
●There are cosmetic measures that are helpful for camouflaging hair loss that does not improve
with treatment. (See 'Cosmetic measures' below.)
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Therapeutic approach — The best approach to the treatment of LPP is
unclear due to a paucity of high quality data on therapies for this disorder, the unpredictable clinical
course of LPP, and a lack of consistency in methods used to assess the response to treatment in the
literature. As a result of the uncertainty about treatment efficacy, recommendations for the
management of LPP vary. Our approach to the treatment of LPP is reviewed below.
Classic lichen planopilaris — The major treatment options for classic

LPP include local and systemic therapies. In most cases, local treatments are the initial therapeutic
choice due to the relative safety of these interventions. Systemic therapy is primarily used for
patients who fail to respond to local therapy or who initially present with rapidly progressive or
extensive disease. (See 'Second-line therapy' below and 'Refractory disease' below.)
First-line therapy — Topical corticosteroids and intralesional corticosteroid injection

are commonly utilized as first-line therapy for classic LPP [43]. Data are insufficient to determine the
comparative efficacy of these interventions.
We often combine topical corticosteroid and intralesional corticosteroid therapy in an attempt to

augment the response to treatment. However, the superiority of combination therapy is unproven.
Topical corticosteroids — Data on the efficacy of topical corticosteroids for LPP are
limited to case reports and retrospective case series that document improvement in some patients
[43]. A 2013 systematic review of the English language literature identified 79 patients with biopsy-
proven LPP who had documentation of their response to topical corticosteroid therapy [43]. The
review found author documentation of good, partial, and absent treatment responses in 53, 27, and
15 percent of patients, respectively.
The largest case series identified in the systematic review was a retrospective case series of 30
patients with LPP. Treatment with a topical corticosteroid (twice daily for three weeks, once daily for
three weeks, and every other day for approximately six weeks) was associated with clearing of
inflammation and inhibition of progression of cicatricial lesions in 20 patients (67 percent) [4]. Six
patients (20 percent) had a lesser degree of improvement, and four patients (13 percent) did not
appear to respond to therapy.
The best topical corticosteroid regimen for LPP is unknown. Our preference is to prescribe a high
potency or super high potency topical corticosteroid (table 1). We instruct patients to apply the
topical corticosteroid twice daily to areas of active disease. Once it appears that disease activity has
subsided, we slowly taper the frequency of application. If there is no evidence of a response to
topical corticosteroid therapy within four months, we consider alternative modes of treatment.
Cutaneous atrophy is a potential adverse effect of topical corticosteroids. However, the scalp is less
likely to develop cosmetically significant atrophy from topical corticosteroid use than many other
areas. Additional adverse effects of topical corticosteroids are reviewed in detail separately. (See
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Intralesional corticosteroids — The goal of intralesional injection of corticosteroids
is to inhibit inflammation through the delivery of corticosteroids directly to the site of inflammation
in the dermis. Only a few retrospective case series and case reports have evaluated intralesional
corticosteroid therapy for LPP [43]. The largest series, a retrospective case series of 20 patients
treated with intralesional corticosteroid injections documented good responses in 40 percent of
patients [44]. "Good" responders were required to demonstrate stabilization of disease with greater
than a minimal response to treatment, greater than minimal hair regrowth, and a greater than
minimal reduction in symptoms. Unstable disease with a lesser degree of improvement was
observed in 50 percent of patients, and 10 percent of patients worsened.
The authors of a separate retrospective case series that included seven patients treated with
intralesional corticosteroid injection did not document improvement in any patients, but also did not
report the measures used to assess response [7]. The regimen used for intralesional corticosteroid
therapy was not described in either series.
Our experience suggests that intralesional corticosteroid therapy can be beneficial. We find that
intralesional corticosteroids reduce clinical signs of inflammation significantly. We have also noticed
that symptoms such as tenderness, itching, and burning can improve after one or two sessions of
intralesional corticosteroid therapy.
Our typical treatment regimen consists of the injection of 10 mg/mL of triamcinolone acetonide (5
mg/mL for lesions in the frontal hairline) with a 30-gauge needle every four to six weeks into areas of
active disease. Active areas are most commonly found at the periphery of patches of alopecia [2,21].
Injections of approximately 0.1 mL are spaced approximately 1 cm apart within the involved area.
The target depth of injection into the skin is approximately 1 to 2 mm. The dose of triamcinolone
acetonide should not exceed 40 mg per treatment session. If a significant reduction of clinical signs
of inflammation and symptoms is not evident within four months, we transition to alternative
treatment.
A disadvantage of intralesional corticosteroid therapy compared with topical corticosteroid therapy

is the pain associated with treatment. However, most patients tolerate injections without the need for
anesthesia; topical anesthetics may be used for those patients who need them.
Intralesional corticosteroid therapy occasionally causes cutaneous atrophy that manifests as

indentations in the scalp. When this occurs, we discontinue treating the site of atrophy until it
resolves (usually several months). Other adverse effects of intralesional corticosteroid injection are
reviewed separately. (See "Intralesional corticosteroid injection", section on 'Side effects,
complications, and pitfalls'.)
Second-line therapy — Systemic therapy is usually reserved for patients who fail to
respond sufficiently to local corticosteroid therapy or for patients who initially present with rapidly
progressing or extensive disease. Commonly used systemic therapies for LPP include systemic
1607
glucocorticoids and hydroxychloroquine. Of note, there is only low quality evidence to support the
use of both therapies. Intralesional or topical corticosteroid therapy typically is continued during
systemic therapy.
Systemic glucocorticoids — Although systemic glucocorticoids are considered

useful for attaining rapid improvement in LPP, published data on the efficacy of systemic
glucocorticoids are limited [43]. A retrospective case series that included 11 patients treated with a
systemic glucocorticoid documented improvement in 9 patients (82 percent) [7]. The treatment
regimen and response criteria were not reported. Case reports have documented mixed results for
systemic glucocorticoid treatment [43].
Because of the serious adverse effect profile associated with long-term systemic glucocorticoid
treatment, systemic glucocorticoids are preferably used as short-term therapies for attaining
disease control. Relapse may be common following cessation of systemic glucocorticoids [7]; thus,
transitioning to an alternative topical or systemic therapy prior to discontinuation is prudent.
The optimal systemic glucocorticoid regimen for LPP has not been established. We typically treat
adults with oral prednisone at an initial dose of 1 mg/kg per day, with a plan to taper to
discontinuation over two to four months [45,46].
The adverse effects of systemic glucocorticoid therapy are reviewed in detail separately. (See "Major
side effects of systemic glucocorticoids".)
Hydroxychloroquine — Hydroxychloroquine is a non-immunosuppressive agent with

immunomodulatory properties. The generally well-tolerated nature of hydroxychloroquine
contributes to its frequent use for LPP.
Similar to other therapies for LPP, data on the efficacy of hydroxychloroquine are limited. A 2013
systematic review of the English literature found 71 patients with both biopsy-proven LPP and
documentation of their response to hydroxychloroquine [43]. The proportion of hydroxychloroquine-
treated patients who had documentation of good, partial, or absent responses to treatment were 23,
30, and 48 percent, respectively.
The rate of response of LPP to hydroxychloroquine has varied widely across studies, a finding likely
influenced by differences in patient population and assessment measures. Examples include:
●A retrospective study of adults with LPP that used a novel scoring system (LPP Activity Index
[LPPAI]) to assess symptoms and signs of LPP found that the majority of patients appeared to
benefit from hydroxychloroquine therapy, though most did not achieve complete remission [47]. At
assessments six and twelve months after starting treatment with hydroxychloroquine, patients were
classified as responders (>85 percent reduction in LPPAI), partial responders (25 to 85 percent
reduction in LPPAI) or nonresponders (<25 percent reduction in LPPAI). Among 27 patients with LPP
who were assessed at six months, 0, 70, and 30 percent were responders, partial responders, and
1608
nonresponders, respectively. After 12 months of treatment, the number of responders increased.
Among 29 patients assessed at 12 months, 14, 72, and 14 percent were responders, partial
responders, and nonresponders, respectively.
●A retrospective study that included 22 patients with LPP treated with hydroxychloroquine (6.5
mg/kg per day for 6 to 12 months) as initial treatment or after failure of doxycycline found that 9
patients (41 percent) had documentation of improvement during treatment [48]. Improvement was
defined as an absence of symptoms (pruritus, burning, and/or dysesthesia), lack of progression,
reduction in erythema and follicular hyperkeratosis, and an ability to discontinue therapy.
Lower rates of response to hydroxychloroquine have been reported in smaller series [7,15].
Hydroxychloroquine is typically prescribed for adults in a dose of 200 mg twice daily. At least two to
three months of treatment are often required to achieve initial signs of a response. Because of the
slow onset of action, systemic glucocorticoids are sometimes used as interim therapy.
Adverse effects of hydroxychloroquine include gastrointestinal distress, ocular toxicity, and

neurologic or hematologic abnormalities. The adverse effects of hydroxychloroquine and
recommendations for monitoring for ocular toxicity during hydroxychloroquine therapy are reviewed
separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse
effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye
examinations'.)
Refractory disease — Case reports and small series suggest that cyclosporine
[4,15,35] and mycophenolate mofetil may be useful for some patients with refractory LPP. These
therapies are typically reserved for refractory cases due to concern for their adverse effects and the
limited data in support of their efficacy.
Cyclosporine — A beneficial effect of cyclosporine on LPP was suggested in a report in

which three patients who failed to respond well to local corticosteroid therapy and
hydroxychloroquine had improvement in disease signs and symptoms as well as progression of hair
loss with three to five months of cyclosporine treatment (300 mg per day) [35]. Two patients
remained symptom-free 12 months after stopping therapy. In a subsequent series, 10 of 13 patients
with LPP were reported to have improvements in clinical and hair count assessments after treatment
with cyclosporine [15]. The authors observed that doses between 4 and 5 mg/kg per day and
treatment courses of four to five months seemed to yield the best responses. In this series, relapse
was common within the first year of treatment.
When treating patients with cyclosporine, we typically utilize doses between 3 and 5 mg/kg per day.
Our typical duration of treatment is 4 to 8 months, after which we monitor disease progression every
4 weeks for at least 12 months. Side effects of cyclosporine are reviewed separately. (See
"Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)
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Mycophenolate mofetil — Mycophenolate mofetil has a more benign side effect
profile than cyclosporine and a few reports suggest that the drug may be useful in some patients
with refractory disease. A retrospective case series documented the use of mycophenolate mofetil
(0.5 g twice daily for four weeks, then 1 g twice daily for at least 20 weeks) in 16 patients with LPP
who had failed one or more other systemic treatments [49]. Among the 12 patients who completed
at least 24 weeks of treatment (four patients withdrew due to mild adverse effects), 42 percent were
classified as complete responders (>85 percent improvement in LPP Activity Index [LPPAI] score), 42
percent were partial responders (25 to 85 percent improvement in LPPAI score), and 17 percent were
treatment failures (<25 percent improvement in LPPAI score).
In a separate series in which 10 patients with LPP were treated with mycophenolate mofetil after
failing to respond to hydroxychloroquine, 3 (30 percent) improved after treatment with
mycophenolate mofetil (defined by absence of symptoms, lack of progression, reduction in erythema
and follicular hyperkeratosis, and ability to discontinue therapy) [48].
Improvement with mycophenolate mofetil is usually apparent within the first six months of therapy
[49]. We usually treat adults with 1 g of mycophenolate mofetil twice daily. Adverse effects of
mycophenolate mofetil are reviewed separately.
Other therapies — Although improvement in LPP during oral pioglitazone therapy has
been reported in a case report, case series, and uncontrolled studies, relatively few of these patients
have achieved complete remission and further study is necessary to confirm efficacy of the drug [50-
53]. Additional treatments that have been reported to be effective in small numbers of patients with
LPP include tetracyclines [44,48], griseofulvin [7], minoxidil [44], naltrexone [54], and the 308 nm
excimer laser [55].
Treatment with oral retinoids has been attempted based upon reports of successful use of these
drugs for lichen planus [56]. However, there are few data to support their efficacy in LPP [43]. In
addition, the additional hair loss that can occur as a side effect of oral retinoids can be distressing
for patients who already have hair loss from LPP.
Frontal fibrosing alopecia — The best approach to the treatment of

frontal fibrosing alopecia (FFA) remains unclear. The response to topical corticosteroids has been
disappointing [43]. The response to intralesional corticosteroids, which are commonly used as first-
line treatment, is variable [8,10,43,57]. Systemic therapies that have been associated with at least
partial responses include hydroxychloroquine [8,11,47], finasteride [8], finasteride plus minoxidil [19],
dutasteride [8,58,59], and oral glucocorticoids [27].
Our typical first-line regimen consists of a combination of intralesional injection of triamcinolone

acetonide (2.5 to 5 mg/mL) every four to six weeks into areas of active disease, a mid-potency to
high-potency topical corticosteroid applied once daily, and topical minoxidil (5% solution or foam)
applied once daily. We instruct patients to apply minoxidil first. Once the site of application of
minoxidil is dry, application of the topical corticosteroid can follow.
1610
Graham-Little-Piccardi-Lasseur
syndrome — Compared with FFA, there are even fewer data to guide the management of
Graham-Little-Piccardi-Lasseur syndrome (GLPLS). Scalp involvement often fails to respond to
medical intervention. Responses to topical or intralesional corticosteroids, systemic glucocorticoids,
retinoids, and/or psoralen plus ultraviolet A (PUVA) phototherapy are variable [12,60]. Cyclosporine
(4 mg/kg per day) was linked to partial improvement in one patient [33].
COSMETIC MEASURES The cosmetic effects of scalp and

eyebrow hair loss from lichen planopilaris (LPP) can be psychologically distressing for patients.
Patients who are interested in reducing the visibility of hair loss can benefit from nonsurgical
cosmetic interventions and hair transplantation.
Products and techniques — Patients with LPP should be advised about

different possibilities of camouflaging hair loss. Options include hair styling techniques and the use
of hair pieces, wigs, hair powder, and hair color. A cosmetologist with experience in dealing with
patients with hair loss can be a valuable resource. Patients with eyebrow hair loss may benefit from
eyebrow tattooing, a form of permanent makeup.
Hair transplantation — Hair transplantation and scalp reduction are surgical

techniques that aim to restore hair coverage on the scalp. To achieve the best results, the patient
must have a sufficient amount of healthy scalp hair for donation and the inflammatory process must
be quiescent and stable prior to treatment. We perform a scalp biopsy from the margin of an
alopecic patch to confirm the absence of active inflammation before these procedures. Of note, LPP
has been reported to occur after hair transplantation surgery in patients without a history of LPP [61-
63].
Case reports suggest that patients with frontal fibrosing alopecia (FFA) are at risk for poor long-term
results from hair transplantation [64-66]. A retrospective study of 51 patients with FFA who
underwent hair transplantation found that although 42 (82 percent) reported satisfaction with the
procedure, mean graft survival rates after one, two, three, and five years were 87 percent (n = 51), 71
percent (n = 51), 60 percent (n = 38), and 41 percent (n = 12), respectively.
PATIENT SUPPORT The Cicatricial Alopecia Resource Foundation

(www.carfintl.org) is a useful resource for patient information and patient support.
SUMMARY AND
RECOMMENDATIONS
1611
●Lichen planopilaris (LPP) is an uncommon hair disorder that is classified as a primary lymphocytic
cicatricial alopecia and is considered a follicular variant of lichen planus. There are three major
variants of LPP: classic LPP, frontal fibrosing alopecia (FFA), and Graham-Little-Piccardi-Lasseur
syndrome (GLPLS). (See 'Introduction' above and 'Classification' above.)
●LPP most commonly occurs in adults. Women are more likely to be affected than men. Most
reported cases of FFA have occurred in postmenopausal women. (See 'Epidemiology' above.)
●The major clinical features of classic LPP are perifollicular erythema, perifollicular hyperkeratosis,
and skin-colored or erythematous patches of alopecia on the scalp (picture 1). Patients may
experience symptoms of itching, burning, or scalp tenderness. In addition, patients may have
accompanying cutaneous, mucosal, or nail findings of lichen planus. (See 'Classic lichen
planopilaris' above.)
●FFA is characterized by progressive, band-like frontotemporal hair loss that results in the
appearance of a receding frontal hairline (picture 2). Often, a few spared hairs can be found within
the area of alopecia ("lonely hair sign"). Eyebrow involvement is common. Patients may also exhibit
hair loss in the axillary, pubic, beard, or limb areas. (See 'Frontal fibrosing alopecia' above.)
●GLPLS is a rare variant of LPP that is defined by the presence of three features. Patients exhibit
cicatricial alopecia of the scalp, noncicatricial alopecia involving axillary and pubic hair, and a
lichenoid follicular eruption. (See 'Graham-Little-Piccardi-Lasseur syndrome' above.)
●The clinical course of LPP is unpredictable. The condition may stabilize or continue to slowly
progress over time. (See 'Clinical course' above.)
●The diagnosis of LPP is based upon the clinical examination and biopsy results (picture 3). A
biopsy should always be performed to confirm a diagnosis of LPP. Proper selection of the biopsy site
is crucial. (See 'Diagnosis' above.)
●There is a paucity of high-quality data on treatments for LPP resulting in uncertainty about the best
approach to patient management. For patients with active, slowly progressing classic LPP, we
suggest topical or intralesional corticosteroid therapy as initial treatment based upon limited data
that suggest efficacy in some patients and the relative safety of these therapies (Grade 2C). (See
'First-line therapy' above.)
●We treat classic LPP patients who fail to respond to local corticosteroid therapy or who present
with rapidly progressing disease or extensive disease with systemic therapy. Commonly used
treatments include systemic glucocorticoids and hydroxychloroquine. Patients with disease that is
refractory to these treatments may benefit from cyclosporine or mycophenolate mofetil. Additional
studies will be useful for confirming the efficacy of these and other systemic agents. (See 'Second-
line therapy' above and 'Refractory disease' above.)
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1613
Vulvar lichen planus - UpToDate
uptodate.com/contents/vulvar-lichen-planus/print
INTRODUCTION Lichen planus is a relatively uncommon inflammatory

dermatologic condition with subtypes that can affect the skin, mucosa, nails, and scalp. Vulvar
lichen planus is a subtype of lichen planus that is characterized by erosive, papular, or hypertrophic
lesions on the vulva, with or without concomitant vaginal involvement.
Erosive lichen planus (also known as mucosal lichen planus) can result in severe tissue destruction
that leads to vulvar pain and urinary and sexual impairment. Erosive lichen planus also can affect
other mucosal sites, such as the oral cavity, nasal mucosa, esophagus, larynx, conjunctiva, and
urethra [1].
High quality studies to guide treatment of vulvar lichen planus are lacking. Superpotent topical
corticosteroids are well accepted as the first-line treatment for erosive disease.
Vulvar lichen planus will be discussed here. Other clinical presentations of lichen planus are
reviewed separately. (See "Lichen planus", section on 'Clinical features' and "Oral lichen planus:
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EPIDEMIOLOGY Lichen planus is estimated to affect 0.5 to 2 percent of
the population; estimates have varied based upon geographic location and diagnostic criteria [2].
The incidence and prevalence of vulvar lichen planus has not been clearly established, but vulvar
disease may be a common manifestation of lichen planus in women. In one series of 37 women
diagnosed with lichen planus, vulvar lesions were present in 51 percent [3].
ETIOLOGY The etiology is unknown. The characteristic skin lesions of lichen

planus are thought to arise from a T-cell mediated autoimmune response against basal
keratinocytes. The disorder is often associated with other autoimmune diseases [4].
CLINICAL MANIFESTATIONS Vulvar lichen planus

often occurs in women 50 to 60 years of age, though younger and older women can be affected [5-
7]. Women with vulvar lichen planus frequently present with complaints of vulvar pain, burning,
pruritus, soreness, or dyspareunia (sometimes with post-coital bleeding) [8,9]. Another prominent
symptom that may be present is an irritating vaginal discharge that does not respond to standard
therapies for vaginitis. However, this clinical scenario is not specific to lichen planus, as it occurs
with other vulvar disorders (table 1).
The coexistence of vulvar lichen planus with cutaneous lichen planus, oral lichen planus, or lichen
planopilaris (including frontal fibrosing alopecia) is common (picture 1A-F) [3,10-12]. (See "Lichen
planus" and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Lichen
planopilaris".)
Signs and symptoms of vulvar lichen planus can be constant or intermittent. A minority of women
are asymptomatic or have only minimal symptoms [13].
Four types of lichen planus affect the vulva: erosive lichen planus, papulosquamous lichen planus,
hypertrophic lichen planus, and lichen planopilaris [3,14,15].
Erosive lichen planus — Erosive lichen planus is the most common type of
vulvar lichen planus seen in the secondary care setting. The desquamative, erosive, chronic
dermatitis often also involves the vagina. Recurrent exacerbations, slow healing, and scarring are
common. Scarring can cause significant anatomic disruption, including severe stenosis of the
vagina and urethral obstruction (picture 2). Dyspareunia, apareunia, difficulty with urination, and
dysuria are the major symptoms.
Lesions are characterized by well-demarcated, glazed, brightly erythematous patches or erosions

with white striae or a serpentine, white border along the margin (Wickham striae) (picture 3A-B).
Occasionally, a violaceous border is noted. The lesions may occur on the labia minora and vestibule
1615
as isolated lesions on an otherwise normal vulva, or they may be associated with marked
architectural destruction, including loss of the labia minora and narrowing of the introitus. Small,
localized lesions on the labia majora are less common [13]. Anal involvement is rare [16].
●Vaginal involvement – Vaginal involvement has been reported in up to 70 percent of patients with
erosive lichen planus; in contrast, vaginal involvement is rare in lichen sclerosus [17,18] (see "Vulvar
lichen sclerosus"). The vaginal epithelium in lichen planus is friable, easily bleeding upon speculum
insertion or with coitus. It may have small areas of inflammation and increased vaginal discharge, or
it may be massively inflamed and denuded with a seropurulent exudate, pseudomembrane, or
serosanguinous vaginal discharge [13,19]. In severe cases, adhesions and synechiae develop, which
can lead to narrowing or obliteration of the vagina.
Vaginal involvement can occur in the absence of any vulvar involvement, and vaginal
synechiae/adhesions can form in the absence of any symptomatology if the patient is not sexually
active or menstruating. The Papanicolaou smear may show atypia if the cervix is affected [20].
●Vulvo-vaginal-gingival syndrome – The vulvo-vaginal-gingival (VVG) syndrome is a variant of

erosive lichen planus that involves the epithelium of the vulva, vestibule, vagina, and mouth (picture
4); additional sites (eg, skin, esophagus) may also be involved [19,21-24]. Although all three areas
can be affected, the lesions may not be concurrent. The gingival epithelium is usually involved, and
erosions, white plaques, or a whitish and lace-like reticular pattern may occur on the buccal mucosa,
tongue, and palate. Scarring and stricture formation are common and a major cause of long-term
morbidity [24]. VVG is particularly resistant to treatment.
Erosive lichen planus also can affect other mucosal sites, such as the nasal mucosa, esophagus,
larynx, conjunctiva, and urethra; concomitant involvement in these sites is often missed [1]. (See
'Clinical evaluation' below.)
Papulosquamous lichen planus — Papulosquamous lichen

planus consists of small, intensely pruritic papules with a violaceous hue that arise on keratinized
and perianal skin. It is associated, occasionally, with milky striae on the inner aspects of the labia
[25]. Resolution of papulosquamous lesions is often followed by postinflammatory
hyperpigmentation [5].
Hypertrophic lichen planus — Hypertrophic lichen planus

characteristically exhibits hyperkeratotic, rough lesions on the perineum and perianal region (picture
5) [13]. The appearance is similar to vulvar intraepithelial neoplasia or invasive squamous cell
carcinoma. This type of lichen planus is rare and can be difficult to diagnose clinically because it
resembles other hypertrophic vulvar lesions [25].
Lichen planopilaris — Lichen planopilaris is an uncommon follicular variant of

lichen planus that presents with perifollicular erythema and hyperkeratosis as well as scarring
alopecia. It typically presents on the scalp; however, a patient with lichen planopilaris on the labia
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majora and mons pubis has been reported [15]. (See "Lichen planopilaris".)
DIAGNOSIS
Clinical evaluation — The diagnosis of the erosive and papulosquamous
variants of vulvar lichen planus is primarily based upon the recognition of characteristic clinical
manifestations. Erythematous erosions with a glazed appearance on the vulva demonstrating
Wickham striae (white striae within involved areas or a serpentine white border) are highly
suggestive of erosive lichen planus and pruritic violaceous papules are consistent with the
papulosquamous variant, particularly when accompanied by papulosquamous lichen planus in other
body sites and postinflammatory hyperpigmentation. However, a biopsy of lesions suspicious for
erosive vulvar lichen planus or papulosquamous vulvar lichen planus should be obtained to rule out
other disorders if there is any uncertainty regarding the clinical diagnosis [9]. A biopsy is usually
indicated in patients with suspected hypertrophic lichen planus because this variant can closely
resemble squamous cell carcinoma. (See 'Biopsy' below.)
In addition to examination of the vulva and vagina, the physical examination of patients with
suspected vulvar lichen planus should include an evaluation of other mucosal and cutaneous
surfaces, including the oral cavity, scalp, nails, anus, and entire skin surface. Patients with vulvar
lichen planus frequently have other manifestations of lichen planus, and the detection of lichen
planus in other body areas increases suspicion for the diagnosis (picture 1A-F). Examination of the
oral cavity also allows for the detection of patients with the vulvo-vaginal-gingival (VVG) syndrome.
(See "Lichen planus", section on 'Clinical features' and 'Erosive lichen planus' above.)
The clinical evaluation should also include a review of systems for signs or symptoms suggestive of
involvement of hidden mucosal areas, such as the nasal mucosa, esophagus (eg, dysphagia,
odynophagia), larynx (eg, hoarseness, stridor), conjunctiva (eg, foreign body sensation or visual
changes), urethra (eg, hematuria, dysuria), and anus. Erosive lichen planus in these areas often is
not recognized, and can result in functional impairments if untreated.
Biopsy — A biopsy is usually recommended for vulvar lichen planus, particularly in the
erosive and hypertrophic forms of disease. Patients with classic clinical features of
papulosquamous lichen planus (ie, small, violaceous, pruritic papules) may not require a biopsy for
confirmation. (See 'Clinical manifestations' above.)
The identification of classic histologic features of lichen planus in biopsy specimens from patients
with clinical features suggestive of vulvar lichen planus confirms the diagnosis. Classic histologic
features of lichen planus include:
●Irregular acanthosis of the epidermis (in sites of keratinized skin)
●Vacuolar change of the epidermal basal cell layer
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●A band–like dermal infiltrate of lymphocytes in the upper dermis
●Apoptotic keratinocytes scattered within the epidermis
In addition, plasma cells are often present in biopsy specimens from mucosal lesions.
However, the failure to detect classic histologic features of lichen planus in patients with vulvar
disease does not rule out the diagnosis. Classic histologic features of lichen planus are identified in
only 70 to 80 percent of patients with vulvar lichen planus [7,11,26].
A 4 mm punch biopsy of an involved area is performed to obtain tissue for histologic examination. In
patients with erosive disease, typical features of lichen planus are most likely to be found at the
margins of ulcers [27]. Therefore, a specimen taken from a site of erosive disease should include
intact epithelium adjacent to the ulcer. (See "Skin biopsy techniques".)
Immunofluorescence studies are typically reserved for erosive presentations in which an

autoimmune blistering disease is in the differential diagnosis. If performed, direct
immunofluorescence of vulvar lichen planus may show shaggy staining of the basement membrane
zone, suggesting deposition of fibrinogen, IgM, cytoid bodies, and, occasionally, granular IgG or IgA
[28].
Proposed diagnostic criteria — Although additional study is

necessary to validate diagnostic criteria for the various presentations of vulvar lichen planus, the
lack of a defined set of diagnostic criteria stimulated a 2012 electronic Delphi consensus exercise
that attempted to identify the important diagnostic features of erosive lichen planus of the vulva
through a series of surveys administered to a multidisciplinary group of 73 experts in vulvovaginal
disease [9]. The following nine criteria were identified by at least 75 percent of the participants as
findings supportive of a diagnosis of the disease:
●Presence of well-demarcated erosions or glazed erythema at the vaginal introitus
●Presence of a hyperkeratotic white border to erythematous areas or erosions ± Wickham striae in

surrounding skin
●Symptoms of pain or burning
●Scarring or loss of normal architecture
●Presence of vaginal inflammation
●Involvement of other mucosal sites
●Presence of a well-defined inflammatory band in the superficial connective tissue that involves the
dermoepidermal junction
●Presence of an inflammatory band that consists predominantly of lymphocytes
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●Signs of basal cell layer degeneration (eg, Civatte bodies, abnormal keratinocytes, or basal
apoptosis)
There was some disagreement among participants about whether at least three supportive features
or at least four supportive features are required for a diagnosis of erosive lichen planus of the vulva.
One study of 72 women with erosive vulvovaginal lichen planus found that 97 percent had at least
three of the nine diagnostic criteria [29]. Further study may be useful for identifying the ideal
diagnostic criteria for this disease.
DIFFERENTIAL DIAGNOSIS Other inflammatory and

erosive diseases of the vulva may mimic lichen planus. Some examples include:
●Lichen sclerosus causes architectural distortion and labial adhesions, but unlike vulvar lichen
planus, rarely affects the vagina. The classic presentation consists of white, atrophic papules or
plaques on the vulva that may become hemorrhagic, purpuric, hyperkeratotic, bullous, or eroded
(picture 6A-B). Erosive lesions due to lichen sclerosus respond to therapy better than those related
to lichen planus. (See "Vulvar lichen sclerosus".)
●Autoimmune bullous diseases (eg, mucous membrane pemphigoid and pemphigus) can have
clinical vulvovaginal features identical to erosive lichen planus; immunofluorescence studies on
biopsy specimens are necessary to make a definitive diagnosis [30]. (See "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Plasma cell vulvitis is an uncommon erosive disease that results in tender, velvety, raised
erythematous lesions of the vestibule and, rarely, the clitoris; oral and vaginal involvement are
unusual (picture 7) [31-33]. On histologic examination, plasma cells contribute to one-half of the
dermal infiltrate.
●Desquamative inflammatory vaginitis (DIV) is an intensely inflammatory vaginitis, also called

lichenoid vaginitis. The purulent vaginal discharge has an elevated pH and consists of sheets of
white blood cells and parabasal cells, indicative of desquamating vaginal epithelium. There may be
bacterial overgrowth, except for Lactobacillus, which is reduced or absent. Whether DIV is a form of
lichen planus [34] or caused by an unidentified bacterium [35] is controversial. (See "Approach to
females with symptoms of vaginitis".)
●Vulvar lichen planus can be confused clinically and pathologically with vulvar intraepithelial
neoplasia (VIN), differentiated type [36]. (See "Vulvar intraepithelial neoplasia".)
●Behçet syndrome causes recurrent oral and genital ulcerations and ocular inflammation (picture
8). These three major criteria are often associated with the minor criteria of arthritis,
thrombophlebitis, acneiform skin eruptions, ulcerative colitis, and neurologic involvement [37]. (See
"Clinical manifestations and diagnosis of Behçet syndrome".)
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●Crohn's disease may affect the vulva or perineum; the vulvar manifestations may precede or follow
bowel involvement by many years. Vulvar signs of Crohn's disease include edema of the labia
majora, labia minora, and prepuce; edematous perianal skin tags; ulcers; fissures; sinuses; and
fistulae (picture 9). Vulvar edema may be an isolated and unilateral finding [38]. (See "Perianal
Crohn’s disease".)
●Erythema multiforme and Stevens-Johnson syndrome produce lesions of the mouth, eye, and
genitals consisting of painful, shallow ulcers and bullae on the labia and surrounding skin. The acute
onset helps to differentiate this disorder from erosive lichen planus. (See "Erythema multiforme:
Pathogenesis, clinical features, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal
●A lichenoid drug eruption can be indistinguishable clinically and histologically from lichen planus
[39]. A positive history of medication use and disappearance of skin lesions following withdrawal of
the medication suggest this possibility. (See "Lichenoid drug eruption (drug-induced lichen planus)".)
●Genitourinary syndrome of menopause (vulvovaginal atrophy or atrophic vaginitis) is common in

peri- or postmenopausal women, in women with hypoestrogenism, and may coexist in women with
vulvar lichen planus. The clinical features can be similar to erosive lichen planus; however,
hyperkeratosis and Wickham striae are not evident. Histology should not show any of the features of
lichen planus. (See "Clinical manifestations and diagnosis of genitourinary syndrome of menopause
(vulvovaginal atrophy)".)
NATURAL HISTORY The oral and genital lesions of lichen planus,

especially erosive disease, are persistent and tend to be resistant to therapy [3,40]. In contrast, the
natural history of most cases of cutaneous lichen planus elsewhere on the body is spontaneous
remission within a couple of years. (See "Lichen planus".)
Associated malignancy — The relationship between lichen planus and

squamous cell malignancy is uncertain; the best evidence is for an association between oral
malignancy and oral lichen planus, which causes chronic inflammation of the oral mucosa [41]. A
systematic review of observational studies that included 7806 patients with oral lichen planus (and
no dysplasia on initial biopsy) found an overall transformation rate of approximately 1 percent [41].
A slightly increased risk of vulvar malignancy in women with vulvar lichen planus has been
postulated, but not confirmed in large series [42-48].
Vulvar squamous cell carcinoma that develops in patients with vulvar lichen planus may
demonstrate aggressive features. In a retrospective study of 38 women diagnosed with both vulvar
lichen planus and vulvar squamous cell carcinoma, inguinal metastases were present at the time of
presentation in 16 women (42 percent) and squamous cell carcinoma was the cause of death in 14
women (37 percent) [49]. All cancers in this series arose in non-hair-bearing vulvar mucosa and the
1620
majority were in the vestibular area between the clitoris and urethra. Although data are insufficient to
determine the impact of early and aggressive treatment of vulvar lichen planus on the risk for
malignancy, data from this study highlight the vulvar sites of highest risk [49].
MANAGEMENT Data on the treatment of vulvar lichen planus are limited.

The approach to treatment is largely guided by uncontrolled studies and reports of clinical
experience.
Erosive vulvar lichen planus — The physical discomfort and

disfigurement that result from erosive vulvar lichen planus justify a treatment approach aimed at
rapidly reducing signs and symptoms of the disease. Consultation with a clinician experienced in the
assessment and treatment of patients with erosive vulvar lichen planus often is of value for the
management of patients with this disease.
Adjunctive measures — Although medical therapy is the mainstay of treatment of

vulvar lichen planus, other interventions play important roles in patient management.
●Patient education and support –Although patients with vulvar lichen planus can experience
periods of remission with treatment, there is no cure. Clinicians should educate patients about the
chronic course of vulvar lichen planus and the need for continued treatment after symptoms
improve. Patients who understand the expected course of the disease may be more likely to adhere
to clinical follow-up and prescribed treatments. Written, patient-directed information and referral to
local or national patient support groups can be a useful supplement to verbal communication.
In addition, because vulvar lichen planus can be emotionally distressing and can have a significant
negative effect on patient quality of life [50], addressing the psychologic and emotional concerns of
the patient is an important component of treatment. Resources for psychologic support or
counseling should be provided if needed.
●Vulvar care –Factors that irritate the vulvar skin may exacerbate symptoms. In addition to
discouraging scratching of the vulva, we encourage patients to engage in vulval hygiene practices
that may reduce risk for irritation. Our recommendations for vulvar hygiene reviewed in a table (table
2).
●Review of medications – Lichenoid drug eruptions (also known as drug-induced lichen planus) are
cutaneous or mucosal eruptions that clinically and histologically resemble idiopathic lichen planus
and occur as a result of drug exposure. Lichenoid drug eruptions have been associated with a wide
variety of medications and may occur weeks to several months or longer after initiation of the
causative medication [51]. Most of the literature on lichenoid drug eruptions focuses on cutaneous
lichenoid drug eruptions (the most common form of lichenoid drug eruption) and oral lichenoid drug
eruptions. There is a paucity of data on drug-induced lichenoid eruptions of the vulva leaving
uncertainty about the relationship between drugs and this presentation of disease. (See "Lichenoid
drug eruption (drug-induced lichen planus)".)
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Based upon the known association of drugs with lichenoid eruptions of the skin and oral mucosa,
we routinely review the medications of patients diagnosed with vulvar lichen planus to determine
whether drugs that have been associated with lichenoid eruptions are present. Drugs that have been
linked to lichenoid eruptions are reviewed separately. (See "Lichenoid drug eruption (drug-induced
lichen planus)", section on 'Medications'.)
If it is feasible to discontinue a drug that has been linked to lichenoid drug eruptions, we proceed
with a trial of drug cessation [52]. Oral lichenoid drug reactions typically resolve within weeks to
months after the inciting drug is stopped although delayed responses may occur [53]. We have
treated several women with erosive vulvar lichen planus refractory to topical therapy who
experienced improvement in symptoms after the discontinuation of NSAIDs or hydrochlorothiazide.
We have also observed the development of flares of vulvar lichen planus during NSAID treatment.
First-line therapy — The treatment of erosive lichen planus of the vulva (with or
without vaginal involvement) is challenging. The paucity of data on the efficacy of treatments for
lichen planus precludes definitive conclusions about the best approach to therapy. Most commonly,
treatment is initiated with a superpotent topical corticosteroid ointment, a generally well-tolerated
local therapy.
However, other approaches to initial treatment may be reasonable. In patients presenting with severe
disease, where application of topical therapy would be intolerable, systemic glucocorticoid therapy
may also be used. Other clinicians have advocated using systemic glucocorticoid therapy more
routinely [54].
Topical corticosteroids — Although topical corticosteroids are the mainstay of therapy

for erosive vulvar lichen planus [8] and have demonstrated efficacy for oral lichen planus in a
randomized trial [55], randomized trials in vulvar lichen planus are lacking.
Efficacy — The use of topical corticosteroid therapy is supported by the findings of an

uncontrolled prospective study of 114 women with erosive lichen planus of the vulva [7]. In the
study, a variety of topical corticosteroid therapies were used for initial treatment, with most patients
receiving either clobetasol 0.05% ointment or a combined preparation containing clobetasone
butyrate, oxytetracycline, and nystatin. Of the 89 women who received clobetasol 0.05% ointment as
a first-line treatment, 94 percent experienced good or partial symptomatic improvement and 71
percent had complete resolution of symptoms during treatment. Good responses were also
observed among patients treated with the combined preparation; good or partial improvement
occurred in all 14 treated women, and 13 women became symptom free during treatment.
Retrospective studies also suggest that topical corticosteroid is effective in some patients; however,
treatment regimens and reported success rates have varied widely [6,56,57]. In one retrospective
study a response to treatment was documented in 85 of 129 patients (66 percent) treated with a very
potent topical corticosteroid as first-line therapy. The measures used to define response were
unclear.
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Administration — Our topical corticosteroid regimen for vulvar lichen planus consists of an
initial treatment course to induce remission followed by a plan for long-term maintenance therapy
with a less intense treatment regimen. Our typical treatment plan is as follows:
●The patient performs nightly application of a super high-potency topical corticosteroid (eg,
clobetasol propionate 0.05% ointment or halobetasol propionate 0.05% ointment (table 3)) to the
affected area. As a guide, half of one finger-tip-unit (the amount of ointment expressed from a tube
with a nozzle of 5 mm in diameter, applied from the distal skin-crease to the tip of the index finger)
should be sufficient to cover both labia majora and minora and the perianal skin.
●The patient returns for clinical reevaluation of the response after two to three months:
•If there is satisfactory improvement (ie, symptom resolution and healing of all erosions), we
commence maintenance therapy
•If no improvement is evident after eight weeks with persistent erosions, treatment with a systemic
glucocorticoid or systemic glucocorticoid-sparing agent may be required. (See 'Refractory disease'
below.)
Maintenance therapy is necessary after remission is achieved because symptoms often recur once
treatment is discontinued. The goal of the maintenance phase is to maintain improvement while
reducing the frequency and potency of topical corticosteroid treatment to minimize risk for local
corticosteroid side effects. This is performed as a stepwise process that eventually reveals the
lowest dose and frequency that sustains remission.
The first step in the transition to a maintenance regimen is usually the reduction of the frequency of
application of the superpotent topical corticosteroid from application every night to application every
other night. Treatment is tailored to the patient's response; most patients need to continue
application of a topical corticosteroid one to three times per week indefinitely [25]. Consultation with
a dermatologist can be helpful for managing topical corticosteroid therapy. Lower-potency topical
corticosteroids may also be utilized, as can combination preparations containing both a topical
corticosteroid and an antimicrobial. (See "Topical corticosteroids: Use and adverse effects".)
If relapse occurs during the maintenance phase, we restart treatment with a superpotent topical
corticosteroid nightly, as in the initial course of treatment. Once the disease is in remission, we taper
the frequency and potency of treatment to the lowest effective maintenance regimen.
Skin atrophy is a potential side effect of topical corticosteroid therapy that is most likely to occur
with the use of high-potency topical corticosteroids on areas of relatively thin skin; however, the
vulvar area is relatively resistant to corticosteroid side effects. The least intense topical
corticosteroid regimen for long-term maintenance treatment is preferred. The adverse effects of
topical corticosteroids are reviewed in greater detail separately. (See "Topical corticosteroids: Use
and adverse effects", section on 'Adverse effects'.)
1623
Second-line therapy — Topical tacrolimus (a topical calcineurin inhibitor) is an
alternative local therapy that is used in the treatment of vulvar lichen planus. Similar to topical
corticosteroids, high quality data on the efficacy of topical tacrolimus for this indication are lacking.
Topical tacrolimus — Topical tacrolimus may improve vulvar lichen planus via its
immunosuppressive properties. Potential disadvantages of topical tacrolimus therapy include
greater cost in comparison to some topical corticosteroids and the frequent occurrence of local
burning or tingling sensations with application of this therapy [26]. However, burning sensations
often resolve with continued use of this therapy [26].
Efficacy — Support for the use of topical tacrolimus for erosive vulvar lichen planus primarily
stems from retrospective studies and case reports [6,26,58-60]. As an example, a telephone
questionnaire administered to 16 patients whose records indicated that they received topical
tacrolimus for erosive vulvar lichen planus after failure to respond to other therapies revealed that 15
patients (94 percent) recalled symptomatic improvement within three months (mean response time
4.2 weeks) and noted partial or complete resolution of lesions [26]. In addition, of 13 patients who
returned for clinical follow-up, review of medical records indicated that 10 patients had no clinical
evidence of erosions on examination.
No randomized trials have compared the efficacy of topical tacrolimus and topical corticosteroids in
erosive vulvar lichen planus. The results of one small retrospective study suggested greater patient
satisfaction after treatment with topical tacrolimus than after treatment with topical clobetasol;
however, additional studies are needed to validate this finding [60]. There are few data on the
efficacy of topical pimecrolimus, an additional topical calcineurin inhibitor [6,61]. The findings of a
small series suggest that topical pimecrolimus may be beneficial [61].
Administration — Clinicians vary on the approach to topical tacrolimus therapy. Our

instructions for use of topical tacrolimus aim to minimize the burning sensation that may occur early
in the course of treatment. Although most of the literature on topical tacrolimus therapy for vulvar
lichen planus describes the use of tacrolimus 0.1% ointment, we usually initiate treatment with
tacrolimus 0.03% ointment in an attempt to improve tolerance. We begin with every other day
treatments, gradually working up to twice daily as tolerated. Daily sitz baths for the first week of
therapy or application of topical tacrolimus on top of a layer of petrolatum or a topical corticosteroid
ointment for the first few weeks of treatment also can help alleviate burning.
We typically reevaluate patients for initial signs of a response to treatment after one to two months,
and if the 0.03% formulation is tolerated, the dose can be increased to 0.1% ointment. Once
remission is achieved, the frequency of application is gradually reduced to a maintenance regimen,
which in some patients may be application one to three times per week [60].
Severe erosive lichen planus — Patients who present with severe erosive
vulvar lichen planus that prevents the application of topical therapy due to pain may benefit from an
alternative initial approach to treatment. In our experience, initiating treatment with a systemic
1624
glucocorticoid can be beneficial for these patients.
We prescribe a four- to six-week course of oral prednisone (40 to 60 mg per day, tapered over four to
six weeks) and commence topical corticosteroid therapy after one week [62]. Twice-daily sitz baths
in water followed by the application of a greasy emollient (such as petroleum jelly) may also help
restore the epithelial barrier.
An alternative approach is the use of intramuscular triamcinolone. Intramuscular triamcinolone (1

mg/kg) may be given as a single dose or as a series of injections separated by one month.
Although systemic glucocorticoid therapy can improve erosive vulvar lichen planus, systemic
glucocorticoids are associated with a wide variety of adverse effects that make long term treatment
with these agents unfavorable. The adverse effects are reviewed in detail separately. (See "Major
side effects of systemic glucocorticoids".)
Refractory disease — There are few data to guide the treatment of patients who fail
topical therapy, manifested by persistent painful erosions or tender lacy papules and plaques. Prior
to considering an alternative approach to treatment we assess for factors that may exacerbate
symptoms or inhibit healing, including:
●Incorrect application of topical medication
●Exposure to skin irritants or nighttime scratching
●Superinfection by bacteria, Candida, or herpes simplex virus (see 'Treatment of concurrent infection'
below)
●Vulvar pain that persists despite clinical resolution of vulvar lichen planus (this may indicate
neuropathic pain possibly precipitated by lichen planus [63]) (see "Treatment of vulvodynia (vulvar
pain of unknown cause)")
If an exacerbating factor responsible for the persistence of symptoms is not identified, treatment
with systemic agents can be attempted. A variety of systemic immunomodulatory and
immunosuppressive agents (eg, methotrexate, mycophenolate mofetil, oral or intramuscular
glucocorticoids, hydroxychloroquine, acitretin, minocycline, cyclosporine, and others) have been
utilized in individual patients [54,57,64], but data are insufficient to confirm efficacy of specific
interventions.
Vaginal involvement — Similar to vulvar disease, our first-line treatment for vaginal
involvement is local administration of a corticosteroid.
Intravaginal corticosteroids — Corticosteroids are administered vaginally to women

with vaginal involvement. In one case series, 16 of 17 patients noted improvement with
hydrocortisone 25 mg suppositories inserted into the vagina twice daily for two months [65]. In
1625
another series of 60 patients treated with 25 mg hydrocortisone suppositories, 80 percent improved
[66].
Treatment will be guided by the medications available in the country of practice. In our experience,
prednisolone foam (20 mg metered dose as an aerosol foam) or hydrocortisone acetate 10% foam
(125 mg metered dose) prescribed on alternate nights at bedtime for six weeks can be effective.
Subsequently, treatment is reduced to a maintenance regimen of the lowest dose that controls
symptoms (usually one to two applications per week).
Where hydrocortisone suppositories are available, these may be prescribed nightly at bedtime for 14
days (50 mg for early and mild disease or 100 mg for severe disease), followed by applications on
alternate nights for an additional 14 days. The dose is then tapered to find the lowest maintenance
dose that controls symptoms, which may be as low as 25 mg every other week.
Of note, medication that leaks from the vagina may cause vulvar irritation and burning. The vulvar
skin can be protected by coating the perivaginal area with petroleum jelly or zinc oxide, or a tampon
can be cut in half and inserted in the distal vagina as a "plug" to control leakage.
Other therapies — The best approach to the treatment of severe vaginal lichen planus that
fails to respond to intravaginal corticosteroids unclear. If the response to topical corticosteroid
therapy is insufficient, oral or intramuscular glucocorticoids and tacrolimus suppositories are
additional therapeutic options for vaginal involvement.
●Oral or intramuscular glucocorticoids – Either oral prednisone 40 to 60 mg daily, tapered over four
to six weeks, or intramuscular triamcinolone, 60 to 80 mg once per month for three to four months,
may be tried before local maintenance therapy is initiated.
Systemic glucocorticoid therapy may exacerbate underlying medical disorders, such as diabetes
and hypertension. Coordination of care with the patient's primary care clinician may be beneficial.
(See "Major side effects of systemic glucocorticoids".)
●Tacrolimus– An alternative to systemic glucocorticoids is compounded tacrolimus 2 mg

suppositories nightly for 30 days. Once symptoms improve, treatment is gradually tapered to the
lowest frequency sufficient to maintain disease control. Monitoring tacrolimus drug levels is
unnecessary with topical therapy.
Adhesions and scarring — Vulvar or vaginal involvement by lichen planus can

lead to anatomic distortion and functional limitations secondary to the formation of adhesions and
scarring. Dilators and surgery can be useful for improving these complications after mucosal
inflammation is controlled with medical therapy. Follow-up care is necessary to maintain benefit
after these procedures.
●Dilators – Dilator therapy (with rigid dilators) can be effective for distending mild to moderate
vaginal synechiae that interfere with intromission or speculum insertion. We determine the correct
dilator size during an office visit and show the patient how to insert it and then have her demonstrate
1626
that she can perform the insertion. Application of topical 5% lidocaine around the vaginal orifice 15
minutes before insertion and application of a lubricant such as petrolatum to the dilator can be
helpful.
In our experience, the dilator should be used several times per week, for 5 to 10 minutes, with the
woman gently rotating the dilator during this time. Once she can comfortably insert the dilator at
home (typically after about three months of regular use), she should commence using the next larger
size of dilator. Medical maintenance therapy for vaginal lichen planus (eg, intravaginal
hydrocortisone) should be continued during dilator treatment.
Once satisfactory vaginal dilatation has been achieved, use of a dilator can be continued two to
three times weekly to maintain a patent, functional vagina. Women who are able to resume weekly
intercourse may be able to stop dilator use.
●Surgery – Severe vaginal synechiae require surgical release. All surgical approaches to vaginal
occlusion must be followed by diligent therapy with dilators, topical therapy to maintain control of
the inflammation of lichen planus, topical estrogen, and topical corticosteroids. Isolated vaginal
procedures without this follow-up therapy invariably result in recurrent vaginal occlusion [25].
Although topical estrogen has no therapeutic role in treatment of the lichen planus, its contribution
to epithelial integrity of the vagina cannot be underestimated. Many women with lichen planus are
postmenopausal, making the estrogen an important adjunct to restore suppleness, elasticity and
moisture to the area.
Emerging therapy — Photodynamic therapy (PDT) may be an emerging treatment

option for vulvar and vaginal lichen planus. A observer-blinded randomized trial that compared one
session of vulvovaginal hexyl 5-aminolevulinate hydrochloride (HAL)-PDT to daily application of
clobetasol propionate 5% ointment (with or without intravaginal hydrocortisone acetate 1% foam) in
40 women with genital erosive lichen planus found similar mean reductions in clinical scores in the
PDT and corticosteroid groups after six weeks (25 versus 22 percent) [67]. PDT is painful; all
patients were sedated during treatment. Additional study is needed to confirm the efficacy of PDT.
Treatment of hypertrophic and

papulosquamous lichen planus — Hypertrophic and
papulosquamous lichen planus involving the vulva is more responsive to therapy than erosive lichen
planus. A two-week course of a moderate or superpotent topical corticosteroid, as described above,
usually results in complete remission or significant improvement of the disease. The adjunctive
measures used for erosive vulvar lichen planus are also employed for hypertrophic and
papulosquamous disease. (See 'Adjunctive measures' above.)
Hyperkeratotic lesions may fail to respond well to topical corticosteroids due to the limited ability of
the drugs to penetrate a thickened stratum corneum. We have found intralesional corticosteroid
therapy useful for these cases. The procedure is similar to that used for vulvar lichen sclerosus. (See
"Vulvar lichen sclerosus", section on 'Topical corticosteroids'.)
1627
Treatment of vulvo-vaginal-gingival
syndrome — Vulvovaginal disease is treated as discussed above. Treatment of oral
lesions is reviewed separately. (See "Oral lichen planus: Management and prognosis".)
Treatment of concurrent infection — An associated bacterial

or fungal infection should be treated with antimicrobials concurrently with corticosteroid therapy.
Antibiotic selection should be based upon culture and sensitivity results. We prescribe oral
fluconazole for vulvar candidiasis to avoid the irritant effects of topical creams. (See "Candida
vulvovaginitis: Treatment", section on 'Recurrent treatment'.)
OUTCOME Most women report improvement or resolution of symptoms with initial

therapy [6,7,66]. Symptomatic improvement corresponds with healing of erosions and reticulation on
physical examination, but scarring is not reversible. As an example, a series in which 89 women with
erosive lichen planus of the vulva were treated with 0.05% clobetasol ointment reported 71 percent
had a good response, 24 percent had a partial response, and 5 percent had a poor response to initial
treatment [7]. The response rate was similar during maintenance therapy. A reliable estimate of the
efficacy of second-line therapies could not be made because each agent was used by only one to
seven patients.
Burning and itching that persist after therapy and despite the clinical appearance of skin
improvement suggest superimposed vulvar pain (see "Treatment of vulvodynia (vulvar pain of
unknown cause)"). Symptoms with characteristic skin changes suggest relapse.

provided separately. (See "Society guideline links: Lichen planus" and "Society guideline links: Vulvar
dermatitis".)

1628
SUMMARY AND
RECOMMENDATIONS
●Lichen planus refers to a relatively uncommon inflammatory dermatologic condition that may be
generalized or isolated to the vulva. (See 'Introduction' above.)
●The four types of vulvar lichen planus are erosive lichen planus, papulosquamous lichen planus,
hypertrophic lichen planus, and lichen planopilaris. Clinical manifestations include irritating vaginal
discharge, vulvar soreness, intense pruritus, burning, and dyspareunia. A few patients are
asymptomatic or have only minimal symptoms. (See 'Clinical manifestations' above.)
●Erosive lichen planus is the most severe form of vulvar lichen planus and can result in marked
architectural destruction, including loss of the labia minora and narrowing of the introitus. The
vagina is often involved, as well. (See 'Erosive lichen planus' above.)
●The diagnosis of vulvar lichen planus is based upon the presence of characteristic clinical
manifestations and biopsy findings. A biopsy is recommended for all patients with suspected
erosive or hypertrophic lichen planus. (See 'Diagnosis' above.)
●The management of all chronic vulvar disorders requires patient education, behavioral
modification, support, and medication. (See 'Adjunctive measures' above.)
●For most women with erosive vulvar lichen planus, we suggest a superpotent topical corticosteroid
for first-line therapy (table 3) (Grade 2C). Patients who present with severe erosive vulvar lichen
planus that prevents the application of topical therapy may be given oral or intramuscular
glucocorticoids as initial therapy. (See 'Erosive vulvar lichen planus' above.)
●For women with vaginal lichen planus, we suggest intravaginal corticosteroids given as foam or
suppositories as first-line therapy (Grade 2C). Other therapeutic options include tacrolimus
suppositories and systemic glucocorticoid therapy. (See 'Vaginal involvement' above.)
●Vaginal involvement with lichen planus can lead to the formation of adhesions and scarring. After
mucosal inflammation is controlled with medical therapy, dilators and surgery can be useful for
improving these complications. Surgery is necessary for the treatment of severe vaginal synechiae.
(See 'Adhesions and scarring' above.)
1629
to acknowledge Elizabeth G Stewart, MD, who contributed to an earlier version of this topic review.
1630
Oral lichen planus: Pathogenesis, clinical features, and
diagnosis
uptodate.com/contents/oral-lichen-planus-pathogenesis-clinical-features-and-diagnosis/print
INTRODUCTION Lichen planus (LP) is a chronic inflammatory disorder

that affects the skin and mucous membranes. Oral LP is a mucosal subtype of LP that most
commonly occurs in middle-aged adults. Oral LP may occur alone or in conjunction with other forms
of LP (picture 1A-C). (See "Lichen planus", section on 'Clinical features'.)
The clinical findings of oral LP range from reticular white plaques to mucosal erythema, erosions,
ulceration, and hyperkeratotic plaques (picture 2A-C). Although reticular lesions are often
asymptomatic, pain frequently accompanies the other manifestations of oral LP.
The pathogenesis, clinical manifestations, and diagnosis of oral LP will be reviewed here. Discussion
of the management of oral LP and reviews of other forms of LP are provided separately. (See "Oral
lichen planus: Management and prognosis" and "Lichen planus" and "Lichen planopilaris" and
"Vulvar lichen planus" and "Overview of nail disorders", section on 'Lichen planus' and "Lichenoid
drug eruption (drug-induced lichen planus)".)
EPIDEMIOLOGY Epidemiologic data on oral lichen planus (LP) vary.

Population-based studies performed in Asia, Europe, North America, and the Middle East have found
disease prevalence rates between less than 1 percent and 3 percent [1].
1631
Oral LP most commonly occurs in middle-aged adults. Large retrospective studies from Europe and
the United States indicate that the average age of patients presenting with oral LP is around 50 to 60
years [2-4]. Oral LP is rare in children [5-9].
In contrast to cutaneous LP, which is more likely to occur in men than women, women may be more
likely to develop oral LP than men [1-3,10-13]. In a retrospective study of 723 patients with oral LP
seen in an outpatient dermatology office in the United States, 75 percent of the patients were women
[2]. Moreover, a retrospective study of 808 patients referred to an oral medicine department in Italy
found that 60 percent of the patients were women [3].
PATHOGENESIS The pathogenic mechanisms that lead to oral lichen

planus (LP) are not fully understood.
Inciting factors — A common theory on the pathogenesis of oral LP is that an

immune reaction against an exogenous or endogenous antigen triggers the onset of an aberrant
immune response to an intrinsic skin antigen and the onset of the disease. Exposures to infections,
trauma, drugs, and contact allergens as well as autoimmune disorders and abnormal histamine
metabolism and transport in oral keratinocytes have been proposed as potential contributing factors
[14,15]. However, a causative role for any of these factors in oral LP is unconfirmed.
In particular, the relevance of hepatitis C virus in the pathogenesis of LP is uncertain. An increased

prevalence of hepatitis C virus infection among patients with LP has been detected in numerous
geographic locations, such as southern Europe and Japan [16,17]. Some Italian studies have
identified the HLA-DR6 allele as a potential risk factor for hepatitis C virus-associated oral LP [18,19].
Other studies have not found an association [20]. The relationship between LP and the hepatitis C
virus is discussed in greater detail separately. (See "Lichen planus", section on 'Hepatitis C virus'.)
Although associations between oral LP and thyroid disease [21] and oral LP and dyslipidemia [22]
have been reported, definitive links between oral LP and these disorders are not established.
Mechanism — Oral LP is considered to be a T cell-mediated chronic inflammatory

tissue reaction that results in a cytotoxic reaction against epithelial basal cells [14]. The
inflammatory infiltrate in oral LP is primarily composed of CD8+ T cells. A potential pathway for CD8+
T cell-mediated cytotoxicity in oral LP is described below [14]:
●CD8+ T cells are activated by antigens presented on MHC 1 molecules on keratinocytes or by

encounters with activated CD4+ helper T cells or cytokines produced by activated CD4+ helper T cells
●Activated CD8+ T cells induce keratinocyte apoptosis through mechanisms such as secretion of
tumor necrosis factor (TNF)-alpha, secretion of granzyme B, or Fas-Fas ligand interactions
●Activated CD8+ T cells produce chemokines that attract additional inflammatory cells, thereby
promoting continued inflammation
1632
Other factors that have been proposed as contributors to oral LP include the upregulation of matrix
metalloproteinases that disrupt the epithelial basement membrane zone and allow entry of immune
cells into the epidermis, the release of proinflammatory mediators and proteases by mast cells, and
perturbations in the innate immune response that may involve toll-like receptors [14,23-25].
Genetic factors — Genetic factors that influence immune function may contribute
to oral LP. An Italian study found a significant increase in a genetic polymorphism of the first intron
of the interferon (IFN)-gamma promoter in patients with oral LP compared with controls [26]. A
separate study performed in China found an association between a polymorphism in the TNF-alpha
gene and risk for oral LP in a subset of patients [27].
CLINICAL MANIFESTATIONS Oral lichen planus

(LP) may be divided into three clinical subtypes: reticular, erythematous (atrophic), and erosive
[2,28,29]. More than one subtype of oral LP may be present in an individual patient.
Clinical subtypes — Reticular oral LP is the most common manifestation. It often

occurs in conjunction with erythematous or erosive disease. As an example, in a retrospective study
of 723 patients with oral LP, erythematous and erosive manifestations were the predominant
findings in 37 and 40 percent of patients, respectively [2]. In almost all cases, reticular disease also
was present. The remaining 23 percent of patients had isolated reticular oral LP.
●Reticular oral LP –Reticular oral LP is usually asymptomatic and characterized by the presence of
white lines, papules, or plaques in a reticulated or lacy pattern on the oral mucosa (picture 2A, 2D-E).
The term "Wickham's striae" is often used to describe this clinical presentation. Large, painful,
hyperkeratotic plaques on the tongue are a less common manifestation [2,28].
●Erythematous oral LP –Erythematous oral LP typically occurs in conjunction with reticular lesions.
Areas of mucosal atrophy, appearing as red patches among the white papules, patches, or plaques
of reticular LP are usually present (picture 2C).
●Erosive oral LP –Erosive oral LP is characterized by erosions or frank ulcers (picture 2B). Rarely,
bullae that easily rupture occur. Lesions consistent with erosive oral LP are usually accompanied by
both reticular and erythematous lesions (picture 3) [29].
The manifestations of oral LP are usually seen bilaterally and in a symmetric distribution. The most
common site of involvement for reticular oral LP is the posterior buccal mucosa [30]. Other common
sites of reticular oral LP are the labial mucosa, tongue, and vermillion of the lower lip (picture 4).
Gingival oral LP typically presents as prominent erythema. Infrequently, lesions develop on the
palate, floor of the mouth, or upper lip.
Desquamative gingivitis, a term which refers to the development of widespread erosions on the
gingiva, may be seen in a variety of inflammatory mucosal disorders, including oral LP (picture 5).
Around 10 percent of patients with oral LP have isolated gingival disease [31].
1633
Unlike reticular LP, which is often asymptomatic, the erythematous and erosive forms of oral LP are
typically accompanied by symptoms. Patients may note pain, a burning sensation, swelling, or
irritation, and may experience mucosal bleeding in response to mild trauma, such as toothbrushing
[29]. Additional clinical findings that may be noted in oral LP include the Koebner phenomenon (the
development of new lesions at sites of trauma) and mucoceles [32,33].
Residual postinflammatory hyperpigmentation, manifesting as brown to black pigment on the oral

mucosa, has been reported in association with oral LP, and may be most likely to occur in dark-
skinned individuals [34]. Lesions of erosive LP may resolve with scarring.
Extraoral findings — Oral LP may occur in isolation or in conjunction with other

clinical manifestations of LP, including cutaneous LP, genital LP, nail LP, and lichen planopilaris
(scalp LP). As an example, a retrospective study of 584 patients with oral LP found cutaneous LP,
nail LP, and lichen planopilaris were present in 16, 2, and 1 percent of patients, respectively [35].
Genital involvement was detected in 77 of 399 examined women (19 percent) and 8 of 174 men (5
percent). Brief descriptions of these extraoral forms of LP are provided below:
●Cutaneous LP – Cutaneous LP is typically characterized by the appearance of polygonal,

violaceous, pruritic papules on the trunk or extremities (picture 1A, 1D-E). Oral LP is common among
individuals with cutaneous LP. It is estimated that more than 50 percent of individuals with
cutaneous LP also have oral lesions [28,36]. (See "Lichen planus", section on 'Clinical features'.)
●Lichen planopilaris – Lichen planopilaris is a form of scarring alopecia characterized by atrophic

plaques and subtle follicular hyperkeratosis (picture 1B). (See "Lichen planopilaris".)
●Nail LP – Nail involvement in LP may manifest as grooves or ridges in the nail plate
(trachyonychia) (picture 1C) or with onycholysis and pterygium formation (picture 6) [37]. (See
"Overview of nail disorders", section on 'Lichen planus'.)
●Genital (vulvar, vaginal, or penile) LP – The clinical findings of vulvar LP include erythema,
erosions, white reticulated plaques, and scarring (picture 7) [38,39]. Lesions may be asymptomatic,
pruritic, or painful, and may be accompanied by dysuria or dyspareunia. Annular lesions are a
common manifestation of penile LP (picture 8A-B). The terms "vulvovaginal-gingival syndrome" and
"peno-gingival syndrome" describe patients who have both genital LP and gingiva-predominant oral
LP [40,41]. (See "Vulvar lichen planus", section on 'Clinical manifestations'.)
Rarely, LP involves the ocular, nasal, laryngeal, esophageal, anal, or ear mucosa. Involvement of
these areas may lead to scarring that results in functional limitations. Patients with ocular
involvement usually present with symptoms of erythema and irritation of the palpebral and bulbar
conjunctiva, which can eventually progress to a cicatrizing conjunctivitis and blindness (picture 9)
[42,43]. LP of the nasal mucosa usually presents with erythema and erosions; reticular findings are
rare. Laryngeal involvement may initially present with hoarseness [44], and esophageal involvement
1634
may be associated with dysphagia or odynophagia [45]. Anal erythema, erosions, or papules may be
noted in patients with anal LP [41]. Involvement of the external auditory canals with erosive LP
leading to conductive deafness has been reported [46].
DIAGNOSIS A diagnosis of oral lichen planus (LP) is confirmed through review of

the patient history, physical examination, and histologic findings.
Clinical evaluation — The clinical evaluation should include a patient history

that assesses the following:
●History of LP involving other body sites or other skin disorders that may present with similar
findings (eg, autoimmune blistering diseases)
●Presence of associated symptoms (eg, pain, burning)
●Presence of symptoms suggestive of other sites of mucosal involvement (eg, dysphagia,

hoarseness, stridor, ocular irritation, dysuria, dyspareunia, hematuria)
●Medication list to evaluate for the possibility of an oral lichenoid drug eruption (may occur weeks to
months after drug initiation) (table 1)
●History of dental restorations, use of dental appliances, or oral exposure to substances that may
cause oral lichenoid contact eruptions (table 2)
A full examination that includes the evaluation of the mucosal and cutaneous surfaces, including the
vulva, vagina, penis, scalp, and nails should be performed. Thorough examination may lead to the
detection of extraoral manifestations of LP that provide additional support for the diagnosis or the
identification of clinical findings that suggest another diagnosis. In addition, the presence of dental
restoration materials (eg, amalgam fillings) that could contribute to a lichenoid contact reaction
should be noted. (See 'Extraoral findings' above and 'Differential diagnosis' below.)
Biopsy — Tissue biopsies of oral LP help to confirm the diagnosis and are particularly of
value for erythematous and erosive LP, which share features with multiple other mucosal disorders,
including oral malignancy. Thus, we biopsy all patients who exhibit features of these subtypes.
Biopsies to confirm oral LP are less essential in patients who present with classic reticular LP,
particularly in patients in whom a diagnosis of LP has already been confirmed through biopsy of an
extraoral manifestation of this disorder.
A 4 mm punch biopsy of lesional tissue that extends into the submucosa usually provides a
sufficient specimen for histologic examination [47,48]. If reticular LP is present in conjunction with
erythematous or erosive manifestations, biopsy of the reticular area is preferred for diagnosis of oral
LP. Biopsies taken from reticular areas have intact epithelium and may be less likely to yield
1635
nonspecific findings [2]. However, erythematous or erosive lesions should be biopsied when
considering possible malignancy transformation. (See "Oral lichen planus: Management and
prognosis", section on 'Risk of oral squamous cell carcinoma'.)
The histologic findings of oral LP can offer strong support for the diagnosis, but are not
pathognomonic. Clinical correlation is required. Common histologic findings of oral LP include
(picture 10A-B) [28]:
●Parakeratosis and slight acanthosis of the epithelium
●Saw-toothed rete ridges
●Liquefaction degeneration of the basal layer with apoptotic keratinocytes (referred to as Civatte,
colloid, hyaline, or cytoid bodies)
●An amorphous band of eosinophilic material at the basement membrane
●A lichenoid (band-like) mixed lymphohistiocytic infiltrate in the submucosa
In cases where the clinical and histologic findings are inconclusive, direct immunofluorescence (DIF)
microscopy of perilesional mucosa is used to exclude autoimmune vesiculobullous disorders (eg,
pemphigus, pemphigoid, linear IgA bullous dermatosis). In oral LP, DIF usually demonstrates
globular deposits of IgM in the submucosa. (See "Clinical features and diagnosis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Direct immunofluorescence'.)
Additional evaluation — Additional tests may be ordered based upon

clinical suspicion for other conditions. The possibility of Candida infection or herpes simplex virus
reactivation should be considered in patients who experience acute exacerbations of disease
severity despite previously effective treatment. Erosions or ulcers that fail to resolve or exhibit
atypical features should be biopsied to rule out malignancy. (See "Clinical manifestations of
oropharyngeal and esophageal candidiasis", section on 'Diagnosis' and "Epidemiology, clinical
manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis' and
"Oral lichen planus: Management and prognosis", section on 'Risk of oral squamous cell carcinoma'.)
Screening for hepatitis C virus infection in patients with LP is reviewed separately. In general, it
appears reasonable to screen patients with oral LP for hepatitis C virus infection. (See "Lichen
planus", section on 'Additional testing'.)
DIFFERENTIAL DIAGNOSIS An evaluation to

determine the underlying cause of red or white oral lesions should be performed in all patients who
present with such lesions. The differential diagnosis of oral lichen planus (LP) is particularly broad,
given the various clinical manifestations of the condition (see 'Clinical subtypes' above). Careful
review of the patient history, examination findings, and biopsy results is useful for distinguishing oral
LP from other disorders.
1636
Select disorders in the differential diagnosis of oral LP are reviewed below:
●Leukoedema – Leukoedema is a common, benign finding in the oral cavity that presents as white-
gray, somewhat translucent plaques on the mucosa (picture 11) [49,50]. The buccal mucosa is the
most common site for involvement. Symptoms are absent, and no treatment is necessary.
●Oropharyngeal candidiasis – Oropharyngeal candidiasis (also known as thrush) is a common

infection that has a predilection for infants, older adults with dentures, immunosuppressed
individuals, and individuals utilizing intraoral corticosteroid therapy. Patients present with white
plaques or erythematous patches on the buccal mucosa, palate, tongue, or oropharynx that may be
mistaken for reticular LP (picture 12A-C). The diagnosis can be made quickly by performing a
potassium hydroxide (KOH) preparation. Oropharyngeal candidiasis may coexist with oral LP as a
result of topical corticosteroid therapy. (See "Clinical manifestations of oropharyngeal and
esophageal candidiasis", section on 'Oropharyngeal candidiasis' and "Office-based dermatologic
diagnostic procedures", section on 'Potassium hydroxide preparation'.)
●Leukoplakia – Leukoplakia is a manifestation of squamous epithelial hyperplasia that may be a

precursor to oral squamous cell carcinoma. White patches or plaques develop on the oral mucosa
(picture 13A-B). A biopsy of leukoplakia is indicated to rule out malignancy. (See "Oral lesions",
section on 'Leukoplakia' and "Oral leukoplakia", section on 'Introduction'.)
●Oral squamous cell carcinoma – Oral squamous cell carcinoma can present as erythematous or
white patches, ulcers, or exophytic masses (picture 14). A biopsy is useful for diagnosis. (See "Oral
lichen planus: Management and prognosis", section on 'Risk of oral squamous cell carcinoma' and
"Oral lesions", section on 'Oral squamous cell carcinoma'.)
●Oral lichenoid drug reaction – Lichenoid drug eruptions may be caused by a variety of systemic
medications (table 1) and share clinical features with oral LP. Histologic findings of a deep mixed
infiltrate with lymphocytes, plasma cells, and neutrophils (with or without eosinophils) and
perivascular inflammation favor this diagnosis [28]. (See "Lichenoid drug eruption (drug-induced
lichen planus)".)
●Oral lichenoid contact reaction (allergic contact mucositis) – Oral lichenoid contact reactions may
be caused by a variety of substances (table 2). Mercury-containing amalgam used for dental
restoration is the most common cause [28]. The clinical and histologic features of oral lichenoid
contact reactions are similar to oral LP [51]. Patch testing and recognition of the proximity of an
offending substance to the eruption can aid with diagnosis.
●Autoimmune blistering diseases – Mucous membrane pemphigoid and other autoimmune

blistering diseases may present with oral erosions and desquamative gingivitis similar to that seen
in erosive LP. Biopsies for routine histologic examination and direct immunofluorescence are useful
for distinguishing these disorders from oral LP. (See "Clinical features and diagnosis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Clinical features' and "Linear IgA
1637
bullous dermatosis", section on 'Mucosal involvement' and "Epidermolysis bullosa acquisita", section
on 'Clinical manifestations' and "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus".)
●Graft-versus-host disease –Lacy, reticulated plaques or erosions that resemble oral LP may occur
in chronic graft-versus-host disease (GVHD) (picture 15A-C). The histologic findings of these
disorders are also similar. The patient history is useful for differentiating chronic GVHD from oral LP.
Oral involvement in acute GVHD is less well characterized than chronic GVHD, but has been
associated with erythematous, erosive, ulcerative, or lichenoid oral lesions [52]. (See "Cutaneous
manifestations of graft-versus-host disease (GVHD)", section on 'Chronic cutaneous graft-versus-
host disease' and "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on
'Acute cutaneous graft-versus-host disease'.)
Examples of other disorders that may present with oral white plaques include syphilis (picture 16),
oral hairy leukoplakia (picture 17), oral condyloma (picture 18), and white sponge nevus (picture 19).
Additional disorders in the differential diagnosis of erythematous and erosive oral LP include
aphthous stomatitis (picture 20), erythroplakia (picture 21), and syphilis (picture 22).


SUMMARY AND
RECOMMENDATIONS
1638
●Oral lichen planus (LP) is a subtype of LP that most commonly occurs in middle-aged adults.
Women are more likely to develop oral LP than men. Individuals of all ethnic backgrounds may be
affected. (See 'Epidemiology' above.)
●The pathogenesis of oral LP is not fully understood, but appears to involve an immune-mediated
cytotoxic reaction against epithelial cells. Activated CD8+ T cells may play a key role. The inciting
factors for oral LP are unknown. (See 'Pathogenesis' above.)
●The clinical findings of oral LP can be divided into reticular, erythematous (atrophic), and erosive
subtypes. Many patients with reticular LP also have erythematous or erosive lesions. The buccal
mucosa is the most common site for reticular oral LP. Nonspecific erythema is prominent on the
gingiva. (See 'Clinical manifestations' above.)
●Oral LP may occur as the only manifestation of LP or in conjunction with other features of the
disorder. Oral LP is common among individuals with cutaneous LP, and many women with oral LP
have associated genital (vaginal or vulvar) involvement. (See 'Extraoral findings' above.)
●Patients with oral LP may have involvement of other mucosal surfaces, which can result in
functional limitations if untreated. Thus, the patient evaluation should include inquiries regarding the
presence of ocular, nasal, laryngeal, esophageal, or anogenital symptoms. (See 'Extraoral findings'
above and 'Diagnosis' above.)
●The diagnosis of oral LP can usually be made based upon the review of clinical and histologic
findings. Direct immunofluorescence is helpful for ruling out autoimmune blistering diseases that
involve the mucosa in challenging cases. (See 'Diagnosis' above.)
1639
Oral lichen planus: Management and prognosis
uptodate.com/contents/oral-lichen-planus-management-and-prognosis/print
INTRODUCTION Oral lichen planus (oral LP) is a mucosal subtype of LP

that presents with a variety of clinical features. Patients may develop reticular oral LP (white papules
and plaques), erythematous (atrophic) oral LP (mucosal atrophy and red patches), and/or erosive
oral LP (erosions or ulcers) (picture 1A-B). Although reticular LP is usually asymptomatic, pain
typically accompanies the erythematous and erosive forms of oral LP. The discomfort associated
with these last two clinical subtypes is the reason why many patients seek treatment.
The management and prognosis of oral LP will be reviewed here. The diagnosis of oral LP and
information on other manifestations of LP are discussed separately. (See "Oral lichen planus:
Pathogenesis, clinical features, and diagnosis" and "Lichen planus" and "Vulvar lichen planus" and
"Lichen planopilaris" and "Overview of nail disorders", section on 'Lichen planus' and "Lichenoid drug
eruption (drug-induced lichen planus)".)
APPROACH TO TREATMENT Since there is no cure

for oral LP, the primary goals of treatment are the alleviation of symptoms and the minimization of
scarring from erosive lesions. Patients with asymptomatic reticular oral LP do not require treatment.
1640
Oral LP is managed with a combination of nonpharmacologic and pharmacologic measures, with
some variability in the therapeutic approach based upon patient-specific factors (eg, disease extent,
tolerance to treatment, comorbid disease) and treatment availability. In general, local therapy is
preferred over systemic therapy to minimize the risk of serious adverse effects related to treatment.
Topical corticosteroids are the first-line local treatment; additional options for local therapy include
topical calcineurin inhibitors and intralesional corticosteroid injections. Systemic therapy is primarily
reserved for patients who fail to respond sufficiently to local therapy or for patients with both oral LP
and extraoral mucosal involvement.
An important component of patient management is the recognition of ocular, laryngeal, esophageal,

or vulvovaginal LP. Patients with signs or symptoms suggestive of such involvement should be
referred to an appropriate specialist (ophthalmologist, otolaryngologist, gastroenterologist, or
gynecologist) for an evaluation and the coordination of care. (See "Oral lichen planus: Pathogenesis,
clinical features, and diagnosis", section on 'Extraoral findings'.)
Additional study is necessary to determine the role of direct-acting antiviral therapy for hepatitis C
virus (HCV) infection in the treatment of oral LP. In an uncontrolled study, all seven patients with
HCV-associated oral LP improved with daclatasvir-asunaprevir given for HCV infection, with
resolution occurring in four patients [1]. However, worsening of oral LP during treatment of HCV with
ledipasvir-sofosbuvir is documented in a case report [2]. (See "Overview of the management of
chronic hepatitis C virus infection", section on 'Antiviral therapy'.)
NONPHARMACOLOGIC
MEASURES Several nonpharmacologic measures may help to reduce morbidity
associated with oral LP. Exposure to factors that may exacerbate the disease should be minimized.
We typically encourage the following:
●Maintenance of good oral hygiene (brushing twice daily, flossing daily, professional dental cleaning
every three to four months)
●Elimination of mechanical irritation from dental restorations, dental appliances, or sharp or

malaligned teeth
●Avoidance of habits that cause trauma (eg, chewing on lips or mucosa)
●Cessation of smoking or use of smokeless tobacco
●Reduced consumption of acidic, salty, spicy, hot, sharp, or rough foods
Patients with oral LP may find maintenance of oral hygiene challenging due to the discomfort
elicited during oral care. However, the accumulation of dental plaque and calculus may cause local
irritation and exacerbation of oral LP (Koebner phenomenon) [3,4]. Patients with significant gingival
1641
involvement may be especially prone to periodontal disease [5]. (See "Overview of gingivitis and
periodontitis in adults".)
We instruct patients to brush their teeth twice daily with a soft bristle toothbrush and bland
toothpaste (ie, unflavored or at least devoid of mint or cinnamon flavoring). Use of a sonic
toothbrush may provide effective cleaning while minimizing discomfort and tissue trauma. In
addition, colorimetric plaque indicators may facilitate the identification of plaque that should be
removed during brushing [6].
Patients should be instructed to floss once daily with unflavored dental floss or tape. Professional
dental cleanings should be performed every three to four months.
FIRST-LINE THERAPY
Topical corticosteroids — Topical corticosteroids are the first-line
treatment for oral LP [7-11]. High potency or medium potency topical corticosteroids (potency
groups 1 to 3) are typically used (table 1) [7,12-17].
Efficacy — The efficacy of topical corticosteroids for oral LP was evaluated in a small
placebo-controlled randomized trial. In the nine-week trial, 40 patients with reticular and/or erosive
oral LP were treated with either a group 3 potency topical corticosteroid (a 0.025% concentration of
fluocinonide in an adhesive base) or placebo. Both substances were applied at least six times per
day [14]. Among the 20 patients treated with fluocinonide, four (20 percent) had complete responses
and 12 (60 percent) had good or partial responses to therapy. In contrast, no complete responses
and only six partial responses (30 percent) occurred in the placebo-treated patients.
Beneficial effects of treatment with topical corticosteroids have also been reported in several
randomized trials that have compared individual corticosteroid therapies [12,15-18]. A systematic
review of randomized trials that evaluated the efficacy of treatments for reducing pain due to oral LP
found insufficient evidence to conclude superiority of any specific topical corticosteroid therapy
[8,19].
Administration — We usually prescribe a high potency topical corticosteroid, such as

clobetasol propionate 0.05%, fluocinonide 0.05%, or betamethasone propionate 0.05% gel or
ointment, and instruct patients to dry the affected areas (with gauze) prior to application. The topical
corticosteroid is applied three to four times per day using a fingertip or cotton-tipped applicator (eg,
Q-tip). Eating or drinking should be avoided for at least 30 minutes after application. As symptoms
improve, the frequency of application is reduced as tolerated.
Gingival trays may facilitate treatment for patients with significant gingival involvement (picture 2)
[20]. Oral elixirs or suspensions (eg, 5 mL of dexamethasone [0.5 mg/5 mL] used as a mouth rinse
up to six times per day) are an option for patients with widespread oral disease and patients who
1642
have difficulty applying topical corticosteroids to the affected areas [21].
Topical corticosteroids have also been formulated in adhesive dental bases with the intent of
augmenting the response to treatment. However, superior efficacy of these formulations is not
proven [22,23].
Side effects — Oropharyngeal candidiasis is a common side effect of intraoral topical

corticosteroid use that can be prevented or treated with antifungal therapy [7,24]. In a small
randomized trial, the addition of prophylactic miconazole to clobetasol therapy did not affect the
efficacy of treatment and was associated with a lower rate of oropharyngeal candidiasis [24]. (See
"Clinical manifestations of oropharyngeal and esophageal candidiasis", section on 'Oropharyngeal
candidiasis' and "Treatment of oropharyngeal and esophageal candidiasis", section on
'Oropharyngeal candidiasis'.)
We monitor patients closely for symptoms and signs of candidiasis and perform confirmatory
testing (usually with a potassium hydroxide [KOH] preparation) when the diagnosis is suggested. If a
fungal culture is performed, the results should be carefully correlated with the clinical presentation
since oral colonization with Candida species is common [25].
To minimize the risk of oral candidiasis, patients with dental appliances should remove them
overnight. In addition, appliances should be soaked twice daily for 20 minutes in dilute (0.02%)
sodium hypochlorite solution, 0.12% chlorhexidine gluconate, or nystatin suspension (100,000
units/mL) [21].
Systemic absorption of intraoral topical corticosteroids may be related to the extent of erosive
disease, pharmacologic characteristics of the corticosteroid (ie, potency), and/or patient utilization
practices (ie, quantity, frequency of use). A pilot study of triamcinolone acetonide 0.1% in the
treatment of 20 patients with oral LP demonstrated no systemic absorption over four weeks of use
[26]. However, systemic absorption of intraoral topical corticosteroids has been documented [27]
and may rarely result in systemic adverse effects, including adrenal suppression [28]. The risk for
adrenal suppression in patients treated for oral LP appears to be low [29]. (See "Topical
SECOND-LINE THERAPY Treatment options for patients

who fail to respond to topical corticosteroids or who cannot tolerate topical corticosteroid therapy
(eg, allergic contact mucositis, recurrent oropharyngeal candidiasis) include topical calcineurin
inhibitors (pimecrolimus, tacrolimus, and cyclosporine) and intralesional corticosteroids. A
disadvantage of topical calcineurin inhibitors is the higher cost in comparison with topical
corticosteroids. Intralesional corticosteroid injection can be painful, may require multiple office
visits, and has little available data on treatment efficacy.
1643
Topical pimecrolimus and tacrolimus — The topical
calcineurin inhibitors pimecrolimus and tacrolimus are effective for oral LP [30,31]. Randomized
trials that have compared the efficacy of these agents with topical corticosteroids indicate that
pimecrolimus 1% can be at least as effective as triamcinolone 0.1% [32] and tacrolimus 0.1% can be
at least as effective as clobetasol 0.05% [33-35]. Pimecrolimus has not been directly compared with
clobetasol or any other superpotent topical corticosteroid (table 1). A systematic review of
randomized trials failed to find conclusive evidence of superiority of either class of agents for
reducing pain due to oral LP [8,19].
Efficacy — Efficacy data on topical pimecrolimus and topical tacrolimus are reviewed below:
●Pimecrolimus– The efficacy of pimecrolimus in oral LP is supported by small randomized placebo-
controlled trials [36-38]. In a randomized trial in which 20 adults with erosive oral LP were treated
with either pimecrolimus 1% or a vehicle cream twice daily for 30 days, 7 of 10 patients in the
pimecrolimus group achieved complete clearance or marked improvement of lesions compared with
only 2 of 10 patients in the vehicle group. In addition, a significantly greater reduction in the disease
severity score was detected in the treatment group. The three patients who had not responded to
pimecrolimus at the 30-day time point all achieved major improvement after an additional 30 days of
treatment.
The efficacy of four times daily application of pimecrolimus 1% cream and triamcinolone acetonide
0.1% paste were compared in a separate randomized trial of 40 patients with oral LP [32]. The two
treatments had similar efficacy at two months.
●Tacrolimus– The efficacy of topical tacrolimus is evident in randomized trials that have compared
treatment with tacrolimus 0.1% ointment to clobetasol 0.05% ointment [33-35]. Based upon these
trials, tacrolimus appears to be at least as effective as clobetasol. The trials are reviewed in greater
detail below:
•In a randomized trial in which 32 patients described as having moderate to severe oral LP were
treated with application of either tacrolimus or clobetasol four times per day for four weeks,
statistically significant reductions in disease symptoms and signs occurred in both groups [33].
However, median scores for pain, burning sensation, and mucosal lesion extension at the end of
therapy were significantly lower in the tacrolimus group.
•In a randomized trial of 30 patients with erosive LP treated with tacrolimus or clobetasol four times
per day for two weeks, followed by a progressive taper to one time per day over a total of six weeks,
the efficacy of the two agents was similar [34]. Twenty-nine patients were analyzed and all but one
patient who had received clobetasol responded to treatment. The differences in the percent
reduction in lesion size at week six (83 percent for tacrolimus and 82 percent for clobetasol) and the
percent reduction in pain score at week six (52 percent for tacrolimus and 38 percent for clobetasol)
were not statistically significant.
1644
•In a randomized trial in which 40 patients with symptomatic oral LP were treated with twice daily
application of tacrolimus or clobetasol for eight weeks, statistically significant reductions in the net
clinical score were seen in both groups, and the score reductions were not significantly different
between the groups [35]. In addition, the differences in the rates of complete response (70 versus 40
percent, respectively) and complete or partial response (95 versus 90 percent, respectively) were not
statistically significant among the tacrolimus and clobetasol groups.
Administration — We administer topical pimecrolimus and topical tacrolimus in a

similar manner as topical corticosteroids, instructing patients to apply medication to the affected
areas after drying the sites with gauze. Treatment is applied two to four times daily [30] and patients
should avoid eating and drinking for at least 30 minutes after application. The frequency of
application is tapered as tolerated.
Pimecrolimus is commercially available as a 1% cream. Tacrolimus is commercially available as

both 0.03% or 0.1% ointment. The literature supports the use of the 0.1% concentration [30].
Side effects — Burning sensation may occur after application of topical calcineurin
inhibitors [30]. Tacrolimus has been detected in the blood of patients treated with topical tacrolimus
for oral LP, indicating that systemic absorption occurs [39].
Concerns have been raised regarding the potential for pimecrolimus and tacrolimus to increase the
risk for cancer, evidenced by the US Food and Drug Administration’s placement of a "black box"
warning on these agents. However, a causative relationship between these agents and cancer has
not been demonstrated to date and remains controversial. (See "Treatment of atopic dermatitis
(eczema)", section on 'Long-term safety concerns'.)
Intralesional corticosteroids — Intralesional injections of

triamcinolone acetonide, in concentrations between 10 and 40 mg/mL, have been used successfully
for oral LP. A study of 45 patients with ulcerative oral LP on the bilateral buccal mucosa in which
only one side was treated with an intralesional corticosteroid injection (0.5 mL of triamcinolone
acetonide 40 mg/mL) found statistically significant reductions in signs and symptoms of oral LP
within two weeks after treatment [40]. On the treated side, the mean sizes of the areas affected by
erythema or ulceration were reduced by 78 percent. In contrast, the untreated areas remained
unchanged.
In our experience, intralesional injection using triamcinolone acetonide (5 to 10 mg/mL) has been
effective. Using 30-gauge one-half inch-length needles, we inject into the submucosa of recalcitrant
oral LP lesions. Injections may be repeated every two to four weeks as needed [40-42]. If lesions fail
to respond, we perform a biopsy to rule out malignant transformation.
Intralesional injection of betamethasone, a more potent corticosteroid than triamcinolone acetonide,

may be an effective alternative treatment. In a trial in which 61 patients with erosive oral LP were
randomly assigned to intralesional injection of 1.4 mg of betamethasone or 8 mg of triamcinolone
1645
acetonide (each given once weekly for two weeks), significantly more patients in the betamethasone
group compared with the triamcinolone acetonide group achieved healing (27 of 29 [93 percent]
versus 20 of 30 [67 percent]) [43]. Additional study will be useful for confirming the relative efficacy
of these treatments.
Side effects related to systemic absorption are risks of intralesional corticosteroid therapy [42]. (See
"Intralesional corticosteroid injection", section on 'Side effects, complications, and pitfalls'.)
Topical cyclosporine — Studies have yielded variable results regarding the

efficacy of topical cyclosporine in oral LP [13,44,45]. A small placebo-controlled randomized trial in
which 16 patients with symptomatic oral LP used topical cyclosporine (5 mL of a 100 mg/mL
solution, swished for five minutes and then spit) or its vehicle three times daily supported the use of
topical cyclosporine for this indication [44]. After eight weeks, clinical improvement in erythema,
erosions, reticulation, and pain were significantly greater in the treatment group than in the placebo
group. All eight patients treated with cyclosporine had marked clinical improvement, whereas the
eight patients in the vehicle group had no improvement or minimal benefit. In contrast, a randomized
trial that compared cyclosporine given in a similar swish and spit regimen to triamcinolone
acetonide 1 mg/g paste found that both treatments resulted in only slight clinical improvement [45].
There was no significant difference between the two groups in efficacy.
SEVERE AND REFRACTORY

DISEASE Oral LP that cannot be adequately managed with topical therapy and
extensive oral LP accompanied by extraoral mucosal involvement may respond to more aggressive
treatment with systemic glucocorticoids. Less commonly, other systemic immunomodulatory
agents are used for treatment. Data on the efficacy of systemic agents are primarily limited to small
uncontrolled studies, case reports, and case series. The potential for serious drug-induced adverse
effects is a concern for these therapies.
Oral glucocorticoids — Oral glucocorticoids have appeared to be effective

for oral LP in small uncontrolled studies [46,47]. In one open-label study, 7 of 10 patients with oral LP
who were treated with prednisone (40 to 80 mg once daily, or 1 mg/kg/day) achieved complete
remission within 26 days [46].
We typically treat patients with prednisone at a dose similar to the dose above, with the goal of
tapering to discontinuation within two to four weeks to minimize the risk for drug-related adverse
effects. Because relapses frequently occur after the discontinuation of prednisone, we use topical
corticosteroids to sustain improvement during tapering and after the cessation of systemic therapy.
(See 'Topical corticosteroids' above.)
1646
Although oral glucocorticoids may be useful for patients with resistant disease, most patients with
oral LP do not require an oral glucocorticoid as initial therapy. This concept is supported by a study
in which 49 adults with oral LP were treated with either a prednisone taper followed by clobetasol or
clobetasol without systemic therapy [48]. Significant differences in patient outcomes were not
detected.
The adverse effects of systemic glucocorticoids are reviewed separately. (See "Major side effects of
systemic glucocorticoids".)
Other systemic immunomodulatory

agents — Additional agents that may be useful in patients with severe or refractory oral LP
based upon data from case reports and small retrospective studies include immunosuppressants,
such as azathioprine (50 mg twice daily) [47,49,50], cyclosporine (5 mg/kg per day) [51],
methotrexate (2.5 to 15 mg per week) [52,53], mycophenolate mofetil (1 to 2 g per day) [54-56], and
thalidomide (50 to 200 mg per day) [52,57-59]. The role of rituximab in oral LP is unclear with both
initial development and improvement noted in case reports [60,61]. Data for the use of apremilast in
oral LP are preliminary but promising [62]. We await larger, controlled clinical trials that assess the
efficacy of various biologic agents in the treatment of oral LP [63].
ADDITIONAL THERAPIES Other therapies that have been

reported to be effective for oral LP include topical retinoids [64,65], oral retinoids [66-70],
hydroxychloroquine [52,71], topical rapamycin [72], oral dapsone (100 to 150 mg per day) [73,74],
oral metronidazole [75], and cryotherapy [76]. In a small randomized trial, oral circuminoids,
components of the root tumeric (Curcuma longa), reduced symptoms and signs of oral LP to a
greater extent than placebo [77].
Treatment of oral LP with a variety of ultraviolet light-based modalities has been attempted [78].
Small uncontrolled studies and case reports have documented improvement in patients treated with
psoralen plus ultraviolet A (PUVA) therapy, a 308 nm ultraviolet B (UVB) excimer laser, UVB
phototherapy administered via a flexible fiber, and extracorporeal photochemotherapy [79-83].
Whether ultraviolet light therapy increases the risk for malignant transformation to oral squamous
cell carcinoma, independent of the underlying risk inherent to oral LP, is unknown. Further study of
the efficacy and safety of these interventions is necessary before these treatments can be routinely
recommended. (See 'Risk of oral squamous cell carcinoma' below.)
Additional physical interventions for oral LP have included surgery [78], photodynamic therapy
[84,85], carbon dioxide lasers [86,87], and cryotherapy [41].
PAIN MANAGEMENT Nonsteroidal antiinflammatory agents or

acetaminophen may be added for pain management. In our experience, few oral LP patients have
required more aggressive pain medication regimens.
1647
Local pain control with use of intraoral topical anesthetics (viscous lidocaine 2% solution, lidocaine
2% gel) can provide temporary benefit and improved oral intake. Potential risks include systemic
absorption with potential toxicity and suppression of gag reflex with increased risk of aspiration.
Topical benzocaine is not advised due to a rare risk of potentially fatal methemoglobinemia with
even one application [88]. The risk appears to be greatest in young children. (See
"Methemoglobinemia".)
PATIENT SUPPORT Oral LP and concomitant chronic pain may be

associated with increased risk for anxiety and depression [89,90]. Patients who are experiencing
these symptoms may benefit from referrals to psychological or psychiatric health services for help
with coping skills and psychosocial support.
Stress appears to alter a variety of endocrine and immune responses in patients with LP [91].
Further study is necessary to determine whether stress is an exacerbating factor for oral LP.
PROGNOSIS AND FOLLOW-UP The clinical

course of oral LP is chronic, with waxing and waning severity. In a retrospective study of 808 Italian
patients with oral LP who were followed for 6 to 304 months, sustained remission off-therapy was
documented in only 2.5 percent of patients [41].
Risk of oral squamous cell carcinoma — The magnitude

of the risk of malignant transformation of oral LP to oral squamous cell carcinoma (SCC) is unclear
[92]. Systematic interpretation of the available data is compromised by marked variability in study
inclusion criteria. Reported rates for malignant transformation range from 0.4 to more than 5
percent [41,93-95]. The highest risk for oral SCC may occur in patients with erythematous or erosive
oral LP [96,97].
Due to the possibility that oral LP may increase risk for oral cancer, we encourage patients with oral
LP to avoid activities known to increase the risk for oral cancer, such as smoking and alcohol use.
Additional study is necessary to determine the impact of these factors and oral human
papillomavirus infection on risk for malignant transformation of oral LP. Future studies also may
offer clarity on whether analysis for genetic alterations, such as determination of MYC status, in
lesional oral LP tissue will be useful for identifying patients at risk for progression to oral SCC [98]. It
is not known whether treatment of oral LP influences the risk of malignancy. (See "Epidemiology and
risk factors for head and neck cancer", section on 'Risk factors'.)
Follow-up — We follow all patients with oral LP at least every 6 to 12 months, which
allows for the assessment for early signs of malignancy. In addition to the oral exam, we palpate
cervical lymph nodes to evaluate patients for the presence of lymphadenopathy. A biopsy to rule out
oral cancer should be performed if signs suggestive of an oral cancer are detected (eg, leukoplakia,
1648
exophytic nodules, or persistent ulcers or erosions that fail to respond to therapy). The need for
more frequent follow-up for disease management is dependent on disease activity and
symptomatology.


SUMMARY AND
RECOMMENDATIONS
●Oral lichen planus (LP) is a subtype of LP that presents with reticular, erythematous (atrophic), or
erosive lesions on the oral mucosa. Although reticular oral LP is often asymptomatic, patients with
the erythematous and erosive subtypes of oral LP usually have associated pain. (See "Oral lichen
planus: Pathogenesis, clinical features, and diagnosis", section on 'Clinical subtypes'.)
●Treatment of oral LP is implemented to improve symptoms and to minimize the risk for scarring
from erosive lesions. Patients with asymptomatic reticular LP do not require treatment. (See
'Approach to treatment' above.)
●For patients with symptomatic oral LP, we suggest treatment with a high potency topical
corticosteroid (eg, clobetasol propionate 0.05% or betamethasone propionate 0.05%) as first-line
therapy (Grade 2B). (See 'First-line therapy' above.)
1649
●For patients who fail to improve adequately with topical corticosteroids or who cannot tolerate
topical corticosteroids, we suggest treatment with tacrolimus 0.1% ointment or pimecrolimus 1%
cream (Grade 2B). Additional options for these patients include topical cyclosporine and
intralesional corticosteroid injections. (See 'Second-line therapy' above.)
●Patients who do not respond adequately to local therapy may benefit from treatment with oral
glucocorticoids or other systemic immunomodulatory therapies. (See 'Severe and refractory disease'
above.)
●Oral LP is a risk factor for oral squamous cell carcinoma, though the magnitude of this risk remains
unclear. A biopsy should be performed if patients develop lesions suspicious for oral malignancy.
(See 'Risk of oral squamous cell carcinoma' above.)
●Patients with oral LP should be followed clinically at least every 6 to 12 months. More frequent
follow-up may be indicated based upon disease activity and symptomatology. (See 'Follow-up'
above.)
1650
Pityriasis rosea
Authors: Adam O Goldstein, MD, MPH, Beth G Goldstein, MD
Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Moise L Levy, MD
INTRODUCTION
Pityriasis rosea (PR) is an acute, self-limited, exanthematous skin disease characterized by the
appearance of slightly inflammatory, oval, papulosquamous lesions on the trunk and proximal areas
of the extremities (picture 1A-E). The diagnosis and management of this disorder are reviewed here.
ETIOLOGY
A viral etiology for PR has been hypothesized based upon the following observations:
● PR is sometimes preceded by a prodrome.

● It occasionally occurs in small case clusters.
● It has not been shown to be associated with bacterial or fungal organisms.
This supposition is reinforced by the finding of viral-like particles in PR biopsy specimens examined
with the electron microscope [1]. A significant literature supports the hypothesis that PR is a
manifestation of human herpesvirus 7 (HHV-7) reactivation [2,3]. However, others have failed to
detect HHV-7 DNA sequences and antigens in a significant number of PR cases, arguing against a
causative role for this agent [4]. Some studies have also implicated HHV-6 in the pathogenesis of PR
[3,5,6]. Possible associations with HHV-8 and 2009-2010 pandemic H1N1 influenza A virus have also
been reported [7-9].
More study is needed before this issue can be definitively resolved.
1651
CLINICAL FEATURES
PR is largely a disease of older children and young adults. It is slightly more common in women than
men. A prodrome of headache, malaise, and pharyngitis may occur in a small number of cases, but
except for itching, the condition is usually asymptomatic.
In 50 to 90 percent of cases, the eruption begins with a "herald" or "mother" patch, a single round or
oval, sharply delimited, pink or salmon-colored lesion on the chest, neck, or back (picture 1C, 1F) [10].
The herald patch is usually 2 to 5 cm in diameter. The lesion soon becomes scaly and begins to clear
centrally, leaving the free edge of the cigarette paper-like scale directed inwards toward the center.
This clinical finding is often described as a "collarette" of scale.
A few days or one to two weeks later, oval lesions similar in appearance to the herald patch, but
smaller, appear in crops on the trunk and proximal areas of the extremities (picture 1A-E, 1G). The
long axes of these oval lesions tend to be oriented along the lines of cleavage of the skin. This
characteristic arrangement is most evident on the back, where it is emphasized by the oblique
direction of the cleavage lines in that location. This morphologic pattern has been referred to as a "fir
tree" or "Christmas tree" distribution.
The eruption spreads centrifugally or from the top down over the course of a few days. Erythema
gradually subsides, desquamation is completed, and the eruption fades, leaving few residual
changes, except postinflammatory dyspigmentation. In most cases the papules and plaques resolve
in four to six weeks; occasionally the disease will persist for several months. Postinflammatory
hyperpigmentation is a common sequela in dark-skinned individuals and often takes several months
or longer to resolve.
In children, the distribution of the lesions is often atypical, involving the scalp and face; it may be
completely "inverse," affecting the face and distal extremities, while sparing the trunk, or may be
concentrated in the pubic, inguinal, and axillary regions (picture 1G-J) [11]. The lesions themselves
also are sometimes atypical in children; they may be folliculo-papular, vesicular, pustular, urticarial, or
purpuric. PR generally has only mild effects on quality of life in children [12].
Oropharyngeal abnormalities have been reported in patients with PR. In a review of 527 patients with
PR, 149 patients (28 percent) had oropharyngeal lesions, with petechial, macular, and papular
eruptions as the most common findings [13]. Oropharyngeal swabs for culture were performed in 90
patients and showed normal flora in all patients. Mucosal biopsies were not performed.
DIAGNOSIS
1652
The presence of a herald patch by history or on examination, the characteristic morphology and
distribution of the lesions, and the absence of symptoms other than pruritus combine to make PR an
easy diagnosis in most instances. However, the herald patch can resemble tinea corporis so closely
that potassium hydroxide (KOH) examination of scales for dermatophyte hyphae may be necessary
to distinguish these conditions. (See 'Differential diagnosis' below and "Office-based dermatologic
diagnostic procedures", section on 'Potassium hydroxide preparation'.)
There are typically no laboratory abnormalities with PR. Serologic testing to rule out syphilis is
recommended for sexually active patients. The cutaneous manifestations of secondary syphilis
resemble PR (picture 3B). (See 'Differential diagnosis' below and "Syphilis: Screening and diagnostic
testing", section on 'Approach to testing'.)
Skin biopsy is rarely necessary, but when performed shows focal parakeratosis with or without
acanthosis, spongiosis, a perivascular infiltrate of lymphocytes and histiocytes, and occasionally
extravasation of red cells (picture 2). The biopsy picture is characteristic, but not pathognomonic. A 3
mm or 4 mm punch biopsy typically provides an adequate specimen for analysis. (See "Skin biopsy
Differential diagnosis — A differential diagnosis should always be considered in patients who present
with lesions that are suspicious for PR [14]. When the diagnosis is in question, a skin biopsy can be
performed. A potassium hydroxide preparation is useful for ruling out fungal infections (see "Skin
biopsy techniques", section on 'Punch biopsy' and "Office-based dermatologic diagnostic
procedures", section on 'Potassium hydroxide preparation'):
● Secondary syphilis – The papulosquamous eruption of secondary syphilis can closely resemble
PR; however, unlike the latter, secondary syphilis often presents with red-brown macules on the
palms and soles (picture 3A-B). Patients with secondary syphilis also may recall the appearance
of a chancre and will lack a history of a herald patch. In patients in whom secondary syphilis is
suspected, appropriate serologic testing should be performed. (See "Syphilis: Screening and
diagnostic testing" and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in
HIV-uninfected patients", section on 'Clinical manifestations'.)
● Guttate psoriasis – Guttate psoriasis is a variant of psoriasis that most frequently affects
children and young adults. Small, erythematous, scaly plaques are distributed primarily on the
trunk (picture 4). The scale tends to be coarser than the scale associated with PR, and a herald
patch does not precede the eruption. Guttate psoriasis frequently is associated with a preceding
streptococcal infection. (See "Guttate psoriasis".)
● Tinea corporis – The herald patch of PR may be mistaken for tinea corporis, which may also
present with an annular plaque with peripheral scale (picture 5). A KOH preparation from a lesion
1653
of tinea corporis will reveal fungal hyphae. (See "Dermatophyte (tinea) infections", section on
'Tinea corporis'.)
● Tinea versicolor – Tinea versicolor presents with hypopigmented or hyperpigmented macules

that are most commonly located on the neck and trunk (picture 6A-B). Unlike in PR, erythema is
absent or minimal. The scale in tinea versicolor is fine, and lesions lack the peripheral rim of
scale that is often seen in PR. A KOH preparation easily confirms a diagnosis of tinea versicolor.
(See "Tinea versicolor (pityriasis versicolor)".)
● Nummular eczema – Nummular eczema presents with intensely pruritic, coin-shaped plaques
that may range in size from 2 to 10 cm (picture 7A-B). Involvement of the extremities is more
common in nummular eczema than in PR. Serous exudate may be visible in acute lesions of
nummular eczema. (See "Overview of dermatitis (eczema)", section on 'Nummular eczema'.)
● Pityriasis lichenoides chronica – Pityriasis lichenoides chronica (PLC) is an uncommon

condition that is characterized by recurrent crops of erythematous to brown scaly papules on the
trunk and proximal extremities. Lesions may be asymptomatic or pruritic, and spontaneously
regress over the course of weeks to months. PLC most commonly occurs in children and young
adults. The disorder may persist for years. (See "Pityriasis lichenoides chronica".)
Other disorders that should be considered in the differential diagnosis of PR include Lyme disease,
human immunodeficiency virus (HIV) seroconversion illness, and drug eruptions. Testing for HIV
should be performed in patients with risk factors for or symptoms suggestive of HIV infection. (See
"Acute and early HIV infection: Pathogenesis and epidemiology" and "Screening and diagnostic
testing for HIV infection".)
Therapeutic gold injections also can cause eruptions that mimic PR closely; these eruptions do not
represent allergic reactions, but are dose-related and can be managed safely by reduction in dose
size and the frequency of administration [15]. Other medications and procedures suspected of
producing PR-like reactions are omeprazole [16], terbinafine [17], bone marrow transplantation [18],
interferon alfa-2a [19], naproxen [20], captopril [21], isotretinoin [22], and bacillus Calmette-Guerin
therapy [23].
TREATMENT
General approach — Education, reassurance, and interventions for pruritus are sufficient for the
management of most patients with PR [24].
Patient/parent education — Patients with PR and parents of children with PR typically want
information about clinical course, infectivity, and relapse. We reassure patients and parents that PR
1654
typically spontaneously resolves within two to three months, is thought to have a low likelihood for
transmission, and does not recur in most patients. (See 'Prognosis' below.)
Pruritus — Clinical experience has shown that topical corticosteroids in the medium potency range
(group 4 or group 5) are helpful in the control of itching (table 1). They can be applied to the pruritic
areas two or three times daily for two to three weeks. Long-term use of topical corticosteroids without
medical supervision should be avoided because of risk for corticosteroid-induced skin atrophy. (See
Topical antipruritic lotions that contain pramoxine or menthol and oral antihistamines may also be
helpful for reducing symptoms of pruritus [14,24].
Severe cases — Although the vast majority of patients with PR require no treatment or only topical
treatment to control pruritus, there is some evidence that oral acyclovir and ultraviolet light may
accelerate clinical improvement. Routine treatment with these interventions is not recommended
because efficacy data are limited and PR typically resolves without treatment. We reserve acyclovir or
ultraviolet light therapy for patients with severe symptoms associated with a significant negative
effect on quality of life.
Acyclovir — The proposed link between PR and human herpesvirus (HHV) led to trials of antiviral
therapy in patients with this disorder (see 'Etiology' above):
● Efficacy – Few randomized trials have evaluated the efficacy of acyclovir, and high-quality
studies are lacking. A systematic review and meta-analysis of randomized trials that assessed
outcomes of PR therapy within two weeks (a criterion intended to minimize the impact of
spontaneous resolution) found moderate-quality evidence in support of acyclovir therapy [25].
The meta-analysis included three trials (with a total of 141 patients) that compared acyclovir
(400 or 800 mg given five times per day for one week) with placebo, vitamin C (as a control), or
no treatment. Acyclovir therapy was associated with a greater likelihood for good or excellent
improvement in skin erythema within two weeks (risk ratio [RR] 2.45, 95% CI 1.33-4.53). No
serious adverse effects occurred in the included trials.
The impact of acyclovir therapy on PR-associated itch is uncertain. One randomized trial (n = 27)
found patients who received acyclovir were less likely to achieve resolution of itch at two weeks
than patients who received placebo (RR 0.34, 95% CI 0.12-0.94) [26]. However, an unblinded trial
(n = 24) that randomly assigned patients with PR to either acyclovir plus calamine lotion and
cetirizine or calamine lotion and cetirizine alone found resolution of itch more likely in the
acyclovir group (RR 4.50, 95% CI 1.22-16.62) [25,27].
The rationale for benefit of acyclovir therapy remains unclear. In vitro studies demonstrating that
acyclovir has poor antiviral activity against HHV-6 and HHV-7 raise questions about the etiology
1655
of PR and the reasons for the efficacy of acyclovir [28,29].
● Administration – Doses for adults with PR range from 400 to 800 mg of acyclovir given five
times per day for one week. Improvement is expected within one to two weeks. Further study
may clarify whether the effects of a low-dose regimen for acyclovir (400 mg three times daily for
seven days) are similar [27].
Acyclovir therapy is generally well tolerated. Acute renal failure is a potential severe adverse
effect. Adverse effects of acyclovir are reviewed separately. (See "Acyclovir: An overview",
section on 'Toxicity'.)
Phototherapy — Phototherapy has an extensive history of use for a variety of papulosquamous

and inflammatory disorders of the skin as well as for pruritus. Although clinical experience suggests
that ultraviolet light from natural sunlight or phototherapy devices may have benefit in PR, data on
efficacy are limited (see "UVB therapy (broadband and narrowband)"):
● Efficacy – Three split-body studies in which one-half of the body was treated with broadband
ultraviolet B (UVB) suggest beneficial effects of phototherapy [30-32]. As an example, a study of
101 children and adults with PR found statistically significant reductions in PR severity scores on
the side of the body treated with broadband UVB four times per week, but not on the side treated
with a very low dose of ultraviolet A (UVA) as a control [32]. Patients received a mean of five
treatments. In addition, in a study in which broadband UVB was used to treat one-half of the body
for 10 treatments over two weeks in 17 patients with extensive PR, and a very low dose of UVA
was given contralaterally as a control, UVB significantly decreased disease severity during the
treatment period. However, the difference in effect was no longer present two weeks after the
completion of treatment [30]. UVB had no effect on pruritus in this study. In contrast, a split-body
study of 20 patients with PR found that broadband UVB therapy decreased the extent of disease
and pruritus [31].
Narrowband UVB devices, which emit UVB in the range of 311 to 313 nm rather than the 290 nm
to 320 nm range emitted by broadband UVB devices, are now commonly used for the treatment
of skin diseases previously treated with broadband UVB. A randomized trial in which 100
patients with PR were randomly assigned to narrowband UVB phototherapy (three times weekly
for four weeks) or no treatment found greater improvement in disease severity scores and
itching among patients treated with narrowband UVB [33]. Worsening of PR following
narrowband UVB phototherapy has been reported in one patient [34]; however, it is unclear
whether the exacerbation of disease was secondary to phototherapy or the natural course of the
disease [35]. (See "UVB therapy (broadband and narrowband)".)
1656
UVA1 phototherapy also may have some benefit for the treatment of PR, although it has much
more limited availability. In an uncontrolled study of patients with extensive PR, UVA1 was
associated with improvements in disease severity, and 12 out of 15 patients noted improvement
in pruritus (mean number of treatments = 6.5 ± 1.8) [36]. (See "UVA1 phototherapy".)
In clinical practice, exposure to outdoor sunlight is sometimes suggested to patients with PR.
However, data on the efficacy of this mode of exposure to ultraviolet light are lacking.
● Administration – The best regimen for phototherapy is unclear. When treating PR with
phototherapy, we most frequently treat with broadband or narrowband UVB two to three times
per week. Improvement is expected within the first two to three weeks of treatment. Additional
studies are necessary to confirm the efficacy of phototherapy for PR and to determine the
optimal regimen for phototherapy.
Short-term side effects of phototherapy include erythema, pruritus, dry skin, and blistering. Side
effects of phototherapy are reviewed in detail separately. (See "UVB therapy (broadband and
narrowband)", section on 'Short- and long-term adverse effects' and "UVA1 phototherapy",
section on 'Adverse effects'.)
Other therapy
Macrolide antibiotics — The efficacy of oral erythromycin for PR is uncertain, and other
macrolides, including azithromycin and clarithromycin, do not appear to be effective for PR. Given the
conflicting efficacy data, we do not utilize macrolide antibiotics for the treatment of PR:
● Erythromycin – While some studies have found oral erythromycin effective for accelerating
resolution of PR, data are limited, and additional studies would be useful for confirming benefit.
Moreover, some studies suggest erythromycin might be less effective than acyclovir. Examples
of relevant studies include:
• A systematic review of randomized trials that assessed treatment outcomes for PR within
two weeks (a criterion intended to minimize the impact of spontaneous resolution) identified
two placebo-controlled, randomized trials [25]. Although each trial found patients treated
with erythromycin (1 g per day given for one or two weeks) more likely to achieve complete
cure than patients in the placebo groups, a meta-analysis of these trials (total of 86 patients)
did not find a difference in effect (RR 4.02, 95% CI 0.28-56.61). High heterogeneity between
the two trials was a limitation of the meta-analysis. One of the trials, an unpublished trial (n =
40), found erythromycin (1 g per day for two weeks) effective for reducing the patient-
reported itch score (RR 3.95, 95% CI 3.37-4.53) [25].
1657
• A trial in which 30 patients with PR were randomly assigned to acyclovir (800 mg five times
per day) or erythromycin (400 mg four times per day) for 10 days found patients given
acyclovir were more likely to achieve a complete response after eight weeks (87 versus 40
percent) [37]. In addition, an unblinded, randomized trial performed with 42 children and
adults with PR found a one-week course of acyclovir (20 mg/kg five times per day for
children and 800 mg five times per day for adults) more effective than a one-week course of
erythromycin (40 mg/kg per day in four divided doses for children and 500 mg four times per
day for adults) for reducing the severity and duration of PR [38].
• A trial that alternately assigned 90 patients to erythromycin treatment or placebo and

assessed response after six weeks found that patients who received erythromycin (250 mg
four times daily for 14 days) were more likely to achieve a complete response within two
weeks [39]. A complete response was noted in 73 percent of patients in the treatment group
compared with none in the placebo group.
• A controlled study of 184 patients with PR found no benefit with two weeks of oral
erythromycin (200 mg four times daily in adults and 20 to 40 mg/kg daily in four divided
doses in children) started within seven days of the appearance of secondary lesions of PR
[40]. The trial was not randomized, evaluators were not blinded, and the control was an
emollient cream rather than a pill. No patient in either arm of the trial achieved complete
clearance of lesions at two weeks, and there were also no differences in complete clearance
between the arms at weeks 4, 6, or 8.
● Other macrolides – Trials of azithromycin and clarithromycin for PR support inefficacy of these
therapies. A randomized trial in 49 children with PR found no benefit of five days of treatment
with azithromycin (12 mg/kg per day, up to 500 mg per day) [41]. At four weeks, there were
similar percentages of complete (60 versus 42 percent) and partial (28 versus 29 percent)
responses with azithromycin and placebo. A randomized trial in 70 children and adults with PR
also failed to find a five-day course of azithromycin (12 mg/kg per day) more effective than a
multivitamin placebo [42]. Similarly, clarithromycin was ineffective in a randomized trial in which
60 children and adults with PR were given one-week courses of clarithromycin (200 or 250 mg
twice daily) or placebo pills [43].
Systemic glucocorticoids — Although systemic glucocorticoids may improve manifestations and

pruritus of PR, routine treatment with systemic glucocorticoids is not recommended due to limited
efficacy data and concern for increased risk for relapse after treatment. In a 12-week trial in which 70
patients with PR were randomly assigned to either oral prednisolone (20 mg per day for five days, 15
mg/day for five days, then 10 mg/day for five days) or placebo, prednisolone therapy was associated
with faster improvement in pruritus and the disease severity score [44]. However, benefit of
1658
prednisolone was no longer evident by week 4 for pruritus or by week 8 for the disease severity score,
and at week 12, six relapses of PR after complete or near complete clearance had occurred in the
prednisolone group compared with one relapse in the placebo group. The proportion of patients who
relapsed in each group is unclear because the number of patients who achieved complete clearance
was not reported.
PROGNOSIS
Patients should be advised that the rash may persist for two to three months; no follow-up is
necessary as long as it resolves within this time. New lesions may occur during this period but
should disappear spontaneously. Relapse after resolution is uncommon [3].
PREGNANCY
An analysis of a case series of 61 women who developed PR during pregnancy suggests that PR
increases the risk for spontaneous abortion [45]. Spontaneous abortions occurred in 8 of 61 women
(13 percent) who developed PR during pregnancy and 8 of 14 women (57 percent) who developed PR
within the first 15 weeks of gestation. Further studies are necessary to clarify the impact of PR on
pregnancy.
● Basics topics (see "Patient education: Pityriasis rosea (The Basics)")

1659
● Pityriasis rosea (PR) is an acute, self-limited, exanthematous skin disease felt most likely to be
due to a viral etiology. (See 'Introduction' above and 'Etiology' above.)
● The eruption commonly begins with a "herald" or "mother" patch, a single round or oval, rather
sharply delimited pink or salmon-colored lesion on the chest, neck, or back, 2 to 5 cm in diameter.
A few days or a week or two later, oval lesions similar in appearance to the herald patch, but
smaller, appear in crops on the trunk and proximal areas of the extremities (picture 1A-E). The
long axes of these oval lesions tend to be oriented along the lines of cleavage of the skin. (See
● A prodrome of headache, malaise, and pharyngitis may occur in a small number of cases, but
except for itching, the condition is usually asymptomatic. (See 'Clinical features' above.)
● The diagnosis of PR is typically made based on the history of a herald patch and the clinical
appearance of the rash. Laboratory testing is sometimes needed to exclude other conditions
such as secondary syphilis. (See 'Differential diagnosis' above.)
● Most patients do not require therapy. For patients with mild itching who desire therapy, we
suggest treatment with medium-potency topical corticosteroids (table 1) (Grade 2C). (See
'Pruritus' above.)
● For patients with severe presentations of PR who desire treatment to accelerate improvement of
the skin manifestations, we suggest treatment with oral acyclovir rather than oral erythromycin
(Grade 2C). Phototherapy is an alternative treatment option. Additional studies will be useful for
confirming the efficacy of PR therapies. (See 'Severe cases' above and 'Other therapy' above.)
1660
GRAPHICS
Pityriasis rosea
Oval, erythematous papules and small plaques are present on the abdomen.
1661
Pityriasis rosea
Multiple erythematous, scaly papules and plaques on the trunk in a "Christmas tree" distribution.
1662
Pityriasis rosea
1663
Pityriasis rosea
Hyperpigmented oval plaques on the trunk in a "Christmas tree" distribution.
1664
Pityriasis rosea
Multiple oval macules and patches in a "Christmas tree" pattern on the back.
1665
Herald patch of pityriasis rosea
This patient has a herald patch on her chest. Other, smaller lesions can be seen.
Wilkins.
1666
Pityriasis rosea
Erythematous plaques with scale. The small plaque on the left demonstrates the classic collarette of scale associated with pityriasis rosea.
1667
Atypical (inverse) pityriasis rosea
Atypical (inverse) pityriasis rosea in an inguinal distribution. The herald patch (arrow) is
present in the left inguinal area.
Wilkins.
1668
Pityriasis rosea
Erythematous, scaly plaques with peripheral scale in the inguinal region.
1669
Pityriasis rosea
Erythematous and hyperpigmented papules and plaques on the neck and face.
1670
Secondary syphilis
1671
Pityriasis rosea
Superficial perivascular infiltrate of lymphocytes and extravasated erythrocytes that extend to the epidermis, where
there is moderate acanthosis, spongiosis, decreased granular layer, and mounds of parakeratosis.
Reproduced with permission from: Mobini N, Caire ST, Hu S, Kamino H. Noninfectious erythematous, papular, and squamous diseases.
In: Lever's histopathology of the skin, 11th ed, Elder DE, Elenitsas R, Johnson B Jr, et al (Eds), Lippincott Williams & Wilkins,
Philadelphia 2014. Copyright © 2014 Lippincott Williams & Wilkins. www.lww.com.
1672
Secondary syphilis
Maculopapular rash on the palms, which rarely can be pustular, in a patient with secondary
syphilis. Patients can be quite contagious at this stage.
Courtesy of David H Martin and Tomasz F Mroczkowski. The Skin and Infection: A Color Atlas and Text,
Sanders CV, Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.
http://www.lww.com
1673
Guttate psoriasis
1674
Tinea corporis
This annular lesion with a raised erythematous border, central clearing, and slight scale
was consistent with tinea corporis.
Wilkins.
1675
Tinea versicolor
Multiple small salmon-colored macules are evident on the arm that coalesce in some areas.
Courtesy of Beth G Goldstein, MD, and Adam O Goldstein, MD.
1676
Tinea versicolor
Tinea versicolor. Hypopigmented macules and patches are scattered on the shoulder and
arm of this patient.
Wilkins.
1677
Nummular eczema

hyperpigmentation.
Wilkins.
1678
Nummular eczema
"Coin-shaped" patches and plaques are located on the legs.
Wilkins.
1679
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12

States)

emollient
1680

Kenalog ¶, Triderm


solution

spray

Gel Desonate 0.05

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

Body, Derma-
Smoothe/FS Scalp
¶ ¶
1681

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1682

Author: Amy Musiek, MD
Section Editors: John A Zic, MD, Moise L Levy, MD
INTRODUCTION
Pityriasis lichenoides is a term used to refer to a group of rare acquired inflammatory skin disorders
that includes pityriasis lichenoides chronica (PLC), pityriasis lichenoides et varioliformis acuta
(PLEVA), and the febrile ulceronecrotic Mucha-Habermann disease (FUMHD) variant of PLEVA. The
use of the term pityriasis lichenoides to refer to all three disorders is representative of the theory that
PLC, PLEVA, and FUMHD may represent a clinical spectrum of a single disease.
PLC is clinically characterized by the development of multiple scaly, erythematous to brown papules
on the trunk and extremities. The condition usually has a relapsing and remitting course that persists
for months or years.
The clinical manifestations, diagnosis, and management of PLC will be reviewed here. PLEVA is
discussed separately. (See "Pityriasis lichenoides et varioliformis acuta (PLEVA)".)
EPIDEMIOLOGY
Definitive conclusions on the epidemiology of pityriasis lichenoides chronica (PLC) are hindered by
the frequent lack of distinction between the subtypes of pityriasis lichenoides in the published
literature and limited data. In general, PLC is considered a rare disorder that is most likely to occur in
young adults and children [1]. However, PLC may develop at any age.
The existence of sex, ethnic, or racial predilections in PLC is uncertain [2]. Based upon data from a
few retrospective studies of children with pityriasis lichenoides, there may be a slight male
1683
predilection for pityriasis lichenoides in the pediatric population [3-7]. In one of the largest series of
children with PLC (n = 46), 59 percent of the children were male [4].
PATHOGENESIS
The pathogenesis of pityriasis lichenoides chronica (PLC) is poorly understood. Concordant with the
view that PLC and pityriasis lichenoides et varioliformis acuta (PLEVA) may be related disorders, the
major pathogenic theories for PLC and PLEVA overlap. These theories include the classification of
PLC and PLEVA as hypersensitivity responses to infection or as primary lymphoproliferative
disorders. (See "Pityriasis lichenoides et varioliformis acuta (PLEVA)", section on 'Pathogenesis'.)
Consideration of an infectious trigger for pityriasis lichenoides arises from reports of the occurrence
of PLC or PLEVA in the setting of infection (eg, Toxoplasma gondii, Epstein-Barr virus, parvovirus B16,
HIV, staphylococci, Group A streptococci, others) [2,8-11]. In addition, the relatively young age of
onset and an observation of a familial outbreak of PLEVA have led some authors to propose infection
as a trigger for pityriasis lichenoides [2,12].
The theory that PLC is a primary lymphoproliferative disease is based upon studies demonstrating
clonal CD4+ T cell populations in tissue samples from patients with PLC and PLEVA [13,14]. However,
monoclonality is not uniformly detected in PLC; in one study, only 1 of 13 PLC specimens
demonstrated a monoclonal T cell receptor gene rearrangement [15]. Moreover, the detection of
monoclonality is not sufficient to designate a disorder as a primary lymphoproliferative disease [15].
Occasionally, PLC has been reported to occur in association with drug exposure [16-18]. The
mechanisms through which drugs might induce PLC are unknown.
CLINICAL FEATURES
The development of pityriasis lichenoides chronica (PLC) usually is gradual. Patients develop
numerous red-brown papules that often demonstrate a characteristic overlying mica-like scale
(picture 1A-C). Lesions in different stages of development are present simultaneously.
The trunk, buttocks, and proximal extremities are the most common sites of involvement. However,
other cutaneous areas may be affected. Although the eruption usually is asymptomatic, associated
pruritus occurs in some patients.
Patients with PLC typically exhibit a relapsing and remitting disease course that lasts for months to
years. In a retrospective study of 46 children with PLC, the median duration of disease was 20
months (range 3 to 132 months) [4]. Individual lesions heal over several weeks leaving
1684
hypopigmented or hyperpigmented macules or patches [2]. Scarring is absent. Occasionally, patients
present with widespread hypopigmented macules as the predominant clinical manifestation of the
disease (picture 2) [19,20].
HISTOPATHOLOGY
Compared with pityriasis lichenoides et varioliformis acuta (PLEVA), the pathologic findings of
pityriasis lichenoides chronica (PLC) are less pronounced. (See "Pityriasis lichenoides et varioliformis
acuta (PLEVA)", section on 'Histopathology'.)
The characteristic pathologic features of PLC include [21]:
● Parakeratosis
● Mild spongiosis
● Minimal lymphocyte exocytosis
● Minimal vacuolar change and focal necrotic keratinocytes at the dermoepidermal junction
● Perivascular and lichenoid (band-like) lymphohistiocytic infiltrate in the superficial dermis
● A few extravasated erythrocytes in the papillary dermis
DIAGNOSIS
A diagnosis of pityriasis lichenoides chronica (PLC) is usually suspected based upon the clinical
appearance. We typically perform a skin biopsy to confirm the diagnosis.
A 4 mm punch biopsy of a papule usually provides a specimen that is sufficient for the histologic
evaluation for PLC. (See 'Histopathology' above and "Skin biopsy techniques", section on 'Punch
biopsy'.)
The differential diagnosis of pityriasis lichenoides chronica (PLC) includes other disorders that may
present with widespread papules or small plaques. A skin biopsy often is useful for distinguishing
PLC from other diseases.
Examples of disorders that may resemble PLC include:
1685
● PLEVA – Although pityriasis lichenoides et varioliformis acuta (PLEVA) and PLC are often
considered to be related disorders, the clinical and pathologic features of PLEVA allow for the
distinction between PLEVA and PLC. In contrast to the indolent course and red-brown, scaly
papules of PLC, PLEVA is characterized by the acute onset of hemorrhagic and crusted papules
(picture 3). In addition, pathologic findings of a dense, wedge-shaped lymphohistiocytic infiltrate
in the dermis, necrosis, vesiculation, and dermal hemorrhage support a diagnosis of PLEVA
rather than PLC. (See "Pityriasis lichenoides et varioliformis acuta (PLEVA)".)
● Pityriasis rosea – Pityriasis rosea is a papulosquamous eruption that usually presents with the
acute development of numerous ovoid, erythematous patches with trailing scale on the trunk and
proximal extremities (picture 4). A larger patch or plaque ("herald patch") may precede the more
extensive eruption. Similar to PLC, children and young adults are most commonly affected. The
course of pityriasis rosea tends to be shorter than PLC, with most cases resolving within four to
six weeks. Occasionally, the eruption persists for longer. (See "Pityriasis rosea".)
● Guttate psoriasis – Guttate psoriasis is a form of psoriasis characterized by the acute

development of multiple papules and small plaques with scale on the trunk and extremities
(picture 5). Most cases occur in children or young adults, and the eruption is often preceded by a
streptococcal infection. Untreated, guttate psoriasis usually persists for several weeks to several
months. (See "Guttate psoriasis".)
● Lichen planus – Lichen planus is a chronic disorder characterized by the development of

violaceous, polygonal papules with fine white scales (picture 6A-B). A lace-like pattern
(Wickham's striae) may be evident on the surface of lesions. Unlike PLC, pruritus typically is
prominent. Patients with lichen planus may develop additional lesions in sties of trauma
(Koebner phenomenon). Oral, genital, or nail abnormalities may also be present. (See "Lichen
planus".)
● Secondary syphilis – Cutaneous involvement in secondary syphilis may present with the
development of slightly scaly, erythematous to brown macules, papules, or small plaques in a
generalized distribution (picture 7). Involvement of the palms and soles is a common feature that
suggests this diagnosis. Serologic studies are useful for confirming a diagnosis of syphilis. (See
● Lymphomatoid papulosis – Lymphomatoid papulosis is a rare variant of the primary cutaneous T

cell lymphomas that present with crops of red papules on the trunk and extremities that resolve
spontaneously over four to six weeks (picture 8). Most papules ulcerate and heal with scarring,
unlike PLC, which usually heals with dyspigmentation only. (See "Lymphomatoid papulosis".)
1686
● Hypopigmented mycosis fungoides – Postinflammatory hypopigmentation secondary to PLC
can closely resemble hypopigmented mycosis fungoides, an uncommon presentation of
mycosis fungoides characterized by generalized hypopigmented patches (picture 9). This
concept was demonstrated in a Singaporean retrospective study that found that 24 percent of 46
children with mycosis fungoides were given an initial clinical diagnosis of PLC prior to
performance of a biopsy [22]. Hypopigmented mycosis fungoides most commonly occurs in
juvenile mycosis fungoides or as a presentation of mycosis fungoides in individuals with dark
skin [23]. A skin biopsy demonstrating findings consistent with mycosis fungoides (eg, atypical
lymphocytes, epidermotropism, and individual lymphocytes within the epidermis surrounded by
vacuolated halos) helps to distinguish this condition from PLC [22]. Rarely, cases of progression
of PLC to mycosis fungoides are reported. (See 'Association with malignancy' below and "Clinical
manifestations, pathologic features, and diagnosis of mycosis fungoides".)
TREATMENT
Approach to treatment — Because pityriasis lichenoides chronica (PLC) is a benign, nonscarring

condition that is often asymptomatic and self-limited, treatment is not mandatory. However, we find
that many patients desire therapy to improve the visible signs of the disease.
The best approach to treatment is unclear due to a paucity of high-quality efficacy data. Sources of
data are primarily limited to case reports and retrospective studies [24]. Moreover, many studies have
combined outcome data from patients with PLC and pityriasis lichenoides et varioliformis acuta
(PLEVA), complicating interpretation of treatment efficacy for patients with PLC.
Given the lack of high-quality data on treatment efficacy and the benign course of PLC, the risks
associated with pursuing treatment should always be considered carefully. Our initial approach to
treatment consists of therapies that have been reported to be effective and have a favorable safety
profile. We favor topical corticosteroids, oral antibiotics with anti-inflammatory properties, and
ultraviolet B (UVB) phototherapy for first-line therapy for PLC. Because of concern for serious drug
side effects, we reserve treatment with methotrexate and other systemic immunomodulatory
therapies for patients with severe and refractory disease.
First-line therapy — Topical corticosteroids, oral antibiotics, and phototherapy are our first-line
treatments for PLC.
Topical corticosteroids — Topical corticosteroids are commonly used for PLC despite few
published data on their efficacy. These agents may be useful for improving inflammation and
reducing associated pruritus. In a retrospective review that included 18 adults and 16 children with
PLEVA or PLC who received topical corticosteroid therapy, approximately one-half found the
1687
treatment useful for clearing or virtually clearing symptoms or signs of the disease [3]. We typically
prescribe a medium-potency topical corticosteroid (eg, triamcinolone 0.1% cream) to be applied twice
daily for four to six weeks to sites of active lesions.
Cutaneous atrophy is a potential adverse effect of topical corticosteroid use that is most likely to
occur with long-term use of high-potency corticosteroids. Additional side effects of topical
corticosteroids, including the effects of systemic absorption, are reviewed separately. (See "Topical
Oral antibiotics — Oral antibiotics with anti-inflammatory properties may be useful for the
management of PLC and are commonly used as first-line therapy. In particular, patients with
widespread eruptions may prefer oral therapy over topical therapy due to the difficulty of applying a
topical agent to multiple areas.
Tetracyclines and erythromycin are the oral antibiotics most commonly used for PLC. Tetracyclines
are typically used for the treatment of adolescents and adults. Tetracyclines should not be given to
children under the age of nine or pregnant women due to the risk for permanent discoloration of
developing teeth. Thus, erythromycin is typically used for the treatment of children with PLC.
Improvement with oral antibiotic therapy is usually evident within the first several weeks of treatment.
If benefit is not evident within three months, we discontinue the oral antibiotic and consider initiating
phototherapy.
Tetracyclines — The efficacy of tetracycline was evaluated in an uncontrolled study of 13

patients with pityriasis lichenoides (subtype unspecified) [25]. Patients were treated with 2 g per day
of tetracycline until lesions subsided followed by 1 g per day for one month. Of the 13 patients, 12
achieved marked improvement within four weeks. Seven patients needed to continue tetracycline (1 g
per day) to maintain the response to treatment.
Favorable results following treatment with a tetracycline class antibiotic were also reported in a
separate retrospective study. Three of four adults treated for pityriasis lichenoides (subtype
unspecified) with minocycline (100 mg twice daily for eight weeks) achieved clearance or near
clearance of skin lesions [3].
Our typical regimen of tetracyclines for adults consists of one of the following:
● Doxycycline (200 mg per day in two divided doses)

● Minocycline (200 mg per day in two divided doses)
● Tetracycline (2000 mg per day in four divided doses)
1688
Gastrointestinal distress is a potential side effect of these antibiotics. In addition, tetracyclines
(particularly tetracycline and doxycycline) may induce photosensitivity. Uncommon side effects of
minocycline include skin pigmentation and a lupus-like syndrome.
Erythromycin — The findings of several retrospective studies in children with pityriasis

lichenoides suggest that oral erythromycin may be beneficial in this population [4,5,7,26]. Most
studies have not separated outcomes for patients with PLC from those with PLEVA:
● In a retrospective study that included 124 children with pityriasis lichenoides (71 PLEVA, 46 PLC,
7 with features of both disorders), 67 percent of 57 children treated with oral erythromycin (30 to
50 mg/kg per day) appeared to respond to treatment [4]. The mean time to response was two
months. Among those who improved, 61 percent had complete clearance of skin lesions.
● In a retrospective study of 22 children with pityriasis lichenoides (14 PLEVA, 8 PLC), 11 of 15

children who were treated with erythromycin (varying doses) and were available for follow-up
achieved clinical remission (73 percent) [7]. Remission was generally achieved within two
months, and 7 of the 11 patients were able to discontinue therapy and remained free of lesions
during follow-up periods ranging from six weeks to three years. Four patients who did not receive
erythromycin appeared to have slower rates of improvement.
However, not all studies have yielded a high rate of response. A retrospective study of eight children
with pityriasis lichenoides (type unspecified) treated with erythromycin (40 to 60 mg/kg per day)
found that only two children achieved clearance after three months of treatment, one of whom
relapsed within four weeks of treatment cessation [3].
The dose of erythromycin that we typically use for children is 30 to 50 mg/kg per day. Gastrointestinal
distress is a potential side effect of erythromycin therapy.
Azithromycin, another macrolide antibiotic, has been reported to be effective in a few patients with
PLEVA [27-30]. The efficacy of azithromycin for PLC is unclear. (See "Pityriasis lichenoides et
varioliformis acuta (PLEVA)", section on 'Azithromycin'.)
Phototherapy — Phototherapy is a well-tolerated modality that is often beneficial for PLC.

Phototherapy is easily administered to a wide area of skin, a favorable feature for patients with
widespread involvement. However, the multiple office visits required make phototherapy a less
feasible treatment option for some patients. Narrowband ultraviolet B (NBUVB), broadband UVB, and
psoralen plus ultraviolet A (PUVA) are the primary phototherapeutic modalities used to treat these
diseases. We favor use of UVB phototherapy based upon the more favorable safety profile compared
with PUVA photochemotherapy. (See "UVB therapy (broadband and narrowband)" and "Psoralen plus
1689
Efficacy — Several uncontrolled and retrospective studies have evaluated the efficacy of UVB
phototherapy for PLC in children and/or adults [31-38], with most studies reporting improvement in
the majority of patients. One of the largest retrospective studies of NBUVB phototherapy in patients
with PLC (n = 25, Fitzpatrick skin phototype II or III (table 1)) documented complete (>75 percent
improvement) and partial (50 to 75 percent improvement) responses in 48 and 44 percent of patients,
respectively [32]. In a separate retrospective study that included eight patients with PLC (Fitzpatrick
skin phototype I or II) who were treated with NBUVB, seven (88 percent) achieved a complete
response (at least 90 percent clearance of skin lesions) and one patient achieved a partial response
(50 to 89 percent clearance of lesions) [31]. In a retrospective study that included nine patients with
PLC treated with phototherapy, four patients (44 percent) reported at least 76 percent improvement in
cutaneous lesions [38].
Few studies have directly compared the efficacy of different forms of phototherapy for PLC. Similar
efficacy of NBUVB and PUVA was suggested by an unblinded trial in which 15 patients with PLC were
randomly assigned to either treatment [39]. The trial did not find a significant difference in the rate of
response to therapy; 88 percent of NBUVB-treated patients and 74 percent of PUVA-treated patients
achieved more than 90 percent resolution of papulosquamous and plaque lesions, and the mean
number of treatment sessions required to achieve this response was similar. In addition, a
retrospective study that compared NBUVB with broadband UVB therapy in 29 patients with pityriasis
lichenoides (PLEVA, PLC, or an overlap syndrome) found a similar rate of response [34]. Complete
clearance of lesions was achieved by 93 percent of patients in both groups.
Ultraviolet A1 (UVA1) phototherapy is not widely available and experience with this modality for PLC
is limited. In a prospective study, treatment with UVA1 was associated with complete clinical and
histologic improvement in six of eight patients with PLC or PLEVA [40].
Administration — At least two to three months of treatment is usually required to achieve good
responses to UVB and PUVA phototherapy. Treatment often is initially administered at least three
times weekly and tapered to less frequent treatments once there is a satisfactory response. Relapse
may occur after the discontinuation of treatment. In a retrospective study in which seven of eight
adults with PLC refractory to topical therapy responded to NBUVB therapy, three patients relapsed
within three months after treatment cessation, suggesting that some patients may require long-term
maintenance therapy [37].
Potential adverse effects of UVB and PUVA phototherapy include blistering, burns, and pruritus.
Increased risk for squamous cell carcinoma has been reported in psoriasis patients who have
received high numbers of PUVA treatments [41]. The adverse effects of phototherapy are reviewed in
greater detail separately. (See "UVB therapy (broadband and narrowband)", section on 'Short- and
1690
long-term adverse effects' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on
'Adverse effects'.)
Second-line therapies — There are few data on additional treatment options for PLC.
Topical tacrolimus — A few case reports suggest that topical tacrolimus may be an additional
topical treatment option for pityriasis lichenoides. Improvement of longstanding PLC that failed to
respond sufficiently to topical clobetasol, oral erythromycin, phototherapy, or methotrexate was
documented in a patient in whom lesions on one side of the body were treated with tacrolimus 0.1%
ointment twice daily [42]. Although marked improvement was noted within two weeks, lesions
recurred soon after treatment cessation. Topical tacrolimus also appeared to be useful in two
children with PLEVA [43]. Additional studies will be useful for confirming the efficacy of topical
tacrolimus for PLC.
Transient stinging or burning sensations may occur at sites of tacrolimus application. Although some
safety concerns have been raised regarding the risk for lymphoma in patients treated with topical
tacrolimus, a causative relationship has not been proven. (See "Treatment of atopic dermatitis
(eczema)", section on 'Long-term safety concerns'.)
Methotrexate — Case reports have documented efficacy of methotrexate treatment in a few

patients with PLC, including patients with PLC that appeared to be induced by treatment with a
biologic tumor necrosis factor (TNF)-alpha inhibitor [16,44,45]. Methotrexate has also been used
successfully for the treatment of PLEVA and febrile ulceronecrotic Mucha-Habermann disease
(FUMHD). (See "Pityriasis lichenoides et varioliformis acuta (PLEVA)", section on 'Refractory
disease'.)
Due to the benign clinical course of PLC and the potential side effects of methotrexate, our use of
methotrexate is infrequent. We primarily reserve methotrexate therapy for patients with extensive or
symptomatic PLC who have failed other therapies. The side effects of methotrexate are reviewed
separately. (See "Major side effects of low-dose methotrexate".)
Other — Treatment with other systemic therapies, such as dapsone, acitretin with PUVA, systemic
glucocorticoids, cyclosporine, and intravenous immunoglobulin, have been suggested for the
treatment of refractory PLEVA or FUMHD based upon isolated reports of benefit [2,46-49]. The
efficacy of these agents in PLC is unclear. The risks of treatment should be carefully considered prior
to attempting treatment with such agents. A response to photodynamic therapy has been reported in
one patient with PLC [50].
ASSOCIATION WITH MALIGNANCY
1691
The development of cutaneous lymphoma, most commonly mycosis fungoides, has been reported in
several children and adults with pityriasis lichenoides chronica (PLC) [13,51-55]. In addition, two
patients in whom PLC appeared to be a paraneoplastic phenomenon related to a renal oncocytoma or
an extranodal lymphoma have been reported [54,56]. (See "Clinical manifestations, pathologic
features, and diagnosis of mycosis fungoides", section on 'Clinical features'.)
Given the apparent rarity of associations between PLC and malignancy, PLC is considered a benign
disease. However, as a precaution, we perform a full skin examination on patients with PLC at least
once yearly to evaluate for signs of cutaneous lymphoma. We also encourage patients to return if
atypical skin lesions develop (eg, persistent inflammatory patches, plaques, or tumor-like nodules).
We do not routinely perform cancer screening beyond recommended age-appropriate measures.
● Pityriasis lichenoides chronica (PLC) is a rare inflammatory skin disorder of unknown etiology
that is considered a subtype of pityriasis lichenoides. PLC most commonly occurs in young
adults and children. (See 'Epidemiology' above.)
● Patients with PLC usually present with widely distributed, red-brown papules on the trunk and
extremities (picture 1A-C). A mica-like scale overlying the papules often is visible. Most patients
are asymptomatic. Occasionally, associated pruritus is present. (See 'Clinical features' above.)
● Although PLC has a relapsing and remitting course that persists for months to years, individual
lesions tend to resolve within a few weeks. Hypopigmented macules or patches often remain at
the sites of prior lesions. (See 'Clinical features' above.)
● A diagnosis of PLC is suspected based upon the findings on the physical examination. A skin
biopsy is usually performed to confirm the diagnosis. (See 'Diagnosis' above.)
● Because PLC is a benign, often asymptomatic and self-limited disorder, treatment is not
mandatory. However, many patients desire treatment to improve the appearance of skin lesions.
(See 'Approach to treatment' above.)
● Data on the efficacy of treatments for PLC are limited. For patients with PLC who desire
treatment, we suggest the use of topical corticosteroids, oral antibiotics (tetracyclines for adults
and erythromycin for children), or ultraviolet B (UVB) phototherapy as initial treatment due to the
relative safety of these interventions (Grade 2C). (See 'First-line therapy' above.)
● Although PLC is considered a benign disorder, infrequent reports have linked PLC to the
development of cutaneous lymphoma. As a precaution, we perform skin examinations in patients
1692
with PLC at least once yearly. (See 'Association with malignancy' above.)
1693
GRAPHICS
1694
Multiple red-brown papules with adherent scale and hypopigmented macules on the legs.
1695
Red-brown macules with adherent scale in a patient with pityriasis lichenoides chronica.
1696
Scattered red-brown scaly papules and numerous hypopigmented macules in a patient with pityriasis lichenoides
chronica.
1697
Pityriasis lichenoides et varioliformis acuta
Multiple inflammatory papules are present. Some lesions demonstrate necrosis and crusting.
1698
Pityriasis rosea
1699
Guttate psoriasis
1700
Lichen planus
Violaceous and hyperpigmented, polygonal papules are present on ankles and ventral
wrists.
1701
Lichen planus
Violaceous, polygonal papules are present on the ventral wrists.
1702
Secondary syphilis
1703
Lymphomatoid papulosis
Multiple inflammatory papules are present on the trunk. Some lesions have overlying crust.
1704
Hypopigmented mycosis fungoides
Hypopigmented patches are present in this patient with mycosis fungoides.
1705
1706
Pityriasis lichenoides et varioliformis acuta (PLEVA)

Author: James R Treat, MD
Section Editors: Moise L Levy, MD, John A Zic, MD
INTRODUCTION
Pityriasis lichenoides et varioliformis acuta (PLEVA), otherwise known as Mucha-Habermann

disease, is an uncommon cutaneous inflammatory disorder that most frequently affects young
adults and children. PLEVA usually presents as an acute eruption of inflammatory papules and
papulovesicles that rapidly develop hemorrhagic or necrotic crusts (picture 1A-C). Febrile
ulceronecrotic Mucha-Habermann disease (FUMHD) is a potentially life-threatening, severe
presentation of PLEVA.
Pityriasis lichenoides chronica (PLC), which is characterized by the appearance of multiple scaly, red-
brown papules on the skin, is often considered to be on a disease continuum with PLEVA (picture 2)
[1]. The term "pityriasis lichenoides" is frequently used to refer to the spectrum of these disorders.
The clinical features, diagnosis, and management of PLEVA will be discussed here. PLC is reviewed
separately. (See "Pityriasis lichenoides chronica".)
EPIDEMIOLOGY
PLEVA is a rare disorder. The precise incidence and prevalence are not known. PLEVA may occur at
any age (including infants) [2], but most frequently occurs in children and young adults.
Data on PLEVA and PLC are often combined in the literature under pityriasis lichenoides,
complicating the assessment of the epidemiology of PLEVA. A slight male predominance has been
detected among children with pityriasis lichenoides [1], and in one of the largest series of children
with pityriasis lichenoides, 40 of 71 children with PLEVA (56 percent) were male [3]. A male
1707
predominance is less consistently observed in the general population of patients with pityriasis
lichenoides [1].
Similar to the classic presentation of PLEVA, the severe febrile ulceronecrotic Mucha-Habermann
disease (FUMHD) variant primarily occurs in children and young adults. A 2008 review of 40 reported
cases found that the mean age of affected patients was 27 (range 4 to 82 years) [4]. The majority of
patients (75 percent) were under the age of 35 years.
A separate review of 24 published cases of FUMHD found that seven of the reported patients were of
Mediterranean descent and six patients were of Asian descent [5]. However, ethnic or geographic
differences in the prevalence of PLEVA and FUMHD have not been definitively established.
PATHOGENESIS
The pathogenesis of PLEVA is poorly understood. The two prevailing pathogenic theories involve the
classification of PLEVA as a T cell dyscrasia and the designation of PLEVA as an aberrant immune
response to viral, bacterial, or protozoal infections.
The identification of T cell clones in patients with PLEVA, the clinical resemblance of PLEVA to
lymphomatoid papulosis, and the rare development of lymphoma in patients with PLEVA are used to
support the concept that PLEVA and febrile ulceronecrotic Mucha-Habermann disease (FUMHD)
may be T cell lymphoproliferative disorders [6-8]. In one study of patients with PLEVA, a dominant T
cell clone was detected in 13 of 20 biopsy specimens [7] Based upon this theory, an immune
response that attacks and eventually eliminates the T-cell clone could account for the self-limited
disease course that typically characterizes PLEVA. (See 'Disease course' below.)
The assertion that PLEVA represents a hypersensitivity reaction to infectious agents arises from
multiple reports of the development of PLEVA in the setting of recent or concurrent infections.
Examples include infections due to Toxoplasma gondii, human herpesvirus 8, Epstein-Barr virus,
human immunodeficiency virus, varicella-zoster virus, and group A Streptococcus [9-15]. In
accordance with the infection theory, the detection of T cell clones in PLEVA could represent a clonal
immunologic response to a microbial antigen, rather than a primary lymphoproliferative disease.
Case reports describing the development of PLEVA soon after receipt of a live-attenuated measles
vaccine; the combined measles, mumps, and rubella vaccine; influenza; and tetanus vaccination may
provide additional support for this theory [16-19]. In addition, plasmacytoid dendritic cells, which
produce type I interferons and play a key role in defense against viral infections, have been found in
specimens from lesions of pityriasis lichenoides chronica and PLEVA [20].
1708
An interesting observation is the detection of elevated levels of the proinflammatory cytokine tumor
necrosis factor (TNF)-alpha and the soluble interleukin-2 receptor (a marker of elevated T cell
activation) in patients with FUMHD [5,6,21]. The relevance of these findings in the pathogenesis of
FUMHD remains to be determined. Although successful therapy with infliximab (a biologic TNF-
alpha inhibitor) has been documented in case reports [22,23], there are also case reports describing
pityriasis lichenoides chronica induced by the biologic TNF-alpha inhibitors adalimumab and
etanercept [24,25].
Several exogenously administered substances have been linked to the development of features
consistent with PLEVA in case reports, such as tegafur, astemizole, estrogen-progesterone, and
radiocontrast iodide [26-29]. The mechanisms by which these substances might induce PLEVA are
unknown.
PLEVA — PLEVA usually begins as an acute eruption of multiple erythematous macules that rapidly
evolve to form 3 to 15 mm inflammatory papules and papulovesicles, some of which develop
hemorrhagic or necrotic crusts (picture 1A-C). Although the trunk, proximal extremities, and skin
flexures are the most common sites for involvement, any cutaneous surface may be affected [30].
Mucosal involvement is typically absent.
The individual skin lesions of PLEVA usually appear and resolve over the course of a few weeks [31].
However, new lesions often develop as earlier lesions resolve, resulting in ongoing disease and the
simultaneous presence of lesions in various stages of development. Hypopigmentation and
hyperpigmentation frequently persist after lesion resolution (picture 1C) [3]. Scarring may or may not
develop.
The cutaneous lesions of PLEVA may be asymptomatic, pruritic, or associated with a burning
sensation [30,32]. Systemic symptoms are often absent, but in a minority of patients, fevers or
arthralgias occur [3].
Occasionally, patients experience infectious symptoms prior to the onset of the skin eruption. In one
retrospective series that included 71 children with PLEVA, 46 children with pityriasis lichenoides
chronica (PLC), and 7 children with manifestations of both conditions, an infection (most commonly
an upper respiratory infection) preceded the onset of skin disease in 28 children (23 percent) [3].
FUMHD — Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) may occur de novo or in the
setting of preexisting PLEVA [4]. Compared with PLEVA, the clinical manifestations of FUMHD are
more severe. Affected patients develop an acute eruption of necrotic papules that rapidly evolve to
1709
form necrotic plaques and ulcers that reach up to a few centimeters in diameter (picture 3) [31].
Hemorrhagic bullae and oral, genital, and conjunctival mucosal ulcerations may also occur [1]. The
skin lesions often resolve with atrophic scarring [1].
The cutaneous findings of FUMHD are accompanied by persistent high fevers (up to 40°C) and
fatigue. Internal involvement is common, and may manifest as cardiomyopathy, central nervous
system vasculitis, arthritis, interstitial pneumonitis, hematologic abnormalities, abdominal pain,
diarrhea, sepsis, or other disorders [5,6,33-36].
DISEASE COURSE
PLEVA often follows a relapsing and remitting course prior to spontaneous resolution, and periods of
complete or near complete remission may be interspersed with periods of greater disease activity.
The duration of PLEVA prior to resolution is highly variable, ranging from a few weeks to years. As an
example, a retrospective study that included 71 children with PLEVA found a median duration of
PLEVA of 18 months (range 4 to 108 months), and a study that included 22 children and adults with
PLEVA found a median disease duration of 24 months (range 2 to 132 months) [3,37]. In contrast, a
retrospective study that included five patients with PLEVA and one patient with febrile ulceronecrotic
Mucha-Habermann disease (FUMHD) found an average duration of disease of only 1.6 months [38].
During the course of PLEVA, patients can develop scaly, red-brown papules that are consistent with
pityriasis lichenoides chronica (PLC) alongside lesions consistent with PLEVA, and occasionally,
patients completely transition from PLEVA to PLC [39]. These observations have been used to
support the concept that PLEVA and PLC represent a spectrum of a single disease. (See 'Differential
diagnosis' below.)
FUMHD is a serious and potentially fatal disease. A 2008 review found that 9 of 40 reported cases
(15 children and 25 adults) resulted in death [4]. All deaths occurred in adults. FUMHD usually does
not recur [36].
DIAGNOSIS
The recognition of consistent cutaneous findings raises suspicion for PLEVA. A skin biopsy is
required to confirm the diagnosis and rule out other disorders that can closely resemble PLEVA.
Biopsy — The key histopathologic findings of PLEVA are found in the epidermis and dermis; thus, the
biopsy specimen must adequately sample both of these structures. We typically obtain a tissue
1710
specimen via a 4 mm punch biopsy. Alternatively, an incisional biopsy can be performed. (See "Skin
biopsy techniques", section on 'Biopsy techniques'.)
In febrile ulceronecrotic Mucha-Habermann disease (FUMHD), the recognition of ulceration in the

pathology specimen can assist with the interpretation of the biopsy findings. Therefore, in patients
with suspected FUMHD, the biopsy specimen should include the edge of an ulcer.
Histopathology — The histologic findings of PLEVA are not pathognomonic, but when reviewed in
conjunction with the clinical context, are valuable for diagnosis [3,40]. Typical histopathologic
findings in PLEVA include [1]:
● Parakeratosis, spongiosis, mild to moderate epidermal acanthosis
● Vacuolar alteration of the basal layer
● Exocytosis of lymphocytes and erythrocytes into the epidermis
● Moderately dense, wedge-shaped lymphohistiocytic infiltrate extending from the papillary

dermis into the deep reticular dermis
Additional findings that may be present include epidermal erosions or necrosis, vesiculation,
endothelial swelling, dermal hemorrhage, and papillary dermal edema. Vasculitis is rare.
The histopathologic findings of FUMHD resemble the findings in PLEVA with a few exceptions [1].
The perivascular inflammatory infiltrate tends to be denser and necrosis is more prominent. In
addition, leukocytoclastic vasculitis is a prominent feature in FUMHD.
Immunohistochemistry — Immunohistochemical studies can aid in confirming the diagnosis of

PLEVA. The inflammatory infiltrate is usually primarily composed of CD8+ T lymphocytes. Unlike
lymphomatoid papulosis (LyP), CD30 stains are usually negative [1]. (See "Lymphomatoid papulosis",
section on 'Differential diagnosis' and "Lymphomatoid papulosis".)
Laboratory studies — No serologic tests are specific for the diagnosis of PLEVA. Leukocytosis and
an elevated erythrocyte sedimentation rate or C-reactive protein level are common findings in
FUMHD [41]. Depending on the extent and type of internal involvement, patients with FUMHD may
exhibit a variety of other laboratory abnormalities. (See 'FUMHD' above.)
Based upon the reports of an association of PLEVA with infection, laboratory studies may be used to
evaluate for evidence of existing or preceding infection if the clinical scenario suggests this
possibility. Examples of the infections that are most frequently considered include group A
Streptococcus, Toxoplasma gondii, human immunodeficiency virus, and Epstein-Barr virus infections
[1]. (See 'Pathogenesis' above.)
1711
Multiple inflammatory and infectious disorders share clinical features with PLEVA. Assessment of
the clinical history, examination of the morphology and distribution of skin lesions, and review of the
pathology findings facilitate the differentiation of PLEVA from these disorders.
Examples of disorders in the differential diagnosis of PLEVA are as follows:
● Lymphomatoid papulosis – Lymphomatoid papulosis (LyP) is the disease that most closely
resembles PLEVA (table 1). Patients present with recurrent crops of inflammatory papules and
small nodules that spontaneously regress, usually within several weeks (picture 4). Similar to
PLEVA, crusted, hemorrhagic, and necrotic lesions may be present.
The histologic and immunohistochemical features of LyP differ from PLEVA and are useful for
distinguishing between these diseases. LyP is characterized by a dermal infiltrate composed of
large atypical lymphocytes that are CD30+ (picture 5). In contrast, atypical cells and CD30+ cells
are few or absent in PLEVA. (See "Lymphomatoid papulosis".)
● Pityriasis lichenoides chronica – Pityriasis lichenoides chronica (PLC) is considered to be on a

disease spectrum with PLEVA. Unlike PLEVA, which is characterized by the acute eruption of
crusting and hemorrhagic papules, the lesions of PLC are usually red-brown papules with
overlying micaceous scale that regress over the course of several weeks to months (picture 2)
[31]. Of note, patients with PLEVA may simultaneously develop lesions consistent with PLC and
occasionally transition to PLC from PLEVA [39]. (See "Pityriasis lichenoides chronica".)
● Varicella – The acute development of papulovesicles on multiple areas of the skin is typical of
varicella (picture 6). The lesions are often described as a dewdrop on a rose petal. Pruritus is
usually present. The course of the disease is shorter than PLEVA, usually lasting only one to two
weeks. Immunosuppressed patients may develop disseminated varicella, which presents with
larger, hemorrhagic skin lesions and a longer disease course. Polymerase chain reaction or
direct fluorescent antibody testing can be used to confirm the diagnosis. (See "Clinical features
of varicella-zoster virus infection: Chickenpox" and "Diagnosis of varicella zoster virus
infection".)
● Disseminated herpes simplex virus – In immunocompromised patients and patients who have a
compromised skin barrier (eg, atopic dermatitis, Darier disease), herpes simplex virus infection
may result in the development of widespread vesicles, pustules, and crusts (picture 7). The term
"eczema herpeticum" is used to describe this occurrence in patients with atopic dermatitis.
Polymerase chain reaction or direct fluorescent antibody testing can be used to identify herpes
1712
simplex infection. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex
virus type 1 infection", section on 'Eczema herpeticum' and "Epidemiology, clinical
manifestations, and diagnosis of herpes simplex virus type 1 infection".)
● Arthropod bites – Multiple arthropod bites may result in the acute development of widespread,
often pruritic, inflammatory papules (picture 8). Vesiculation and necrosis are infrequent
findings. The patient history is useful for diagnosis. (See "Insect and other arthropod bites",
section on 'Types of reactions'.)
● Gianotti-Crosti syndrome – Gianotti-Crosti syndrome is an uncommon disorder that usually

occurs in young children. Children often have symptoms of an upper respiratory or
gastrointestinal infection prior to the eruption of papules and papulovesicles primarily
distributed on the face, buttocks, or extremities (picture 9). Hemorrhagic lesions may be present.
Lymphadenopathy and hepatomegaly may accompany the cutaneous symptoms. The eruption
typically resolves spontaneously within weeks to months. The morphology and distribution of
lesions and biopsy findings can aid in distinguishing this disorder from PLEVA. (See "Gianotti-
Crosti syndrome (papular acrodermatitis)".)
● Langerhans cell histiocytosis – In infants and young children, Langerhans cell histiocytosis
(LCH) often presents with hemorrhagic papules (picture 10A-B). Unlike PLEVA, the eruption is
primarily localized in seborrheic or intertriginous areas such as inguinal folds, axillae, scalp, and
posterior auricular areas. A skin biopsy is useful for diagnosing LCH. (See "Clinical
manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on
'Skin and oral mucosa'.)
TREATMENT
Approach to treatment — Because PLEVA is a benign, usually self-limited disorder, clinical follow-up
without pharmacologic treatment is an option for the management of children and adults with
limited, nonscarring disease who are not bothered by the skin lesions. However, patients with
extensive, persistent, symptomatic, scarring, or cosmetically disfiguring disease often desire
treatment.
Due to the wide variation in the duration of PLEVA prior to spontaneous resolution, randomized trials
to evaluate the treatments for PLEVA would be of value for confirming the effectiveness of
interventions. However, PLEVA is a rare disorder, and data on the interventions for PLEVA are limited.
Antibiotic therapy with tetracyclines or erythromycin and phototherapy are considered first-line
treatments based upon retrospective studies and case reports that suggest treatment benefit and the
1713
relatively low risk for severe adverse effects associated with these interventions. Both modalities
often require two to three months of treatment to achieve satisfactory improvement, which may or
may not persist after the discontinuation of therapy.
Data are insufficient to determine the comparative efficacy of oral antibiotics and phototherapy for
PLEVA, and our decision of which modality to utilize as initial therapy primarily rests upon the
consideration of patient characteristics and preferences. Factors such as comorbidities (eg,
photosensitive disorders or melanoma), the cost and availability of phototherapy, and the multiple
clinical visits required for phototherapy limit the use of phototherapy in some patients.
In children, we typically attempt treatment with oral antibiotic therapy prior to phototherapy due to
the paucity of data on the long term effects of phototherapy in children. Moreover, some children are
unable to fully comply with the safety measures necessary for phototherapy.
Methotrexate is an additional treatment option that has appeared to be beneficial in individual

patients with PLEVA. Due to concern regarding the adverse effects of this drug, we typically reserve
methotrexate for patients who have failed oral antibiotics and phototherapy.
First-line therapies — First-line therapies for PLEVA include systemic antibiotics and phototherapy.
Topical corticosteroids may be useful for improving symptoms.
Systemic antibiotics — Antibiotics with anti-inflammatory properties are the primary antibiotics
utilized for PLEVA. Adolescents and adults are usually treated with tetracyclines. Tetracyclines are
contraindicated in children under the age of nine due to deleterious effects on tooth development.
Thus, erythromycin is typically utilized for antibiotic treatment in children.
Our typical treatment regimen for adults is as follows:
● Doxycycline 100 mg once to twice daily

● Minocycline 100 mg once to twice daily
Our typical treatment regimen for children is as follows:
● Erythromycin 30 to 50 mg/kg per day given in two to four divided doses
We continue these doses until complete or almost complete lesion resolution is attained (typically
within one to three months), then taper over one to two months as tolerated. Patients who relapse
upon tapering or drug discontinuation can be given longer courses of therapy. If no response is
evident after three months of treatment with an antibiotic, we discontinue treatment and consider
phototherapy.
1714
Azithromycin is an additional therapeutic option for children and adults, but experience with this drug
in PLEVA is more limited. Data on the efficacy of specific antibiotics are provided below.
Tetracyclines — The use of tetracyclines in PLEVA is based upon an uncontrolled study that
demonstrated efficacy of tetracycline in pityriasis lichenoides and case reports. In the uncontrolled
study, 12 of 13 patients with pityriasis lichenoides who were treated with tetracycline (2 g per day
until lesions subsided followed by 1 g per day for one month) had great improvement within four
weeks [42]. The proportion of responders who had PLEVA or PLC was not specified. However, the
patient who failed to respond to treatment had features of PLEVA. Seven of the responders required
the continuation of tetracycline (1 g per day) to maintain improvement.
Improvement following treatment with tetracyclines has been documented in individual reports of
patients with PLEVA. Complete suppression of skin lesions occurred within three weeks in an
adolescent girl treated with tetracycline (2 g per day) [43], and minocycline (100 mg per day) was
associated with improvement in at least one of two patients with PLEVA in a retrospective series
[32].
Erythromycin — Support for the use of erythromycin in PLEVA is derived from several
retrospective studies, most of which combine patients with PLEVA and PLC [3,38,44,45]. Examples of
studies in which the majority of patients had PLEVA include:
● In a retrospective study that included 71 children with PLEVA, 46 children with PLC, and 7
children with a mixed presentation, 80 percent were treated with erythromycin (30 to 50 mg/kg
per day) [3]. Among the 57 patients who were available for follow-up after treatment with
erythromycin, 34 (67 percent) improved within a median of two months. Sixty-one percent of the
responders achieved complete clearance of active skin lesions. The maintenance of the
response after treatment cessation was not assessed.
● In a retrospective study of 14 children with PLEVA and 8 children with PLC, 11 of 15 children
who received erythromycin and were available for follow-up achieved remission (usually within
two months). Seven children were able to discontinue erythromycin after two to five months of
treatment and remained free of lesions for follow-up periods that ranged from six weeks to three
years [44].
Less favorable results with erythromycin have been reported. In a case series in which eight children
with PLEVA were treated with erythromycin for at least six weeks, two improved, four had no change
in disease severity, and two worsened during treatment [46]. In addition, in a retrospective study in
which eight children with pityriasis lichenoides (subtype unspecified) were treated with oral
erythromycin, only two children had disease clearance after three months of treatment, one of whom
relapsed within four weeks after treatment cessation [32].
1715
Azithromycin — Azithromycin (500 mg for one day followed by 250 mg for four days taken on
the first and third weeks of the month) was effective within one month for an adult woman with
PLEVA who failed to respond to doxycycline and within two months in a child with PLEVA who did
not improve with erythromycin [47]. A child treated with a combination of azithromycin and topical
tacrolimus also seemed to benefit from treatment [48].
The potential adverse effects of azithromycin are reviewed separately. (See "Azithromycin and
clarithromycin", section on 'Adverse reactions'.)
Phototherapy — Phototherapy with ultraviolet (UV) light is frequently utilized for the treatment of
pityriasis lichenoides and appears to be effective in many patients with PLEVA [1,49]. The modalities
utilized include narrowband UVB, broadband UVB, psoralen plus UVA (PUVA), and UVA1.
As noted above, comorbidities and the availability, feasibility, and cost of phototherapy are limiting
factors for some patients. Phototherapy is usually administered at least three times weekly at the
start of therapy and tapered after a satisfactory response. At least two to three months of treatment
is usually required to achieve improvement. Similar to antibiotic therapy, relapses occur with variable
frequency after the discontinuation of treatment.
The types of phototherapy that have been utilized in PLEVA are reviewed below:
● UVB – UVB is our first choice for phototherapy. The use of UVB phototherapy in pityriasis
lichenoides is supported by retrospective studies and case series [49]. In a retrospective study
that included 23 patients with PLEVA (all with skin phototypes I to III (table 2)) who were treated
with narrowband UVB, 15 (65 percent) achieved at least 90 percent clearance of disease (mean
number of treatments = 43, mean cumulative dose = 23 J/cm2) [49]. The remaining eight
patients achieved partial responses (at least 50 to 90 percent clearance). Two of the complete
responders relapsed within one year.
Either narrowband UVB or broadband UVB may be used for the treatment of PLEVA. A
retrospective study of 29 patients with PLC, PLEVA, or an overlap syndrome did not find a
significant difference in response rates to these modalities (93 percent in each treatment group
responded) [50]. Additional studies are necessary to confirm whether differences in efficacy
exist.
● PUVA – Complete responses to PUVA have been documented in multiple case reports, some of
which demonstrated long-term clearance, and others in which recurrences appeared after
treatment cessation [1]. However, in the absence of data that indicate superior efficacy of PUVA
over UVB phototherapy, the need for the administration of a systemic photosensitizer and the
potential for additional adverse effects related to the photosensitizing agent make PUVA a less
1716
favorable first-line option for phototherapy. (See "Psoralen plus ultraviolet A (PUVA)
photochemotherapy", section on 'Safety measures' and "Psoralen plus ultraviolet A (PUVA)
photochemotherapy", section on 'Adverse effects'.)
● UVA1 – Data on the efficacy of UVA1 phototherapy are more limited than for UVB phototherapy.
UVA1 phototherapy has been associated with complete responses in a few patients with PLEVA
[51]. The availability of UVA1 is primarily restricted to academic centers, limiting the use of this
therapy.
Continuing treatment at a reduced frequency (eg, tapering to once every two weeks) after a complete
response is attained has been utilized by some clinicians, including ourselves, in an attempt to
reduce the likelihood of recurrence [49,50]. The value of maintenance regimens has not been
formally studied.
Outdoor sun exposure is sometimes tried for patients in whom phototherapy is not feasible. Patients
are often instructed to expose the affected areas to midday sunlight for 10 to 20 minutes and to then
slowly increase the duration of daily sun exposure to maintain tanned but not burned skin. The
duration of sun exposure required is dependent on skin type (table 2). Patients with very fair skin
who are unable to tan are not favorable candidates for this therapy.
The efficacy of outdoor sun exposure on PLEVA has not been formally evaluated. Our experience
suggests that some patients achieve modest benefits. In temperate climates, this option is limited to
the time period between late spring and early autumn.
Topical agents — Topical corticosteroids may be useful for attaining symptomatic relief or
accelerating the resolution of individual lesions; however, these agents are not thought to alter the
course of PLEVA. Medium or high potency topical corticosteroids are usually applied to individual
lesions once or twice daily for two to three weeks (table 3). In a retrospective study, approximately
half of 18 adults and 16 children treated with topical corticosteroids found these agents useful for
alleviating disease signs and symptoms [32]. Case supports suggest that topical tacrolimus
ointment may also be useful for PLEVA [48,52].
Refractory disease — Case reports indicate that methotrexate may be effective for PLEVA [46,53-55].
Methotrexate is administered once weekly at doses between 7.5 to 20 mg per week. In some
patients, improvement has been noted within a few weeks.
Due to the potential for serious adverse effects related to methotrexate therapy, we typically reserve
this treatment for patients who fail to respond to first-line therapies. Relapses during or after tapering
of methotrexate appear to be common [53-55].
1717
Other therapies that have been suggested for refractory disease include dapsone, acitretin, and
cyclosporine [1]. Combination therapy with acitretin and PUVA was dramatically effective in two
patients with refractory PLEVA within a few weeks [56].
Febrile ulceronecrotic Mucha-Habermann disease — Due to the rarity of febrile ulceronecrotic

Mucha-Habermann disease (FUMHD) and the multiple therapies often administered simultaneously
to these patients, the best approach to the treatment of FUMHD is unknown. Case reports document
the use of a wide variety of therapeutic agents. Methotrexate appears to be the most consistently
beneficial therapy [4]. Systemic glucocorticoids have been utilized in many reported cases, but
whether they are truly beneficial remains unclear. Other agents that have been utilized for FUMHD
include intravenous immunoglobulin, antibiotics, acyclovir, dapsone, cyclosporine, and phototherapy
[36]. Inpatient management is usually required for these systemically ill patients.
Although elevated TNF-alpha levels were detected in a child with FUMHD, a role for TNF-alpha
inhibitors in FUMHD remains to be determined. There are case reports of successful therapy with
infliximab [22,23]. In one report, only two doses were needed and lead to complete remission [23].
ASSOCIATION WITH LYMPHOMA
Rare reports of the development of cutaneous T cell lymphoma in patients with a history of PLEVA
exist. Two children in whom this was thought to have occurred have been reported [57]. PLC has also
been infrequently linked to cutaneous lymphoma [58,59]. (See "Pityriasis lichenoides chronica",
section on 'Association with malignancy'.)
In light of the rarity of such reports, PLEVA is generally accepted as a disease with a benign clinical
course. Signs that may suggest cutaneous lymphoma include the development of persistent
cutaneous inflammatory patches or plaques or tumor-like nodules.
PATIENT FOLLOW-UP
Patients should be followed periodically (every three to six months) if treatment is deferred. This
allows the clinician to discuss treatment if the disorder persists and provides the opportunity for
reevaluation if the clinical findings evolve in a manner that suggests another diagnosis. We typically
follow treated patients closely to monitor the effect of therapy.
1718
● PLEVA is an uncommon cutaneous disorder that is characterized by the acute development of
inflammatory papules and papulovesicles with hemorrhagic or necrotic crusts on the skin
(picture 1A-C). PLEVA may occur at any age, but children and young adults are most frequently
affected. (See 'Epidemiology' above.)
● The pathogenesis of PLEVA is not well understood. Theories on the pathogenesis of PLEVA
include a view of PLEVA as a benign lymphoproliferative disorder or as a hypersensitivity
response to infection. (See 'Pathogenesis' above.)
● The cutaneous lesions of PLEVA tend to appear on the trunk, proximal extremities, and skin
flexures. Although individual lesions often resolve within a few weeks, new crops of lesions
often develop resulting in lesions at different stages of development. (See 'Clinical
● PLEVA is a benign, self-limited disorder. However, symptoms may persist for weeks, months, or
years. (See 'Disease course' above.)
● Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare, severe variant of PLEVA

characterized by systemic illness, fever, and large ulcerated skin lesions. FUMHD can be fatal,
particularly in adults. (See 'FUMHD' above and 'Disease course' above.)
● The diagnosis of PLEVA is made through the assessment of clinical and histopathologic
findings. The disorder that bears the closest clinical resemblance to PLEVA is lymphomatoid
papulosis. A skin biopsy and immunohistochemical studies are useful for distinguishing
between these diseases. (See 'Diagnosis' above and 'Differential diagnosis' above and
"Lymphomatoid papulosis".)
● Data are limited on the treatment options for PLEVA. Since the disease may be asymptomatic
and self-limited, treatment is not always required. For adult patients who desire treatment, we
suggest treatment with oral tetracyclines or UVB phototherapy, based upon patient preferences
and treatment availability (Grade 2C). For children with PLEVA we suggest treatment with oral
erythromycin (Grade 2C). Children who fail to improve with oral erythromycin are candidates for
UVB phototherapy if they can comply with therapy. (See 'Treatment' above.)
● Methotrexate is a treatment option for PLEVA that is refractory to oral antibiotics and
phototherapy. The risks and benefits of treatment with this agent should be considered carefully.
(See 'Refractory disease' above.)
● The best approach to treatment of FUMHD has not been established. Methotrexate and other
systemic immunomodulators may be beneficial. Further study is necessary to determine the
1719
appropriate approach to the treatment of this disease. (See 'Febrile ulceronecrotic Mucha-
Habermann disease' above.)
1720
GRAPHICS
1721
1722
Erythematous papules and papulovesicles are present on the thigh. Postinflammatory

hyperpigmentation is evident at sites of previous lesions.
1723
1724
Febrile ulceronecrotic Mucha-Habermann disease
Hemorrhagic nodules in febrile ulceronecrotic Mucha-Habermann disease.
1725
Differential diagnosis of lymphomatoid papulosis
Systemic Mycosis Pityriasis Arthropod

LyP Scabies
ALCL fungoides lichenoides bite
Clinical Self-healing Frequent Scaling Scaling Exposure Itchy lesions

papulonodular skin secondary skin erythematous erythematous Responds
lesions lesions, patches, plaques, hemorrhagic well to
lymphadenopathy tumors, +/– lesions scabies
B symptoms lymphadenopathy treatment
Histopathology/ Atypical CD30, CD4+ Lack of Epidermotropism Interface Punctum, Presence of

immunophenotype cells surrounded by epidermotropic of cerebriform dermatitis, insect parts mite
inflammatory cells cerebriform cells cells necrotic Polymorphous CD30+ cells
ALK+, EMA+; CD30+ with large keratinocytes, and B cells
Inflammation
ALK– in patients cell extravasated present
erythrocytes CD30+ cells
over 30 transformation
may be
CD8>CD4, few
present
CD30+ cells
Genetics Clonal in 60% t(2;5) often Lack of t(2;5) Clonal TCR No No

Aneuploidy of type A present Complex rearrangement abnormalities abnormalities
No IRF4 karyotype, clonal in 50 percent
Lack of t(2;5)
translocation or oligoclonal TCR
Recurrent rearrangement
Clonal TCR rearrangement
of 6p25.3
rearrangement
ALK: anaplastic lymphoma kinase; EMA: epithelial membrane antigen; TCR: T cell receptor.
1726
Lymphomatoid papulosis
Multiple inflammatory papules are present on the trunk. Some lesions have overlying crust.
1727
Histopathology of lymphomatoid papulosis
(A) Early perivascular lesion.

(B) Neutrophils within and around blood vessels are characteristic.
(C) Mature wedge-shaped lesion.
(D) Advanced ulcerated lesion.
Early lesions have a perivascular lymphoid infiltrate. Mature lesions have a wedge-shaped
appearance. The most common type A lesions have large Reed-Sternberg-like cells and frequent
mitoses in an inflammatory background. Type B lesions resemble mycosis fungoides (MF) and may
be a papular variant of MF. Type C lesions demonstrate a relatively monotonous population of large
CD30+ cells with few inflammatory cells.
Panel C reproduced from: Kadin ME. Primary cutaneous CD30-positive t-cell lymphoproliferative disorders. In:
Hematopathology, Jaffe ES, Harris NL, Vardiman JW, et al. (Eds), Philadelphia, Elsevier 2011. Illustration used with
the permission of Elsevier Inc. All rights reserved.
1728
Primary varicella lesions
Vesicular lesions on an erythematous base are characteristic of chickenpox. The lesions

occur in crops and are present in a variety of stages from maculopapular to vesicular or
even pustular. Central necrosis and early crusting is also visible.
Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr
(Eds), Williams & Wilkins, Baltimore 1995.
http://www.lww.com
1729
Eczema herpeticum
1730
Flea bites ankle
Four flea bites clustered on an ankle.
Disorders, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott
Williams & Wilkins.
1731
Characteristic eruption of Gianotti-Crosti syndrome (papular acrodermatitis)
The characteristic rash of Gianotti-Crosti syndrome consists of symmetric, pink-brown, papular or

papulovesicular lesions that are flat-topped and range from 1 to 10 mm in diameter. The face,
buttocks, extensor aspects of forearms and legs, and feet are predominantly affected.
Courtesy of Moise L Levy, MD.
1732
Langerhans cell histiocytosis
Yellow-brown and erythematous papules, erosions, and crusts are present on this infant
with Langerhans cell histiocytosis.
1733
Langerhans cell histiocytosis
Yellow-pink papules with scale are present in the diaper area of this infant with Langerhans
cell histiocytosis.
1734
1735
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12

States)

emollient
1736

Kenalog ¶, Triderm


solution

spray

Gel Desonate 0.05

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

Body, Derma-
Smoothe/FS Scalp
1737

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1738

Authors: Andreas Katsambas, MD, Clio Dessinioti, MD
INTRODUCTION
Pityriasis rubra pilaris (PRP) is a rare papulosquamous inflammatory dermatosis of unknown origin
and considerable clinical heterogeneity (table 1). The cardinal clinical features of PRP are
hyperkeratotic follicular papules, orange-red scaling plaques, and palmoplantar hyperkeratosis
(picture 1A-F). Well-demarcated areas of spared skin (also known as "islands of sparing") are a
frequent finding in patients with generalized involvement. Erythroderma may occur as a complication
of PRP.
The treatment of PRP can be challenging. Systemic retinoids and methotrexate are the most
commonly employed therapies, and limited data suggest that biologic tumor necrosis factor (TNF)-
alpha inhibitors may be effective. Multiple other therapies have also been utilized for PRP.
The pathogenesis, diagnosis, and treatment of PRP will be reviewed here.
HISTORY
A disorder with features consistent with pityriasis rubra pilaris (PRP) was first reported in 1828 as a
variant of psoriasis, and in 1856, "pityriasis pilaris" was identified as an independent disease [1]. The
term "pityriasis rubra pilaris" was coined in 1889, and remains the accepted terminology for this
disease [2].
EPIDEMIOLOGY
1739
The incidence and prevalence of pityriasis rubra pilaris (PRP) is not precisely known. The disease
has been estimated to account for 1 in 5000 new patients who present with skin disease in Great
Britain [3]. PRP occurs in individuals of all racial backgrounds and appears to affect both genders
equally [3].
Both adults and children may develop PRP. The disorder has a bimodal age distribution with peaks
during the first and fifth decades of life [3].
PATHOGENESIS
The pathways that lead to the development of pityriasis rubra pilaris (PRP) are unclear. The detection
of upregulated expression of tumor necrosis factor (TNF)-alpha in lesional skin from two patients
with PRP and the observation that TNF-alpha inhibitors improve PRP raise the question of whether
TNF-alpha plays a significant pathogenic role [4]. A role for the interleukin (IL)-23-Th17 axis has also
been proposed; in a patient treated with ustekinumab (a human monoclonal antibody that targets IL-
12 and IL-23), clinical and histologic improvement correlated with the level of expression of Th17
cytokines [5]. Further study is necessary to determine the role of these cytokines in the pathogenic
mechanisms of PRP.
In addition, abnormalities in vitamin A metabolism, an aberrant response to infection, and genetic

predisposition have been proposed as factors that may contribute to PRP:
● Abnormal vitamin A metabolism – The recognition of similarities between the follicular

hyperkeratosis of PRP and the cutaneous manifestations of vitamin A deficiency (phrynoderma)
led to speculation that vitamin A is involved in the pathogenesis of PRP. After early theories of
vitamin A deficiency as a cause of the disease were not substantiated, investigations to
determine whether other vitamin A-related factors contribute to PRP were performed. Although a
study of 11 adults and children with PRP found that PRP was associated with decreased levels
of retinol binding protein (a specific carrier of vitamin A) [6], a subsequent study of 3 patients
failed to confirm this finding [7]. Thus, a role for aberrant vitamin A metabolism in PRP remains
uncertain. (See "Overview of vitamin A", section on 'Deficiency'.)
● Infection – The consideration of infection as a contributor to PRP is based upon case reports
documenting the development of PRP following streptococcal and viral infections [8,9]. In
particular, the coexistence of human immunodeficiency virus (HIV) infection and PRP has been
documented in several case reports, and HIV-associated PRP has improved following the
initiation of antiretroviral therapy [10]. (See 'Type VI (HIV-associated)' below.)
1740
● Genetics – Genetic factors play a role in at least some cases of PRP. Although most patients
have acquired disease, familial forms of PRP have been described, including cases that appear
to result from autosomal dominant transmission with partial penetrance [11-13]. Autosomal
dominant PRP has been linked to gain-of-function mutations in the CARD14 gene encoding the
caspase recruitment domain family, member 14 protein, which is an activator of NF-kappaB [11].
Furthermore, CARD14 mutations have been detected in a limited number of patients (12.5
percent) with sporadic PRP [14]. Type V PRP was the clinical variant most strongly associated
with mutations in CARD14 in a study of 22 patients with PRP [15].
Other factors that have been associated with the development of PRP or exacerbations of PRP
include trauma and ultraviolet light [8,16-19]. In one series of 30 children with PRP, the Koebner
phenomenon or trauma preceded the onset of PRP in three children (10 percent) [8]. Ultraviolet light
exposure from the sun or artificial sources infrequently has been reported as an exacerbating factor
for PRP [16-18].
Drugs typically are not considered inciting factors for PRP. However, sorafenib therapy preceded a
PRP-like eruption in one patient with metastatic germ cell cancer [20].
Pityriasis rubra pilaris (PRP) consists of a spectrum of six clinical subtypes. The subtypes of PRP
are defined by age of onset, lesion morphology and distribution, disease course, and an association
with HIV infection (table 1) [3,21,22]. Type I PRP is the most common form of PRP; type III and type
IV are the most common presentations in children [8,16].
Shared features that are present with variable frequency in the subtypes of PRP include follicular
hyperkeratosis, orange-red plaques with fine overlying scale, and palmoplantar hyperkeratosis. When
large areas of skin are involved, islands of unaffected skin (also known as "islands of sparing") are
often evident. Pruritus is common and palmoplantar hyperkeratosis may result in the development of
painful fissures.
The orange-red color of skin lesions classically described in PRP may not be clearly evident in
individuals with dark skin. The orange-red color may be less prominent than in fairer-skinned
individuals, and hyperpigmentation or hypopigmentation may be present.
The clinical subtypes of PRP are reviewed below.
Type I (classic adult) — Type I PRP, an adult-onset form, is the most common subtype of PRP. This
subtype is estimated to account for 55 percent of cases [3]. Patients with type I PRP typically present
with a cutaneous eruption that progresses in a cephalocaudal manner, beginning with the face and
1741
spreading to the trunk, arms, and legs over the course of a few weeks to a few months [3].
Hyperkeratotic red to orange follicular papules and plaques accompanied by islands of sparing, and
orange-hued hyperkeratosis on the palms and soles are characteristic findings (picture 1A-F).
Scaling is fine and powdery (pityriasiform).
Erythroderma (generalized redness involving more than 90 percent of the body surface area)
accompanied by ectropion may develop in PRP [23]. However, due to a paucity of data on this
phenomenon, the frequency with which this occurs in type I PRP is unclear.
Approximately 25 percent of the patients we follow at the First Department of Dermatology of the
University of Athens for PRP have a history of erythroderma requiring hospitalization. However, our
experience likely overestimates the frequency of erythroderma in PRP since patients referred to our
hospital-based clinic may be more likely to have severe PRP than patients seen in the general
outpatient setting.
In addition to the skin findings, other abnormalities may occur. Patients may develop rough,
thickened nail plates with distal crumbling, yellow-brown discoloration of the nail plate, and the
accumulation of subungual debris [23]. Moreover, prolonged facial involvement may lead to
ectropion [23], and lymphadenopathy may develop in the setting of extensive skin involvement [23].
Associated arthropathy (usually seronegative arthritis) also has been reported [24-27].
Although the clinical manifestations of type I PRP can be severe, type I PRP generally has a
favorable long-term prognosis. Approximately 80 percent of patients achieve spontaneous remission
within three years [23].
Type II (atypical adult) — Type II PRP occurs in adults, but lacks the cephalocaudal progression seen
in type I PRP. The most prominent features in this variant are an ichthyosiform dermatitis that tends
to be most prominent on the lower extremities. The palmoplantar hyperkeratosis tends to be coarse
with lamellated scale. Sparse scalp hair is occasionally present.
The prognosis of type II PRP is less favorable than type I PRP. The disease may have a protracted
course of more than 20 years. Fewer than 20 percent of patients achieve clinical resolution within
three years [28].
Type III (classic juvenile) — The clinical manifestations of type I and type III PRP are similar, with the
age of onset as the distinguishing factor (picture 2A-C). While type I PRP develops in adulthood, type
III PRP typically begins around 5 to 10 years of age [23]. Type III PRP is less common than type I PRP,
accounting for approximately 10 percent of cases [3].
Similar to type I PRP, erythroderma can occur in type III PRP. One retrospective series that included
17 children with type III PRP found that 4 of these children (24 percent) had erythroderma [8].
1742
The prognosis of type III PRP is excellent. Most patients experience disease resolution after one year
[23]. Rarely, the disease is persistent [29].
Type IV (circumscribed juvenile) — This form of PRP accounts for approximately 25 percent of cases
of PRP [3]. Type IV PRP primarily occurs in prepubertal children [3]. Young adults may also be
affected.
Patients present with sharply demarcated areas of erythema and follicular hyperkeratosis on the
elbows and knees. Palmoplantar hyperkeratosis may be present [16].
The disease may demonstrate a relapsing and remitting course. Approximately one-third of patients
achieve disease remission within three years [23]. Progression to widespread, classic PRP usually
does not occur.
Type V (atypical juvenile) — Type V PRP is relatively uncommon, representing around 5 percent of
cases [3]. The majority of familial cases of PRP fall into this category. The disease manifestations
begin in the first few years of life and include follicular hyperkeratosis and generalized ichthyosiform
dermatitis [16]. Erythema is usually present, but not prominent [3]. Occasional patients exhibit
scleroderma-like changes on the palms and soles. The disease course is usually chronic.
Type VI (HIV-associated) — PRP may occur in the setting of HIV-infection, in some cases
representing the initial manifestations of disease [10,22,30]. Patients develop widely-distributed
erythematous follicular papules with prominent keratotic spicules and inflammatory plaques. The
presence of nail, palmar, and plantar changes is variable. Erythroderma is a frequent complication
[23].
HIV-associated PRP may occur in concert with other disorders characterized by follicular occlusion,
including acne conglobata, hidradenitis suppurativa, and lichen spinulosus [10,22,31,32].
Mucosal involvement — Oral involvement in PRP is rare and may appear as white papules or plaques
on the palate, buccal mucosa, and/or tongue [33]. Discomfort may be present.
Ocular complications reported in the setting of PRP include cicatricial ectropion and peripheral
ulcerative keratitis [34,35]. The development of bilateral herpes simplex virus keratitis was reported
in one patient with PRP during treatment with prednisone and methotrexate [36].
In addition to HIV infection, several immunodeficient states and autoimmune disorders have been
reported in association with pityriasis rubra pilaris (PRP) [37], suggesting that immunologic
1743
dysfunction may be a contributing factor. In addition, several case reports document the occurrence
of PRP in the setting of internal malignancy [38-44]. The relationship between PRP and these types
of disorders remains uncertain. With the exception of testing for HIV infection, we do not routinely
screen patients for associated diseases in the absence of signs of symptoms suggestive of an
underlying disease.
DIAGNOSIS
The diagnosis of pityriasis rubra pilaris (PRP) is based on the recognition of consistent clinical and
histopathologic features. There are no specific serologic markers for PRP.
Histopathology — A 4 mm punch biopsy is typically utilized to obtain a specimen for histologic

examination. Findings classically seen include [45]:
● Orthokeratosis with spotty parakeratosis (alternating orthokeratosis and parakeratosis in

vertical and horizontal directions; parakeratosis surrounding follicular ostia)
● Epidermal acanthosis
● Intact granular layer
● Mild perivascular lymphohistiocytic infiltrate in the dermis
Occasional additional findings include epidermal spongiosis and focal acantholytic dyskeratosis.
The differential diagnosis of pityriasis rubra pilaris (PRP) varies according to the clinical subtype.
The most common disorder in the differential for type I and type III PRP is psoriasis vulgaris.
● Psoriasis vulgaris – Psoriasis vulgaris can be difficult to distinguish from PRP due to the fact
that both conditions may present with localized or widespread erythematous, scaly plaques.
PRP is characterized by red to orange follicular papules and plaques and orange palmoplantar
keratoderma. Psoriasis is characterized by silvery, coarse scales that are loosely adhered to
sharply demarcated red (erythematous) plaques. These scales contrast with the finer scales that
develop in PRP. Also, typical nail changes (eg, oil spots, pitting) of psoriasis are useful in
distinguishing between psoriasis and PRP (picture 3A-B).
Histologic examination also is of value. Unlike PRP, the granular layer is absent in psoriasis. In
addition, collections of polymorphonuclear leukocytes (Munro microabscesses) are often found
1744
in the epidermis in psoriasis. (See "Psoriasis: Epidemiology, clinical manifestations, and
diagnosis".)
The distribution of early PRP on the face and photo-exposed body areas may stimulate consideration
of a photo-aggravated disorder. (See "Photosensitivity disorders (photodermatoses): Clinical
manifestations, diagnosis, and treatment".)
In patients who present with erythroderma, the possibility of other diseases that cause erythroderma
must be considered. A medical history, careful physical examination for associated clinical features,
and skin biopsy can help to determine the underlying cause. Examples of diseases that may present
with erythroderma include:
● Psoriasis
● Atopic dermatitis
● Drug eruptions
● Cutaneous T cell lymphoma
● Congenital ichthyoses
In the case of inconclusive histology, immunohistochemistry and T cell receptor gene rearrangement
studies (by PCR) may be necessary to rule out cutaneous T cell lymphoma.
Type II and V PRP may present with ichthyosiform changes, and congenital or acquired ichthyoses
should be considered in the differential diagnosis of these subtypes. (See "The genodermatoses: An
overview", section on 'Ichthyoses'.)
For patients with type IV PRP, which is characterized by localized plaques with follicular
hyperkeratosis, other disorders with follicular hyperkeratosis in limited areas, such as lichen
spinulosus and keratosis pilaris, should be considered.
● Lichen spinulosus – Lichen spinulosus is an uncommon disorder that most commonly presents
in children and adolescents as circumscribed plaques with follicular papules that bear keratotic
spines (picture 4). The neck, abdomen, and upper and lower extremities are sites of disease
predilection.
● Keratosis pilaris (follicular hyperkeratosis) – Keratosis pilaris is a common skin condition often
associated with atopy. Patients present with spiny follicular papules on the upper arms, thighs,
and buttocks (picture 5A-B).
TREATMENT
1745
Treatment of pityriasis rubra pilaris (PRP) is largely based upon anecdotal reports of clinical
experience. Because no controlled trials have been performed, there is uncertainty regarding the true
efficacy of individual treatments. No treatments have been approved by the US Food and Drug
Administration (FDA) or the European Medicines Agency (EMA) for use in PRP.
Approach to therapy — The management of PRP involves the combined use of systemic and topical
therapies. Topical therapies help with the management of associated symptoms and may be
sufficient as monotherapy for patients with limited disease. However, most patients require systemic
therapy to attain control of PRP.
Oral retinoids (synthetic vitamin A derivatives) are the preferred first-line systemic treatments for
children and adults with PRP. Case reports and case series support the efficacy of systemic retinoids
in PRP [8,27,35,46-52]. (See 'Systemic retinoids' below.)
Multiple other treatments are utilized for PRP. Methotrexate has appeared effective in case reports
and case series, and is an alternative treatment option for patients who are not good candidates for
systemic retinoids or who fail to respond to systemic retinoid therapy [52]. Additional agents such as
biologic tumor necrosis factor (TNF)-alpha inhibitors, azathioprine, cyclosporine, and phototherapy
may be useful for patients who fail to respond adequately to retinoid or methotrexate therapy.
Data on the treatment of HIV-associated PRP are limited. Improvement after treatment with
zidovudine alone, systemic retinoids plus zidovudine, or triple antiviral therapy has been reported
[10].
Topical therapy — Topical treatments used for PRP include medium to high potency topical
corticosteroids (table 2) [8,27,53], keratolytics, tar, calcipotriene (calcipotriol) [54], topical tretinoin
[55], and tazarotene [56]. Topical treatments are usually combined with a systemic therapy for PRP
types affecting a large body surface area. For patients with limited skin involvement, local therapy
may be beneficial as monotherapy [27].
Topical keratolytics (such as 10% urea or 5% salicylic acid) may be useful for managing
hyperkeratosis and palmoplantar keratoderma. In addition, the application of emollients and the
administration of systemic antihistamines for pruritus may help to reduce associated symptoms. In
our experience, daily application of topical emollients is beneficial for improving skin texture and the
degree of scaling, erythema, and induration of the lesions.
Data on the use of topical agents in PRP are derived mainly from case reports. As a result, there are
no high-quality evidence-based data regarding efficacy and safety of topical treatment. Treatment
with topical corticosteroids should in general be limited to small body areas and for a short period of
1746
time due to the risk of side effects, such as skin atrophy, telangiectasias, and systemic absorption.
(See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Systemic therapy
First-line systemic therapy — Systemic retinoids are used as first-line systemic therapy for adults
and children with PRP based upon data from case reports and clinical experience. The response to
treatment is variable.
Systemic retinoids — The preferred use of retinoids for patients with PRP is based upon the
beneficial effects of retinoids observed in case reports and case series [8,27,35,46-52]. The most
common retinoids used for the treatment of PRP are isotretinoin and acitretin. Case reports and a
small retrospective study suggest that a newer retinoid, alitretinoin, may also be effective for PRP
[57-60].
The response to retinoid therapy is usually evident within three to six months, although longer
courses of treatment are necessary in some patients [46]. Examples of reports documenting
treatment efficacy include:
● A retrospective study of 40 patients with PRP included 12 patients (nine males and three
postmenopausal females) with type I PRP treated with oral acitretin [27]. Eight patients received
acitretin alone at a dose of 25 to 50 mg per day, two patients were treated with acitretin
combined with methotrexate, and two patients were treated with acitretin (50 mg per day)
combined with cyclosporine (300 to 400 mg twice daily). Partial or marked clinical responses
were documented for all 12 patients.
● In an early prospective study in which 45 patients with PRP were treated with isotretinoin (mean
dose 2 mg/kg per day), 28 of 45 patients (62 percent) were noted by clinician evaluators to have
marked improvement within four weeks, and all 34 patients who returned for clinician evaluation
after 12 to 16 weeks of treatment had marked improvement [47].
● Among 15 patients treated with isotretinoin (primarily 40 mg twice daily) in a retrospective study
of adolescents and adults with PRP, 10 patients (67 percent) achieved complete clearance
within an average of 25 weeks (range 16 to 44 weeks), 2 achieved partial clearing after 16 and
24 weeks, and 3 patients failed to respond after 20 to 24 weeks [46].
● In a retrospective review of 18 patients with PRP, among 15 patients who were treated with
isotretinoin (0.5 to 2.2 mg/kg per day), 7 (47 percent) achieved complete clearance (most within
seven months), 3 (20 percent) achieved partial clearance, and 5 (33 percent) failed to respond to
therapy [48]. The average dose of isotretinoin for patients who achieved complete clearance was
1 mg/kg per day.
1747
● In a retrospective study of 30 adolescents and children with PRP who were under the age of 20
years, five of six patients with type III PRP who were treated with isotretinoin (0.75 to 1.5 mg/kg
per day) achieved 90 to 100 percent disease clearance within six months [8]. In contrast, only
one of six patients treated with vitamin A (>100,000 U per day) had excellent improvement.
● In a retrospective study, four of five adults given alitretinoin (30 mg per day) for type I PRP had
reductions in disease severity within four to eight weeks [59]. The fifth patient discontinued
alitretinoin because of disease progression during the first three weeks. Among the responders,
alitretinoin was well tolerated with the exception of one patient who experienced up to threefold
elevations of creatinine kinase and hepatic transaminases compared with normal serum levels
after 22 weeks of treatment.
In clinical practice, typical retinoid doses used for adults with PRP are 1 mg/kg per day of
isotretinoin and 0.5 mg/kg per day of acitretin. The appropriate dose regimen for systemic retinoids
for PRP is less established in children.
Adverse effects of retinoid therapy include dry skin and mucous membranes, hyperlipidemia,
transaminase elevations, and visual or bone changes [61]. Premature epiphyseal closure is a rare
side effect of retinoid therapy that may occur in children, particularly in children treated with high
doses [62]. Retinoids are teratogenic and must not be used by women who are pregnant or who are
at risk of becoming pregnant but decline strict use of reliable contraceptives (two complementary
forms of contraception including a barrier method) to prevent pregnancy. (See "Oral isotretinoin
therapy for acne vulgaris", section on 'Adverse effects'.)
Because alcohol ingestion may stimulate the in vivo conversion of acitretin to etretinate (a retinoid
with an exceptionally long elimination half-life), pregnancy must be avoided during and for three
years after treatment with acitretin [63]. Thus, treatment with acitretin is not recommended in women
of childbearing potential [64]. Pregnancy must be avoided during and for six weeks after isotretinoin
therapy [65]. Participation in the iPLEDGE program (www.ipledgeprogram.com), which is required for
prescribing isotretinoin in the United States, requires that females treated with isotretinoin continue
use of two forms of contraception until one month after the last isotretinoin dose.
Second-line systemic therapy — Methotrexate (5 to 25 mg per week) can be used as next-line

treatment for patients who fail systemic retinoids or who have comorbidities or other characteristics
that prohibit the use of systemic retinoid therapy [51,61,66].
Methotrexate — Small retrospective studies have supported the use of methotrexate in PRP.
Although one author's 1980 review of personal clinical experience and published cases identified a
response to methotrexate in only 17 of 44 patients (39 percent) [3], other studies have found more
favorable results. Among eight patients with type I PRP treated with 10 to 25 mg per week of
1748
methotrexate in a retrospective study, all achieved favorable responses within several months [46].
The average duration of treatment was six months (range 1 to 12 months). In another retrospective
study, all five adults with PRP improved with methotrexate, including two who had previously failed to
respond to retinoids [51]. The average duration of treatment was 12 months.
Methotrexate has also been used in combination with systemic retinoids in difficult cases. In a
retrospective study that included six patients who were given combination therapy with a retinoid
and methotrexate (5 to 30 mg per week) because of severe disease and five patients for whom
methotrexate was added to a systemic retinoid due to a failure to respond to the retinoid alone, 8 of
11 patients achieved at least 50 percent improvement, and four patients achieved greater than 95
percent improvement by 16 weeks [49]. Although treatment appeared to be well tolerated, increased
risk for hepatoxicity is a concern with combination therapy.
Gastrointestinal distress is a common adverse effect of methotrexate. Additional serious adverse

effects include pancytopenia, hepatotoxicity, and pneumonitis. Methotrexate is teratogenic and
should not be given in pregnancy. (See "Major side effects of low-dose methotrexate".)
Additional therapies
Biologic agents — Biologic therapies, including TNF-alpha inhibitors (infliximab, adalimumab,

etanercept), ustekinumab (an anti-interleukin [IL]-12/23 agent), and secukinumab (an anti-IL-17
agent), have been used as off-label treatments for PRP (adult or juvenile onset) [67]. A review on
biologic therapy for PRP between 1999 and 2018 identified only case reports and case series
documenting biologic therapy in a total of 86 patients with PRP types I, II, III, IV, or V [67]. Most
patients were refractory to conventional therapies for PRP. The most common reported treatment
was infliximab (37 patients), followed by etanercept (22 patients), adalimumab (20 patients),
ustekinumab (18 patients), and secukinumab (3 patients). Biologics were combined with other
treatments in some cases. The majority of these case reports and case series documented
successful therapy.
In our practice, a 27-year-old woman with a 14-year history of type III PRP that had been refractory to
systemic retinoids and narrowband ultraviolet B (NBUVB) phototherapy appeared to benefit from
long-term anti-TNF-alpha monotherapy [29]. The patient responded to periodic infusions of infliximab
(5 mg/kg every seven weeks after induction), achieving 80 percent clearance after 2.5 years.
Treatment was well tolerated.
The limited data and possibility of spontaneous resolution of PRP make conclusions regarding the
efficacy of biologic therapies challenging. Additional study is necessary to confirm efficacy of
biologic therapies.
1749
Reactivation or exacerbations of infections are potential side effects of biologic TNF-alpha inhibitors,
ustekinumab, and secukinumab. Thus, pretreatment laboratory investigations for these agents
include screening for hepatitis B and hepatitis C, as well as screening for tuberculosis using a
purified protein derivative (PPD) skin test or interferon-gamma release assay and a chest radiograph
when indicated (see "Approach to diagnosis of latent tuberculosis infection (tuberculosis screening)
in adults"). Testing for human immunodeficiency virus infection should also be considered.
The adverse effects of biologic therapies are reviewed in greater detail separately. (See "Tumor
necrosis factor-alpha inhibitors: An overview of adverse effects" and "Treatment of psoriasis in
Phototherapy — Although a few case reports document photoexacerbation of PRP [17,68-70],

phototherapy may be useful in some patients. PUVA therapy has yielded variable results in case
reports and a small case series [69,71,72], and successful treatment with NBUVB has been reported
in at least two patients [73,74]. In a retrospective study, the Goeckerman treatment regimen, which
combines topical tar and UVB phototherapy, was associated with a good response in one of eight
children [8]; however, this treatment failed to result in clinically significant improvement in any of 17
patients in a separate retrospective series [46].
The combination of retinoids and phototherapy may be effective. Acitretin combined with NBUVB
[75,76], UVA1 [77], or PUVA (Re-PUVA) [35,78,79] has been reported as beneficial in small numbers of
patients.
Due to the possibility of photoexacerbation of PRP, performing phototesting prior to the initiation of
treatment is suggested [23,80].
Immunosuppressants — Immunosuppressants, such as cyclosporine [81-83] and azathioprine

[3,84,85], have been reported to be effective for PRP in case reports. However, cyclosporine (6 mg/kg
per day for six to eight weeks) was associated with minimal clinical improvement in a series of three
adults with PRP [86]. The limited data to support the efficacy of these agents and concerns regarding
the potential for severe adverse effects limit the use of these agents. (See "Pharmacology of
cyclosporine and tacrolimus" and "Pharmacology and side effects of azathioprine when used in
rheumatic diseases", section on 'Adverse effects'.)
Other — Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, was used for PRP type I in
four patients with significant improvement after six to seven months of treatment [87-90]. Additional
therapies that have been reported to be effective in individual patients with PRP include fumaric acid
esters [91], penicillin [92,93], extracorporeal photochemotherapy [94], and intravenous
immunoglobulin [95].
1750
PROGNOSIS
The prognosis of pityriasis rubra pilaris (PRP) is dependent upon the clinical subtype. (See 'Clinical
Recurrence of PRP after treatment cessation is unpredictable. Patients may remain in remission or
may experience disease recurrence after the discontinuation of systemic therapy.
● Pityriasis rubra pilaris (PRP) is a rare papulosquamous inflammatory dermatosis. The cardinal
clinical features of PRP include follicular hyperkeratosis, palmoplantar hyperkeratosis, and
orange-red scaling plaques.
● PRP is classified into six clinical types (I-VI) according to age at onset, clinical presentation, and
expected prognosis (table 1). PRP occurs in both adults and children. (See 'Epidemiology'
above.)
● Classical PRP is the most common form of PRP. It is divided into adult-onset (type I) and juvenile
onset (type III) forms, with similar clinical characteristics (picture 1A-F, 2A-C). Other types are
atypical adult (type II) PRP, circumscribed juvenile (type IV), atypical juvenile (type V), and HIV-
associated (type VI) PRP.
● The most common clinical subtype of PRP, type I (classic adult) PRP, occurs in adults and is
characterized by follicular hyperkeratosis, orange-red inflammatory plaques, and palmoplantar
hyperkeratosis. Well-demarcated areas of uninvolved skin ("islands of sparing") are a common
finding. Erythroderma may occur. (See 'Clinical manifestations' above.)
● The most common forms of PRP in children are type III (classic juvenile) and type IV
(circumscribed juvenile). The clinical features of type III PRP are identical to type I PRP. Type IV
PRP is a unique form that presents with sharply demarcated erythematous plaques with
prominent follicular hyperkeratosis. The elbows and knees are common sites of involvement.
● PRP occurs in association with HIV infection (type VI PRP). Widespread hyperkeratotic and
erythematous follicular papules are typically present. Erythroderma is a frequent complication.
(See 'Type VI (HIV-associated)' above.)
● The diagnosis of PRP is made based upon the clinical and pathologic findings. The differential
diagnosis includes psoriasis, drug eruptions, cutaneous T cell lymphoma, keratosis pilaris, and
1751
ichthyosis. (See 'Diagnosis' above.)
● Data are limited on the treatments for PRP. Patients with limited disease (eg, type IV PRP) may
be managed with topical therapy. For adults and children with more extensive PRP, we suggest
treatment with a systemic retinoid such as isotretinoin or acitretin as initial therapy (Grade 2C).
Due to the need to abstain from pregnancy for three years after treatment with acitretin, use of
acitretin is not recommended in women of reproductive potential.
● Methotrexate is an alternative treatment option for patients with PRP. Methotrexate is

teratogenic and is contraindicated during pregnancy. (See 'Treatment' above.)
● Therapies such as biologic agents and other immunomodulatory drugs have been used to treat
patients who fail to respond to phototherapy, retinoids, or methotrexate. (See 'Additional
therapies' above.)
1752
GRAPHICS
Classification of pityriasis rubra pilaris
PRP type Clinical characteristics Prognosis
I (classic adult)* Wide distribution of follicular papules and plaques Favorable - 80 percent of patients resolve
with cephalocaudal progression and sparing islands spontaneously within three years
of normal-appearing skin
II (atypical adult) Ichthyosiform dermatitis, palmoplantar Chronic course

hyperkeratosis, chronic course
III (classic juvenile) Wide distribution of follicular papules and plaques Often remission after one year
with cephalocaudal progression and spared islands
of normal-appearing skin
IV (circumscribed Circumscribed lesions restricted to the elbows and Unclear

juvenile) knees and frequent palmoplantar hyperkeratosis
V (atypical juvenile) Ichthyosiform dermatitis, palmoplantar Chronic course

hyperkeratosis
VI (HIV-associated) Similar to type I Variable
* Most common form of PRP.
References:
1. Griffiths WA, Ozluer S. [Pityriasis rubra pilaris]. Ann Dermatol Venereol 2001; 128:931.
2. Griffiths WA. Pityriasis rubra pilaris. Clin Exp Dermatol 1980; 5:105.
3. Klein A, Landthaler M, Karrer S. Pityriasis rubra pilaris: a review of diagnosis and treatment. Am J Clin Dermatol 2010; 11:157.
1753
Large orange-red plaques and islands of spared skin in pityriasis rubra pilaris.
1754
Erythematous scaly plaques and islands of spared skin in pityriasis rubra pilaris.
1755
Follicular papules and red-orange plaques in pityriasis rubra pilaris.
1756
Hyperkeratotic follicular papules in pityriasis rubra pilaris.
1757
Plantar hyperkeratosis in pityriasis rubra pilaris.
1758
Diffuse erythema and scale are present on the face and scalp.
1759
Classic juvenile pityriasis rubra pilaris
Classical juvenile-onset pityriasis rubra pilaris (type III), presenting with hyperkeratotic, red to orange, follicular
papules and plaques, with characteristic areas (islands) of uninvolved skin.
1760
Hyperkeratotic red to orange follicular papules and plaques are on the legs.
1761
Characteristic pityriasiform scaling is present.
1762
1763
1764
Lichen spinulosus
Circumscribed plaque with hyperkeratotic follicular papules on the abdomen of a child.
1765
Keratosis pilaris
1766
Keratosis pilaris
1767
Available
Brand names
(United States)
(except as noted)


solution (scalp)

aerosol

States)

(group 2)
dipropionate
formulation (AF)
Gel Topicort 0.05

solution

(group 3)

Foam Luxiq 0.12

States)

emollient
1768

Kenalog ¶, Triderm


solution

spray

Gel Desonate 0.05

solution Lipocream

probutate

ointment

Foam Verdeso 0.05
Shampoo Capex 0.01

Body, Derma-
Smoothe/FS Scalp
1769

(group 7) ≥2%)
Scalacort


Hytone, Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1

Relief
Lotion Nucort 2
US: United States.

Data from:
1770
Confluent and reticulated papillomatosis

Author: Amy Y-Y Chen, MD, FAAD
INTRODUCTION
Confluent and reticulated papillomatosis (CARP) is an uncommon dermatosis characterized by hyperpigmented scaly
macules or papillomatous papules coalescing into confluent patches or plaques centrally with a reticular pattern
peripherally (picture 1A-D). It most commonly occurs on the trunk. Oral antibiotic therapy is the mainstay of treatment.
The clinical features, diagnosis, and management of CARP will be reviewed here. Other causes of cutaneous
hyperpigmentation are reviewed separately. (See "Acquired hyperpigmentation disorders".)
EPIDEMIOLOGY
First described by two French dermatologists, Gougerot and Carteaud, CARP has been reported worldwide and occurs in all
racial groups and ethnicities [1]. It is estimated that the incidence of CARP in the Lebanese population is around 0.02
percent [2]. No epidemiologic study has been conducted in the United States. However, only 39 patients were identified in a
retrospective review collected from 1972 to 2003 at the Mayo Clinic [3].
CARP typically affects young adults; the Mayo Clinic retrospective study found a mean age of onset of 15 years and a
range of 8 to 32 years. CARP occurs in both males and females [3].
ETIOLOGY
Decades after its initial description, the pathogenesis and etiology of CARP remain elusive and controversial. Several
theories have been proposed, although none have been definitively proven.
Among all of the proposed etiologic factors, the strongest evidence exists to support CARP as a disorder of keratinization
resulting in a hyperproliferative state. Electron microscopy (EM) of the affected skin shows alteration of cornified cell
structures, an increased number of lamellar granules in the granular layer, and increased melanosomes in the horny layers
[4]. In another EM study, an increased number of transitional cells between stratum corneum and stratum granulosum were
noted [5]. Furthermore, in one study with siblings with CARP, increased expression of keratin 16 was demonstrated in focal
areas of stratum granulosum [6]. Other genetic factors may also, at least in some part, contribute to the development of
CARP, as several other familial cases have been reported [7-10].
Many reports have linked Malassezia, formally known as Pityrosporum, to CARP due to its clinical resemblance to tinea
versicolor. Although CARP and tinea versicolor may coexist, and it is postulated that CARP may represent an inappropriate
inflammatory response to Malassezia resulting in abnormal keratinization [6,11-13], available evidence does not support the
1771
involvement of Malassezia in the pathogenesis of CARP [3]. Similarly, no bacterial species have been consistently isolated
from CARP patients [1]. Other less likely proposed causes of CARP include a reaction to ultraviolet light, a cutaneous
response to underlying endocrinopathy, and a process involving amyloid [1]. (See "Tinea versicolor (pityriasis versicolor)".)
CARP is most often characterized by hyperpigmented scaly macules or papillomatous papules coalescing into confluent
patches or plaques centrally and exhibiting a reticular pattern peripherally (picture 1A-D). Rarely, CARP can also appear as
atrophic macules with a cigarette paper-like surface [1].
CARP typically starts on the upper trunk, especially in the intermammary and interscapular areas, with subsequent
development of lesions on the neck and axilla, where skin markings are sometimes exaggerated [1,3]. Concurrent or
isolated involvement of the face, shoulders, upper arms, antecubital fossa, popliteal fossa, and pubic areas has been
reported (picture 2A-C) [3,14-19]. CARP does not involve the mucosa or nails. In a retrospective study of 39 CARP patients,
80 percent did not report any symptoms while 20 percent reported mild pruritus [3].
CARP typically persists if not treated, although spontaneous resolution has been reported [3,20]. In a retrospective study of
39 patients with CARP evaluated at an academic medical center, the mean duration of disease up to the time of clinical
presentation was 3 years (range 3 months to 20 years) [3].
HISTOPATHOLOGY
CARP shares histologic features with acanthosis nigricans, including hyperkeratosis, papillomatosis, and a mild superficial
perivascular lymphocytic infiltrate (see "Acanthosis nigricans") [1,2]. Follicular plugging, present in 9 of 10 patients in one
study, can help to distinguish between the two conditions [2]. Fungal stains should be negative.
DIAGNOSIS
A diagnosis of CARP should be strongly suspected in young adults with hyperpigmented reticulated and papillomatous
patches or plaques on the trunk, neck, or flexural areas. In clinical practice, the diagnosis is usually made based upon the
recognition of these classic physical findings and the absence of fungal elements on a potassium hydroxide (KOH)
preparation performed to rule out tinea versicolor. If the diagnosis remains uncertain because of atypical physical findings,
a skin biopsy can be performed to identify histologic features consistent with CARP or other disorders; however, CARP has
no pathognomonic histologic findings.
Several other cutaneous diseases may be confused with CARP [3,21,22].
● Tinea versicolor – Clinically, CARP is most often confused with tinea versicolor, a superficial fungal infection that may
present with hyperpigmented macules or patches on the trunk or proximal upper extremities (picture 3A-B). A
potassium hydroxide (KOH) preparation of the scale will reveal hyphae and yeast cells. (See "Tinea versicolor
(pityriasis versicolor)" and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide
preparation'.)
1772
● Acanthosis nigricans – CARP and acanthosis nigricans share many clinical and histologic features. Acanthosis
nigricans is characterized by velvety, hyperpigmented plaques with predilection for flexural areas and histologic
findings of hyperkeratosis and epidermal papillomatosis (picture 4A-B). Patients with acanthosis nigricans often have
associated obesity, diabetes, and/or polycystic ovarian syndrome (PCOS). (See "Acanthosis nigricans".)
● Epidermal nevus – Epidermal nevi most commonly present at birth or during the first year of life and are often linear.
They start out as subtle linear patches or very thin plaques composed of light brown to skin-colored papules. Around
puberty, epidermal nevi may become thicker and darker (picture 5). (See "Epidermal nevus and epidermal nevus
syndrome".)
● Verruca plana – Verruca plana (flat warts) are skin-colored or hyperpigmented flat-topped papules caused by
cutaneous human papillomavirus (HPV) infection (picture 6). Verruca plana will not have the typical reticular
appearance seen at the periphery of CARP. (See "Cutaneous warts (common, plantar, and flat warts)".)
● Epidermodysplasia verruciformis – Patients with epidermodysplasia verruciformis, an autosomal recessive disorder

characterized by high susceptibility to HPV infection, present with multiple skin lesions during early infancy or
childhood. The cutaneous findings vary widely from verruca-like papillomatous lesions, to skin-colored flat-topped
papules, to red to reddish brown papules or plaques on the face, neck, and trunk (picture 7). (See "Epidermodysplasia
verruciformis".)
● Darier disease – Darier disease is an uncommon autosomal dominantly inherited disease with skin, nail, and mucous
membrane findings. Skin involvement usually appears as yellowish brown, skin-colored, or hyperpigmented waxy
papules on the chest and back that can coalesce into crusted plaques (picture 8). Groin, axilla, and inframammary skin
involvement is also present in most patients. Punctate keratosis and pits are sometimes noted in the palms.
Longitudinal white and red bands on the nails, as well as V-shaped nicks at the free nail margin, are characteristic and
pathognomonic findings. White papules can be noted in the oral mucosa of some patients. Skin biopsy of cutaneous
lesions shows characteristic focal suprabasal acantholysis and dyskeratosis with characteristic pink "corps ronds"
and "grains." (See "Darier disease".)
● Lichen or macular amyloidosis – Lichen amyloidosis presents as pruritic skin-colored and pink to light brown scaly
lichenoid papules that most commonly occur on the bilateral shins (picture 9), while macular amyloidosis typically
appears as pruritic brown rippled macules on the mid-upper back (picture 10). Skin biopsy with amyloid staining will
help to differentiate lichen or macular amyloidosis from CARP.
TREATMENT
Overview — CARP is a benign and often asymptomatic skin condition; therefore, treatment is not mandatory. However,
patients often desire treatment because of cosmetic concerns or associated pruritus.
No randomized trials have evaluated the treatment of CARP. Treatment recommendations are based on data from
retrospective analyses, case series, and case reports. Oral antibiotic therapy with minocycline is a well-accepted first-line
treatment. Macrolide antibiotics are reasonable second-line interventions for patients who cannot tolerate minocycline or
fail to improve with minocycline therapy. Less commonly used treatments that may improve CARP include topical retinoids,
topical vitamin D analogs, topical tacrolimus, and alternative oral antibiotics. Oral isotretinoin is an additional treatment
that is primarily reserved for patients with refractory disease.
If immediate relief from associated pruritus is necessary, medium-potency topical corticosteroids can be applied to
affected areas on the trunk and extremities twice daily for two to four weeks. For facial or intertriginous involvement, a low-
1773
potency topical corticosteroid should be used once or twice daily for two to four weeks (table 1). Long-term use of topical
corticosteroids may cause skin atrophy or dyspigmentation and must be carefully monitored. Alternatively, topical
tacrolimus or pimecrolimus can be used for pruritus if long-term maintenance therapy is needed. These agents do not
cause skin atrophy or dyspigmentation. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse
effects'.)
First-line therapy — Oral antibiotic therapy is typically used in the initial treatment of CARP. The antiinflammatory
properties of antibiotics, such as inhibition of neutrophil migration and reactive oxygen release, may be responsible for
clinical efficacy, as no bacteria are consistently isolated from CARP patients [3,23-25]. Minocycline is the most commonly
used antibiotic for CARP.
Minocycline — Treatment with minocycline is supported by multiple case reports and case series [3,15,17,26-35]. As an
example, in an uncontrolled study of nine CARP patients treated with minocycline (50 mg twice per day for six weeks),
seven patients had a 90 to 100 percent response to therapy and the remainder had lesser degrees of improvement [34]. No
adverse reaction was reported, and the patients were followed for an average of 11 months. Recurrence was noted in three
of nine patients; all responded to retreatment with minocycline.
Benefit of minocycline therapy is also suggested in a retrospective analysis of 39 CARP patients. Minocycline (most
commonly at the dose of 100 mg twice daily for one to three months) was prescribed for 22 patients. One hundred percent
of treated patients improved: 78 percent had complete clearance and 22 percent had a partial response. Minocycline was
well tolerated [3].
When treating CARP in adults, we typically prescribe minocycline at a dose of 50 or 100 mg twice daily for a minimum of
six weeks. Improvement is usually evident within the first several weeks of treatment. If there is no response after three
months, we discontinue minocycline treatment.
Potential side effects of minocycline include gastrointestinal distress, skin discoloration, dizziness, tinnitus, a lupus-like
syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS). Minocycline may cause discoloration of
developing permanent teeth and is contraindicated in children under the age of nine and pregnant women. See Lexicomp
monograph: Minocycline: Drug information, section on Adverse reactions.
Second-line therapy — Patients who cannot tolerate minocycline or who fail to respond to minocycline may be treated with
a macrolide antibiotic.
Macrolide antibiotics — Case reports describe successful treatment with clarithromycin (500 mg daily for five weeks)
[26], erythromycin (1000 mg daily for six weeks) [26], and azithromycin (500 mg daily for three to four weeks) [26,36,37].
Roxithromycin, a macrolide not available in the United States, has also successfully treated CARP at a dose of 300 mg per
day in a patient who failed to respond to minocycline [38].
Potential side effects of macrolides include gastrointestinal distress (particularly with erythromycin), drug interactions, and
QT interval prolongation. The side effects of these drugs are reviewed in greater detail separately. (See "Azithromycin and
clarithromycin", section on 'Adverse reactions' and "Azithromycin and clarithromycin", section on 'Drug interactions'.)
Other therapies — A variety of other treatments may be effective for CARP based upon reports of small numbers of
patients, including topical therapies, alternative oral antibiotics, and oral retinoids. Because of concern for side effects, oral
retinoid therapy is usually reserved for patients with refractory CARP.
Topical agents — Topical agents that may be beneficial for CARP include topical retinoids, topical vitamin D analogs,
and topical tacrolimus. The efficacy of topical retinoid and topical vitamin D analog therapy is postulated to relate to effects
on disordered keratinization in CARP. (See 'Etiology' above.)
1774
● Topical retinoids – Topical tretinoin and tazarotene have appeared effective for CARP in case reports [7,13,39]. Three
patients with CARP treated with once-daily applications of tretinoin 0.01% or 0.025% gel improved markedly within six
to eight weeks [7] and application of tretinoin 0.1% cream cleared treated areas in another patient [39]. Treatment of an
11-year-old girl with twice-daily application of tazarotene 0.1% gel led to noticeable improvement within one week and
clearance of CARP within two months [13]. Subsequently, tazarotene was resumed as needed for recurrences.
● Topical vitamin D analogs – Case reports document successful treatment of CARP with twice-daily application of
topical calcipotriol ointment or topical tacalcitol [11,12,40,41]. Marked improvement has occurred within several
weeks.
● Topical tacrolimus – Treatment with tacrolimus 0.1% ointment twice daily for three months led to marked clinical
improvement in a patient with CARP [42]. A recurrence of CARP two months after discontinuation of tacrolimus
responded to retreatment.
Alternative oral antibiotics — In addition to minocycline and macrolide antibiotics, scattered case reports suggest other
antibiotics may be effective. Doxycycline has yielded good responses at a dose of 200 mg per day for three months [18,43].
Other antibiotics associated with successful treatment include amoxicillin (250 mg three times per day for three months)
[3,16] and cefdinir (300 mg for two weeks) [27]. Fusidic acid, a bacteriostatic antibiotic not available in the United States,
given as 1000 mg daily for four weeks has also resulted in disease clearance [26].
Oral retinoids — Case reports describe successful treatment of CARP with oral isotretinoin given in doses ranging from
0.25 mg/kg per day to 2 mg/kg per day for two to five months [39,44-46]. In one report, two patients who failed to respond
to minocycline had resolution of CARP after treatment with oral isotretinoin (1 mg/kg per day for 14 to 18 weeks) and
topical 10% lactic acid. Both patients remained lesion-free at 1.5 years follow-up [46].
Treatment with oral etretinate (0.25 to 0.35 mg/kg per day or 50 mg per day) has been associated with clearance of CARP
in case reports; however, disease recurred after stopping therapy [47,48]. Etretinate is no longer available in the United
States.
Oral retinoids are teratogenic and may lead to a variety of adverse effects, such as cheilitis, visual changes, lipid
abnormalities, and pseudotumor cerebri. The risks and benefits of oral retinoids must be carefully considered prior to
treatment. Therefore, oral retinoid therapy is usually reserved for patients with refractory disease. (See "Oral isotretinoin
therapy for acne vulgaris", section on 'Adverse effects'.)
● Confluent and reticulated papillomatosis (CARP) is a rare cutaneous disorder that most often occurs in young adults.
The pathogenesis of CARP is unclear. The disorder is postulated to represent a disorder of keratinization resulting in
cutaneous hyperproliferation. (See 'Epidemiology' above and 'Etiology' above.)
● The classic clinical findings of CARP are hyperpigmented, scaly macules or papules that coalesce into confluent
patches or plaques that exhibit a reticular pattern peripherally (picture 1A-D). The upper trunk (particularly the
intermammary and interscapular skin), neck, and axilla are common sites of involvement. CARP is usually
asymptomatic, but may be associated with pruritus. (See 'Clinical presentation' above.)
● The diagnosis of CARP can usually be made based upon recognition of the classic clinical features and performance
of a potassium hydroxide (KOH) preparation to rule out tinea versicolor, a cutaneous fungal infection that may be
1775
mistaken for CARP. If the diagnosis is uncertain, a skin biopsy can be helpful. (See 'Diagnosis' above and
'Histopathology' above.)
● Data are limited on treatments for CARP. For adults with CARP, we suggest oral minocycline as first-line therapy (Grade
2C). Oral macrolide antibiotics are an alternative initial treatment for patients who cannot tolerate minocycline therapy.
(See 'Treatment' above.)
REFERENCES
1. Scheinfeld N. Confluent and reticulated papillomatosis : a review of the literature. Am J Clin Dermatol 2006; 7:305.
2. Tamraz H, Raffoul M, Kurban M, et al. Confluent and reticulated papillomatosis: clinical and histopathological study of
10 cases from Lebanon. J Eur Acad Dermatol Venereol 2013; 27:e119.
3. Davis MD, Weenig RH, Camilleri MJ. Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a
minocycline-responsive dermatosis without evidence for yeast in pathogenesis. A study of 39 patients and a proposal
of diagnostic criteria. Br J Dermatol 2006; 154:287.
4. Jimbow M, Talpash O, Jimbow K. Confluent and reticulated papillomatosis: clinical, light and electron microscopic
studies. Int J Dermatol 1992; 31:480.
5. Griffiths CE. Gougerot-Carteaud still an enigma after all these years. J Dermatolog Treat 2002; 13:1.
6. Inalöz HS, Patel GK, Knight AG. Familial confluent and reticulated papillomatosis. Arch Dermatol 2002; 138:276.
7. Schwartzberg JB, Schwartzberg HA. Response of confluent and reticulate papillomatosis of Gougerot and Carteaud
to topical tretinoin. Cutis 2000; 66:291.
8. Henning JP, de Wit RF. Familial occurrence of confluent and reticulated papillomatosis. Arch Dermatol 1981; 117:809.
9. Baden HP. Familial cutaneous papillomatosis. Arch Dermatol 1965; 92:394.
10. Stein JA, Shin HT, Chang MW. Confluent and reticulated papillomatosis associated with tinea versicolor in three
siblings. Pediatr Dermatol 2005; 22:331.
11. Gülec AT, Seçkin D. Confluent and reticulated papillomatosis: treatment with topical calcipotriol. Br J Dermatol 1999;
141:1150.
12. Ginarte M, Fabeiro JM, Toribio J. Confluent and reticulated papillomatosis (Gougerot-Carteaud) successfully treated
with tacalcitol. J Dermatolog Treat 2002; 13:27.
13. Bowman PH, Davis LS. Confluent and reticulated papillomatosis: response to tazarotene. J Am Acad Dermatol 2003;
48:S80.
14. Lee D, Cho KJ, Hong SK, et al. Two cases of confluent and reticulated papillomatosis with an unusual location. Acta
Derm Venereol 2009; 89:84.
1776
15. Kim BS, Lim HJ, Kim HY, et al. Case of minocycline-effective confluent and reticulated papillomatosis with unusual
location on forehead. J Dermatol 2009; 36:251.
16. Davis RF, Harman KE. Confluent and reticulated papillomatosis successfully treated with amoxicillin. Br J Dermatol
2007; 156:583.
17. Kim MR, Kim SC. Confluent and reticulated papillomatosis on the arm successfully treated with minocycline. J
Dermatol 2010; 37:749.
18. Jo S, Park HS, Cho S, Yoon HS. Updated diagnosis criteria for confluent and reticulated papillomatosis: a case report.
Ann Dermatol 2014; 26:409.
19. Hallel-Halevy D, Grunwald MH, Halevy S. Confluent and reticulated papillomatosis (Gougerot-Carteaud) of the pubic
region. Acta Derm Venereol 1993; 73:155.
20. Sakiyama T, Amagai M, Ohyama M. Chronology of confluent and reticulated papillomatosis: spontaneous regression
in a case after long-term follow-up may imply transient nature of the condition. J Dermatol 2015; 42:335.
21. Groh V, Schnyder UW, Sigg C. 'Papillomatose papuleuse confluente et réticulée Gougerot-Carteaud'--a further form of
skin amyloidosis? Dermatologica 1981; 162:118.
22. Groh V, Sigg C, Schnyder UW. New histochemical and ultrastructural findings in three cases of 'papillomatose
papuleuse confluente et réticulée (Gougerot-carteaud)'. Dermatologica 1982; 165:145.
23. Zalewska-Kaszubska J, Górska D. Anti-inflammatory capabilities of macrolides. Pharmacol Res 2001; 44:451.
24. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad
Dermatol 2006; 54:258.
25. Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res
2011; 63:130.
26. Jang HS, Oh CK, Cha JH, et al. Six cases of confluent and reticulated papillomatosis alleviated by various antibiotics.
J Am Acad Dermatol 2001; 44:652.
27. Yamamoto A, Okubo Y, Oshima H, et al. Two cases of confluent and reticulate papillomatosis: successful treatments
of one case with cefdinir and another with minocycline. J Dermatol 2000; 27:598.
28. Sassolas B, Plantin P, Guillet G. Confluent and reticulated papillomatosis: treatment with minocycline. J Am Acad
Dermatol 1992; 26:501.
29. Poskitt L, Wilkinson JD. Clearance of confluent and reticulate papillomatosis of Gougerot and Carteaud with
minocycline. Br J Dermatol 1993; 129:351.
30. Katayama I, Yokozeki H, Nishioka K. Oral minocycline improved keratosis follicularis squamosa (Dohi) and related
disorder: bacterial factors are possibly involved in abberant keratinization. J Dermatol 1994; 21:604.
31. Shimizu S, Han-Yaku H. Confluent and reticulated papillomatosis responsive to minocycline. Dermatology 1997;
194:59.
32. Puig L, de Moragas JM. Confluent and reticulated papillomatosis of Gougerot and Carteaud: minocycline deserves
trial before etretinate. Arch Dermatol 1995; 131:109.
1777
33. Chang SN, Kim SC, Lee SH, Lee WS. Minocycline treatment for confluent and reticulated papillomatosis. Cutis 1996;
57:454.
34. Montemarano AD, Hengge M, Sau P, Welch M. Confluent and reticulated papillomatosis: response to minocycline. J
Am Acad Dermatol 1996; 34:253.
35. Fung MA, Frieden IJ, LeBoit PE, et al. Confluent and reticulate papillomatosis: successful treatment with minocycline.
Arch Dermatol 1996; 132:1400.
36. Atasoy M, Ozdemir S, Aktaş A, et al. Treatment of confluent and reticulated papillomatosis with azithromycin. J
Dermatol 2004; 31:682.
37. Gruber F, Zamolo G, Saftić M, et al. Treatment of confluent and reticulated papillomatosis with azithromycin. Clin Exp
Dermatol 1998; 23:191.
38. Ito S, Hatamochi A, Yamazaki S. A case of confluent and reticulated papillomatosis that successfully responded to
roxithromycin. J Dermatol 2006; 33:71.
39. Lee MP, Stiller MJ, McClain SA, et al. Confluent and reticulated papillomatosis: response to high-dose oral isotretinoin
therapy and reassessment of epidemiologic data. J Am Acad Dermatol 1994; 31:327.
40. Carrozzo AM, Gatti S, Ferranti G, et al. Calcipotriol treatment of confluent and reticulated papillomatosis (Gougerot-
Carteaud syndrome). J Eur Acad Dermatol Venereol 2000; 14:131.
41. Lang EW, Czosnyka M, Mehdorn HM. Tissue oxygen reactivity and cerebral autoregulation after severe traumatic
brain injury. Crit Care Med 2003; 31:267.
42. Tirado-Sánchez A, Ponce-Olivera RM. Tacrolimus in confluent and reticulated papillomatosis of Gougerot Carteaud.
Int J Dermatol 2013; 52:513.
43. Angeli-Besson C, Koeppel MC, Jacquet P, et al. Confluent and reticulated papillomatosis (Gougerot-Carteaud) treated
with tetracyclines. Int J Dermatol 1995; 34:567.
44. Erkek E, Ayva S, Atasoy P, Emeksiz MC. Confluent and reticulated papillomatosis: favourable response to low-dose
isotretinoin. J Eur Acad Dermatol Venereol 2009; 23:1342.
45. Hodge JA, Ray MC. Confluent and reticulated papillomatosis: response to isotretinoin. J Am Acad Dermatol 1991;
24:654.
46. Solomon BA, Laude TA. Two patients with confluent and reticulated papillomatosis: response to oral isotretinoin and
10% lactic acid lotion. J Am Acad Dermatol 1996; 35:645.
47. Bruynzeel-Koomen CA, de Wit RF. Confluent and reticulated papillomatosis successfully treated with the aromatic
etretinate. Arch Dermatol 1984; 120:1236.
48. Baalbaki SA, Malak JA, al-Khars MA. Confluent and reticulated papillomatosis. Treatment with etretinate. Arch
Dermatol 1993; 129:961.
1778
GRAPHICS
Reticulated, hyperpigmented patches and thin plaques with mild scale are present on the
chest and inframammary areas.
1779
Reticulated, hyperpigmented patches and thin plaques with fine scale are present on the
upper back.
1780
Close view of hyperpigmented, reticulated thin plaques in confluent reticulated

papillomatosis.
1781
Hyperpigmented, reticulated plaques with fine scale on the back.
1782
Hyperpigmented, reticulated plaques on the face.
1783
Hyperpigmented, reticulated plaques on the pubic area and proximal thighs.
1784
Hyperpigmented, reticulated plaques in the antecubital folds and axillary area.
1785
Tinea versicolor
Multiple hyperpigmented, coalescing macules and thin plaques on the chest.
1786
Tinea versicolor
Hyperpigmented macules and patches on the neck.
1787
Acanthosis nigricans
A hyperpigmented, velvety plaque is present on the neck of this patient with acanthosis nigricans.
1788
Acanthosis nigricans
A velvety, hyperpigmented plaque with associated acrochordons is present in the axilla.
1789
Epidermal nevus
A hyperpigmented, verrucous, linear plaque is present on the neck.
1790
Flat warts
Multiple flesh-colored, flat-topped papules are present on the forehead.
1791
Epidermodysplasia verruciformis
Typical pityriasis versicolor-like lesions on the neck of a patient with epidermodysplasia verruciformis.
1792
Darier disease
Multiple hyperpigmented, hyperkeratotic papules are on the chest.
1793
Lichen amyloidosis
Hyperpigmented plaques on the extensor surfaces of the legs in a patient with lichen amyloidosis. The plaques, which
result from coalescing papules, are persistent and intensely pruritic.
1794
Macular amyloidosis
A characteristic rippled pattern of pigmentation in a patient with macular amyloidosis.
1795
Brand names
(United States)
(except as noted)
Super-high potency Betamethasone dipropionate, Gel, lotion, ointment Diprolene 0.05

(group 1) augmented (optimized)
Clobetasol propionate Cream, gel, ointment, solution Temovate 0.05

(scalp)
Lotion, shampoo, spray aerosol Clobex 0.05

(group 2)
Betamethasone dipropionate Ointment Diprosone ¶ 0.05
Cream, augmented formulation Diprolene AF 0.05

(AF)
Gel Topicort 0.05
Fluocinonide Cream, gel, ointment, solution Lidex ¶ 0.05

(group 3)
Betamethasone dipropionate Cream, hydrophilic emollient Diprosone ¶ 0.05
Foam Luxiq 0.12
Diflucortolone valerate (not Cream, oily cream, ointment Nerisone (Canada, United 0.1

Triderm
Medium potency Betamethasone dipropionate Spray Sernivo 0.05

(group 4)

solution
1796
Lower-mid potency Betamethasone dipropionate Lotion Diprosone ¶ 0.05

(group 5)
Gel Desonate 0.05

solution
Prednicarbate Cream (emollient), ointment Dermatop 0.1
Low potency Alclometasone dipropionate Cream, ointment Aclovate 0.05

(group 6)
Foam Verdeso 0.05
Shampoo Capex 0.01

(group 7)
Lotion Hytone, Ala Scalp, Scalacort 2
Hydrocortisone (base, <2%) Ointment Cortaid, Cortizone 10, Hytone, 1

Nutracort
Cream Cortaid ¶, Cortizone 10, Hytone, 1

Synacort
Gel Cortizone 10 1

Cortizone 10
Spray Cortaid 1
Lotion Nucort 2
US: United States.

* Listed by potency according to the US classification system: group 1 is the most potent, group 7 is the least potent. Other countries use a different classification system with
only four or five groups.
¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available generically in the United States.
Data from:
3. U.S. Food & Drug Administration Approved Drug Products with Therapeutic Equivalence (Orange Book). Available at: https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
(Accessed on June 18, 2017).
1797
Amy Y-Y Chen, MD, FAAD Nothing to disclose Jeffrey Callen, MD, FACP, FAAD Equity Ownership/Stock Ownership: Celgene; Pfizer; 3M;
Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; CVS; Walgreens [Various dermatologic conditions
(Thalidomide, apremilast, etanercept, adalimumab, tofacitinib)]. Equity Ownership/Stock Ownership (Spouse): Celgene; Pfizer; 3M;
Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen; CVS; Walgreens [Various dermatologic
conditions (Thalidomide, apremilast, etanercept, adalimumab, tofacitinib)]. Other Financial Interest: Principia Biopharma [Safety
monitoring board member (Developmental drug to treat pemphigus)]. Abena O Ofori, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.
1798
Lichen striatus
Authors: Deepti Gupta, MD, Erin Mathes, MD
Section Editor: Moise L Levy, MD
Deputy Editor: Rosamaria Corona, MD, DSc
INTRODUCTION
Lichen striatus is an acquired, asymptomatic, and self-limited linear inflammatory skin disorder that
predominantly affects children [1,2]. The eruption is typically unilateral, most often involving the
extremities, and follows the lines of Blaschko in a continuous or interrupted pattern. The onset is
sudden, with full progression over a few weeks and resolution typically within 6 to 12 months.
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of lichen
striatus.
EPIDEMIOLOGY
Lichen striatus is a relatively uncommon disease that most frequently occurs in children 5 to 15 years
of age. However, it may occur at any age, from early infancy to adulthood [3-8]. Lichen striatus has
been reported in all ethnic groups and appears to be more common in females [4,6-8]. There are a few
reports of familial cases [4,9-13].
PATHOGENESIS
The precise etiology of lichen striatus is unknown. Viral infections, trauma, hypersensitivity reactions,
vaccines, medications, and pregnancy have been proposed as triggering factors [14-18]. A positive
personal or family history of asthma, atopic dermatitis, or allergic rhinitis has been reported in 60 to
85 percent of individuals with lichen striatus, suggesting that atopy may be a predisposing factor
[6,19,20].
1799
The distribution of lichen striatus along the lines of Blaschko (lines corresponding to the direction of
growth of cutaneous cells during embryogenesis (figure 1)) suggests that lichen striatus is a
condition of cutaneous mosaicism, due to somatic (postzygotic) mutations that produce abnormal
keratinocyte clones during early embryogenesis. These aberrant clones may remain silent until a
triggering event causes a break in immunologic tolerance and initiates an autoimmune response
[5,21]. Potential triggers include viral infections, vaccines, trauma, pregnancy, hypersensitivity
reactions, and medications [6,10,14-17,22-24].
The immunohistologic finding of CD8+ T lymphocytes surrounding necrotic keratinocytes and

activated Langerhans cells suggests that a cell-mediated cytotoxic reaction may be involved in the
pathogenesis of lichen striatus [10,21,25]. This reaction may cause the complete or partial deletion of
the mutant clone, explaining the rarity of recurrence of lichen striatus. Plasmacytoid dendritic cells
have also been seen in lichen striatus, suggesting that they may play a role in pathogenesis. Their
presence and peri-eccrine location may be helpful in distinguishing among other inflammatory
conditions, such as lichen planus [26]. (See 'Pathology' below.)
Lichen striatus typically presents with a sudden eruption of red, pink, or skin-colored flat-topped
papules arranged in a linear band that follows the lines of Blaschko (picture 1A-D). The band is
usually narrow, solitary, and unilateral, and may be continuous or interrupted.
The extremities (picture 1C) are most commonly involved, followed by the trunk (picture 1D),
buttocks, face (picture 1A-B), and nails (picture 2) [27]. A V-shaped pattern over the spine and S-
shaped on the lateral and anterior aspect of the trunk (picture 1D) is characteristic [5,6,28]. Bilateral
or multiple bands have also been described (picture 3) [5,29-31].
There are three morphologic variants of lichen striatus [6]:
● Typical lichen striatus – Discrete 1 to 4 mm flat-topped, flesh-colored to erythematous, smooth

or scaly papules, and rarely vesicles arranged in a narrow band along the lines of Blaschko
(picture 1D and picture 4). This is the most common variant, occurring in approximately 80
percent of patients [6].
● Lichen striatus albus – Hypopigmented macules and/or papules with only a few typical lichenoid
pink papules at onset. This variant is more common in darker-skinned patients (picture 5).
● Nail lichen striatus – Lichen striatus of the nail matrix may present as longitudinal ridging or
fissuring, splitting, fraying, onycholysis, nail pitting, punctate or striate leukonychia, or nail plate
1800
thinning or thickening (picture 2) [24,32-35]. Nail lichen striatus usually involves only one nail and
often affects only the lateral or medial portion of the nail plate [33].
Nail involvement is rare and is usually seen in association with typical skin lesions, although cases
limited to the nail have been reported [6,33,34]. Nail lesions may precede, follow, or develop
concurrently with the skin lesions.
Lichen striatus is usually asymptomatic. Pruritus has been reported in up to one-third of the patients,
most often in individuals with atopy [6,8].
Clinical course — On average, the active phase of lichen striatus lasts six months, ranging from less
than three months to several years [6,36]. Lesions then resolve spontaneously, leaving a transient
postinflammatory hypopigmentation or, rarely, hyperpigmentation. The hypopigmentation resolves
slowly in one to three years and is not influenced by treatment [4,5].
Relapses are rare and usually involve the same site or hemibody, with eventual complete clearance.
Nail lesions may persist for several years, but eventually resolve without permanent nail dystrophy
[6].
DIAGNOSIS
The diagnosis of lichen striatus is usually clinical, based upon the classic finding of erythematous or
skin-colored, flat-topped papules arranged in a linear band along the lines of Blaschko (picture 1B-D).
If the diagnosis is in question, a skin biopsy may be necessary for histopathologic confirmation. (See
'Pathology' below.)
Pathology — The histopathologic features of lichen striatus are variable and may be nonspecific,
depending upon the age of the lesion and area biopsied. However, in the active phase of the disease,
there are several distinctive microscopic findings that may support the clinical diagnosis [37]:
● A superficial, band-like lichenoid infiltrate in the papillary dermis at the dermal-epidermal

junction, with focal vacuolar alteration of the basal layer (picture 6).
● A deeper dermal lymphocytic infiltrate mainly centered around eccrine glands and hair follicles
(picture 7) .
● Variable epidermal changes, such as focal spongiosis, exocytosis, patchy hyperkeratosis,

parakeratosis, and dyskeratosis.
Similar changes can be observed also in lichen striatus of the nail matrix [21,33].
1801
Many conditions may mimic lichen striatus, including:
● Blaschkitis – Blaschkitis is an idiopathic, pruritic, papulovesicular eruption, often arranged in

multiple broad bands along the lines of Blaschko. It is more often seen in adults, but has been
reported also in children [25,38]. Blaschkitis has a sudden onset with rapid resolution and
frequent relapses. On histopathology, blaschkitis tends to have a predominately spongiotic
pattern, in contrast to the lichenoid pattern of lichen striatus.
● Inflammatory linear verrucous epidermal nevus – Inflammatory linear verrucous epidermal

nevus (ILVEN) is a variant of epidermal nevus that can be present at birth, but often presents in
childhood. It is characterized by unilateral pruritic, erythematous, and hyperkeratotic papules that
coalesce into plaques in a linear array (picture 8). ILVEN does not regress spontaneously, but
undergoes periods of exacerbation followed by improvement. (See "Epidermal nevus and
epidermal nevus syndrome", section on 'Inflammatory linear verrucous epidermal nevus'.)
● Linear cutaneous lupus erythematosus – Linear cutaneous lupus erythematosus (LCLE) is a rare
variant of cutaneous lupus occurring most often in children [39,40]. LCLE often presents on the
face and does not resolve spontaneously. A skin biopsy is necessary to confirm the diagnosis.
Patients with LCLE may have other mucocutaneous manifestations of lupus. (See "Overview of
cutaneous lupus erythematosus".)
● Linear morphea – Linear morphea is a form of localized scleroderma that follows Blaschko's
lines. It is often found on the face and extremities of children. It does not resolve spontaneously
and can lead to permanent scarring. Linear morphea can be distinguished from lichen striatus by
the presence of atrophy and sclerosis, although early lesions may be hard to distinguish (picture
9). The histopathology of late linear morphea has epidermal atrophy and dermal fibrosis. The
histopathology of early linear morphea may have some overlapping features with lichen striatus
[41]. Also, there have been few case reports of facial lichen striatus preceding linear morphea,
and therefore, it is recommended that facial lichen striatus lesions be followed until resolution
[41]. (See "Localized scleroderma in childhood".)
● Linear lichen planus – Linear lichen planus (LLP) is a rare variant of lichen planus most
commonly seen in children (picture 10). It can be distinguished from lichen striatus by
histopathologic examination and direct immunofluorescence (DIF). In LLP, cytoid bodies are
typically seen at the dermoepidermal junction and DIF is positive for multiple immunoglobulins.
Lichen planus of the nail tends to involve multiple nails and the entire nail plate (picture 11),
1802
whereas lichen striatus often only involves one nail and only the lateral or medial portion of the
nail plate (picture 2) [42]. (See "Lichen planus".)
● Lichenoid chronic graft-versus-host disease – Lichenoid chronic graft-versus-host disease may

present with a linear eruption along the lines of Blaschko [43,44]. It can be distinguished from
lichen striatus by histopathology and history of bone marrow transplantation. (See "Cutaneous
manifestations of graft-versus-host disease (GVHD)".)
● Linear psoriasis – Linear psoriasis is a rare variant of psoriasis. The presence of well-
demarcated, erythematous papules or plaques with overlying micaceous scale differentiates
psoriasis from lichen striatus. In uncertain cases, histology can clarify the diagnosis. Patients
with linear psoriasis may also have other sequelae of psoriasis. (See "Psoriasis: Epidemiology,
● Linear porokeratosis – Linear porokeratosis is a rare variant of porokeratosis that typically

presents during infancy or early childhood with single or multiple plaques
with hyperkeratotic rims on the limbs or trunk (picture 12A-B) [45]. Histology reveals the
characteristic cornoid lamellae (thin columns of tightly packed porokeratotic cells within a
keratin-filled epidermal invagination (picture 13A-C)). (See "Porokeratosis", section on 'Linear
porokeratosis'.)
● Linear Darier disease – Darier disease is a rare autosomal dominant genodermatosis that
usually appears during the teenage years as skin-colored or yellow-brown keratotic papules on
the face, chest, and back, and, less frequently, the flexural areas. Linear forms of Darier disease
can be differentiated from lichen striatus by the typical histopathologic finding
of acantholytic dyskeratosis [46]. (See "Darier disease".)
● Incontinentia pigmenti – Incontinentia pigmenti is a rare X-linked dominant genodermatosis that

is usually lethal in males and presents in the neonatal period with linear papules and vesicles.
Within weeks or months, the initial lesions progress to verrucous streaks (picture 14) and then
progress to hypopigmented and finally hyperpigmented whorls along the Blaschko lines (picture
15). (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on
'Incontinentia pigmenti'.)
TREATMENT
Lichen striatus is a benign, self-limited condition that is often asymptomatic; therefore, treatment is
often not necessary. Patients and their parents should be reassured that the eruption will resolve
1803
spontaneously in several months without scarring, leaving a transient hypopigmentation. The
hypopigmentation can last several years.
Low to mid potency topical corticosteroids may be used for the symptomatic treatment of pruritus,
but they have no effect on the duration of the disease or postinflammatory dyspigmentation [6]. There
are isolated reports of successful treatment of lichen striatus with topical calcineurin inhibitors [47-
49]. Excimer laser has been used to treat the residual hypopigmentation of lichen striatus and has led
to repigmentation in a small number of cases [50]. Similarly to the skin lesions, nail lichen striatus
often resolves spontaneously, but the course can be prolonged. Treatment with intralesional
triamcinolone injected into the medial and lateral proximal nail folds targeting the nail matrix has
been described to hasten improvement [51].
● Lichen striatus is a benign, self-limited, inflammatory dermatitis that follows the lines of
Blaschko. It predominantly affects young children and adolescents. (See 'Introduction' above and
● Lichen striatus typically presents as a single, unilateral band of red, pink, or skin-colored flat-
topped papules (picture 1C). The most common locations are the extremities, followed by the
trunk (picture 1D), buttocks, face (picture 1A-B), and nails (picture 2). Bilateral or multiple bands
may also occur (picture 3). (See 'Clinical manifestations' above.)
● The diagnosis of lichen striatus is usually clinical. If the diagnosis is in question, a skin biopsy
may be necessary for histopathologic confirmation. (See 'Diagnosis' above and 'Pathology'
above.)
● Lichen striatus resolves spontaneously without treatment over several months, leaving a
postinflammatory hypopigmentation. Topical corticosteroids can be used for the symptomatic
treatment of pruritus. (See 'Treatment' above.)
1804
GRAPHICS
Lines of Blaschko
The pattern assumed by many different nevoid and acquired skin diseases on the human skin
and mucosae. The cause of the pattern of Blaschko lines is unknown; they do not follow
nerves, vessels, or lymphatics. The lines described by these conditions not only did not
correspond to any known anatomical basis, but were remarkably consistent both from patient
to patient and even from one disease to another. The lines may represent a clinical expression
of a genetically programmed clone of altered cells, perhaps first expressed during
embryogenesis.
Reproduced with permission from: Med Art (www.med-ars.it). Copyright © 2010.
1805
Lichen striatus
Linear band of skin-colored papules on the forehead of a child with lichen striatus.
1806
Lichen striatus
Linear band of erythematous papules on the face of an infant with lichen striatus.
1807
Lichen striatus
Erythematous, flat-topped papules grouped in a narrow, linear band along the arm.
1808
Lichen striatus
Flat-topped, erythematous papules coalescing in a narrow, curvilinear band on the abdomen.
1809
Lichen striatus of the nail
Nail ridging and fraying in this child with lichen striatus. Note the subtle, hypopigmented lesions on the dorsum of the
hand.
1810
Lichen striatus
Multiple linear bands of flat-topped, white or skin-colored papules on the buttocks and leg
of this child with lichen striatus.
1811
Lichen striatus
Linear eruption of skin-colored papules in a child with lichen striatus.
1812
Lichen striatus albus
Hypopigmented macules and patches following lines of Blaschko on the leg.
1813
Histopathogic features of lichen striatus
Lymphocytes are present in a band-like, lichenoid pattern with vacuolar alteration of the dermal-epidermal junction and
scattered dyskeratotic keratinocytes (H&E 200x).
Courtesy of Jeffrey North, MD

Assistant Clinical Professor
Department of Dermatology, University of California, San Francisco.
1814
Histopathologic features of lichen striatus
A superficial, band-like lymphocytic infiltrate fills dermal papillae and obscures the dermal-epidermal
junction. The inflammatory infiltrate is also present in the deeper reticular dermis around adnexal
epithelium (H&E 20x).
Courtesy of Jeffrey North, MD

Assistant Clinical Professor
Department of Dermatology, University of California, San Francisco.
1815
Inflammatory linear verrucous epidermal nevus (ILVEN)
Erythematous, hyperkeratotic papules in a linear distribution on the foot of an infant with inflammatory linear
verrucous epidermal nevus.
1816
Linear morphea
Linear morphea in a child presenting as a midline band of skin atrophy and hyperpigmentation on the forehead and scalp.
1817
Lichen planus following the lines of Blaschko
Violaceous plaque with fine scale following the lines of Blaschko.
1818
Trachyonychia induced by lichen planus
Nail plate roughness, longitudinal ridging, and pitting.
1819
Linear porokeratosis
Linear, erythematous plaques with prominent, keratotic rims are present.
1820
Linear porokeratosis
Slightly atrophic, erythematous plaques with peripheral, keratotic rims are present.
1821
Histopathology of porokeratosis
A column of porokeratotic cells consistent with a cornoid lamella is present within the
dermis.
1822
Histopathology of porokeratosis
A thin, vertical column of parakeratotic cells within a keratin-filled epidermal invagination, known as a
cornoid lamella, is present.
1823
Porokeratosis
A column of porokeratosis consistent with a cornoid lamella is present in the center of this specimen.
1824
Incontinentia pigmenti
Verrucous, hyperkeratotic, linear plaques in a female infant with incontinentia pigmenti.
1825
Incontinentia pigmenti
Pigmentary stage of incontinentia pigmenti with linear and whorled, hyperpigmented areas.
1826
New-onset urticaria
Author: Riccardo Asero, MD
Section Editors: Sarbjit Saini, MD, Jeffrey Callen, MD, FACP, FAAD
Deputy Editor: Anna M Feldweg, MD
INTRODUCTION
Urticaria, or hives (sometimes referred to as welts or wheals), is a common disorder, with a

prevalence of approximately 20 percent in the general population [1]. A typical urticarial lesion is an
intensely pruritic, erythematous plaque (picture 1). Urticaria is sometimes accompanied by
angioedema, which is swelling deeper in the skin. A presumptive trigger, such as a drug, food
ingestion, insect sting, or infection, may be identifiable in patients with new-onset urticaria, although
no specific cause is found in many cases, particularly when the condition persists for weeks or
months. (See 'Etiologies' below.)
The epidemiology, clinical manifestations, etiologies, diagnosis, and management of new-onset

urticaria will be reviewed here. Chronic urticaria and isolated angioedema are discussed separately.
(See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural
history" and "Chronic spontaneous urticaria: Standard management and patient education" and "An
overview of angioedema: Clinical features, diagnosis, and management".)
CATEGORIZATION OF URTICARIA
Urticaria (with or without angioedema) is commonly categorized by its chronicity:
Acute urticaria — Urticaria is considered acute when it has been present for less than six weeks.
Chronic urticaria — Urticaria is considered chronic when it is recurrent, with signs and symptoms
recurring most days of the week, for six weeks or longer.
1827
The period of six weeks is somewhat arbitrary and simply represents a timeframe in which new
cases of urticaria usually resolve. More than two-thirds of cases of new-onset urticaria prove to be
self-limited (acute) [2]. The lesions of acute and chronic urticaria are identical in appearance, so
when the problem first develops, it is not possible to differentiate the two disorders [3].
EPIDEMIOLOGY
Urticaria affects up to 20 percent of the population at some point in their lives and occurs across the
age spectrum [1].
Urticarial lesions are circumscribed, raised, erythematous plaques, often with central pallor (picture
2). Lesions may be round, oval, or serpiginous in shape and vary in size from less than 1 centimeter
to several centimeters in diameter. They are intensely itchy. Pruritus may disrupt work, school, or
sleep. Symptoms often seem most severe at night.
Individual lesions are transient, usually appearing and enlarging over the course of minutes to hours
and then disappearing within 24 hours. Lesions may coalesce as they enlarge. Urticarial lesions are
not normally painful and resolve without leaving residual ecchymotic marks on the skin, unless there
is trauma from scratching. If lesions are long-lasting, painful, or leave residual bruising, the diagnosis
of urticarial vasculitis should be considered. (See 'Differential diagnosis' below.)
Any area of the body may be affected, although areas in which clothing compresses the skin (eg,
under waistbands) or skin rubs together (axillae) are sometimes affected more dramatically.
Typically, compressed areas become more severely affected once the restricting clothing has been
removed.
Angioedema, when associated with urticaria, usually affects the face and lips, extremities, and/or
genitals. Angioedema without urticaria should prompt consideration of other angioedema disorders,
such as drug-induced angioedema (eg, angiotensin-converting enzyme [ACE] inhibitors), idiopathic
angioedema, and hereditary and acquired C1 inhibitor deficiency. (See "ACE inhibitor-induced
angioedema" and "An overview of angioedema: Pathogenesis and causes".)
PATHOPHYSIOLOGY
1828
Urticaria is mediated by cutaneous mast cells in the superficial dermis. Basophils have also been
identified in lesional biopsies [4]. Mast cells and basophils release multiple mediators upon
activation including histamine (which causes itching) and vasodilatory mediators (which cause
localized swelling in the uppermost layers of the skin). The same process gives rise to angioedema
when mast cells deeper in the dermis and subcutaneous tissues are activated. (See "Mast cells:
Development, identification, and physiologic roles".)
ETIOLOGIES
The potential causes of new-onset urticaria are numerous, although no specific etiology can be
identified in many patients. Acute urticaria is more likely to have an identifiable etiology compared
with chronic urticaria. The different etiologies activate mast cells through various mechanisms.
Common causes — Common causes of new-onset urticaria include infections; allergic reactions to
medications, foods, or insect stings and bites; reactions to medications that cause nonallergic mast
cell activation (eg, narcotics); and ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) (table
1).
Infections — Viral, bacterial, and parasitic infections are associated with new-onset urticaria.
● Viral and bacterial infections – Acute urticaria may develop during or following a viral or
bacterial infection, particularly in children. Infections are associated with over 80 percent of
cases of acute urticaria in some pediatric series [2,5-8]. Immune activation, involving immune
complex formation and/or complement activation, is a proposed mechanism, although the exact
pathogenesis is unclear.
• In one study, common viral illnesses and bacterial infections (eg, urinary tract infections)
were the leading identifiable trigger for acute urticaria in 57 children between the ages of
one and three years who presented to an emergency department [5]. Many of these children
had also received antibiotics, so it was not clear in these patients if the infection, the drug,
or the combination had triggered urticaria.
• In another study, 88 children presenting to an emergency department with delayed

cutaneous reactions while taking beta-lactam antibiotics were evaluated. Of these, 47 of 88
had urticarial eruptions. All were tested for common childhood viral infections and then
later evaluated for drug allergy with testing followed by drug challenge (regardless of test
results) [9]. Two-thirds had one or more positive viral studies, demonstrating infections with
picornavirus (most common), coronavirus, respiratory syncytial virus, and several others.
When the children were later challenged with the culprit antibiotic, only 4 had recurrent
1829
urticaria. Thus, urticaria was related to the viral infection or the combination of the viral
infection and the antibiotic in most, and only 4 of 88 had a drug allergy. (See "Penicillin
allergy: Delayed hypersensitivity reactions", section on 'Delayed urticarial eruptions'.)
• Acute urticaria, refractory to antihistamines but responsive to azithromycin, has been

associated with documented Mycoplasma pneumoniae infection in children [10,11].
• Acute urticaria can occur in the prodromic, preicteric phase of hepatitis A or B infection and
less commonly with hepatitis C [12]. Urticaria may be an initial manifestation of human
immunodeficiency virus (HIV) infection [13]. (See "Acute and early HIV infection:
Pathogenesis and epidemiology".)
● Parasitic infections – Parasitic infections generally cause acute, self-limited urticaria in

association with prominent eosinophilia [14].
• Infections with Ancylostoma, Strongyloides, Filaria, Echinococcus, Trichinella, Toxocara,

Fasciola, Schistosoma mansoni, and Blastocystis hominis have all been associated with
urticaria. Stool examination is probably only indicated in travelers to endemic areas and in
patients with peripheral blood eosinophilia. (See "Approach to the patient with unexplained
eosinophilia".)
• Ingestion of fish contaminated with the parasite Anisakis simplex can also cause urticaria.
Anisakis can be transmitted through the ingestion of sushi [15]. (See "Seafood allergies: Fish
and shellfish", section on 'Anisakis'.)
IgE-mediated allergic reactions — Immunoglobulin E (IgE)-mediated, type I immediate allergic

reactions often involve urticaria. Urticaria that is caused by an allergic reaction usually occurs within
minutes to two hours of exposure to the culprit allergen. Causes include medications, foods and food
additives, insect stings and bites, latex, and blood products.
Allergic reactions may be limited to the skin or part of a systemic allergic reaction (eg, anaphylaxis)
(table 2 and table 3). Generalized urticaria or angioedema following exposure to a potential allergen
should be interpreted as a systemic reaction with an attendant risk of anaphylaxis upon subsequent
exposure, and patients should be advised to avoid the potential cause until further evaluated. (See
'Referral' below.)
● Medications – The antibiotics most frequently implicated in causing IgE-mediated urticaria

include beta-lactams (penicillins and cephalosporins), although antibiotics from virtually all
classes have been reported (picture 3). (See "Penicillin allergy: Immediate reactions".)
1830
● Stinging and biting insects – Stinging insects that can cause true urticarial lesions as part of an
allergic reaction include Hymenoptera (eg, bees, wasps, hornets, and imported fire ants) and
Triatoma (eg, kissing bugs).
Bedbugs, fleas, and mites can cause papular urticaria, usually on the lower extremities. The
lesions of papular urticaria resolve over the course of weeks. (See "Bee, yellow jacket, wasp, and
other Hymenoptera stings: Reaction types and acute management" and "Reactions to bites from
kissing bugs (primarily genus Triatoma)" and "Bedbugs".)
● Latex – Occupational, recreational, dental, or surgical exposure to latex may cause urticaria,
angioedema, asthma, or anaphylaxis in susceptible individuals [16]. Everyday scenarios in which
patients may be exposed to significant amounts of latex include inflation of balloons and use of
latex gloves. Penile and vulvar/vaginal urticaria and angioedema are seen upon exposure to
latex condoms, with vulvar/vaginal symptoms resembling acute vaginitis. (See "Latex allergy:
● Foods and certain food additives – Allergic reactions to foods can cause urticaria, typically
within 30 minutes of ingestion. Milk, eggs, peanuts, tree nuts, soy, and wheat are the most
common foods to cause generalized urticaria in children. In adults, fish, shellfish, tree nuts, and
peanuts are most often implicated [17]. In Mediterranean areas, the most frequent cause of
food-induced urticaria is the peach, due to sensitization to lipid transfer protein [18]. (See
"Clinical manifestations of food allergy: An overview".)
Synthetic additives in commercially prepared foods are believed to be a relatively rare cause of
urticarial reactions. In contrast, certain natural compounds, such as the yellow food dye annatto
and the red dye carmine red, have been well-documented causes of urticaria and anaphylaxis.
Adverse reactions to food additives are discussed in detail elsewhere. (See "Allergic and
asthmatic reactions to food additives".)
● Contact with allergens – Physical contact with a number of agents may result in urticaria,
including plant products and resins, raw fruits and vegetables, or raw seafood. People employed
in food processing can develop contact urticaria from various exposures [19]. Children
sometimes develop urticaria upon contact with animal saliva, if allergic to those allergens. In
contrast, detergents, soaps, and lotions are more likely to cause contact dermatitis than
urticaria. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Contact
dermatitis in children".)
● Urticarial transfusion reactions – Acute urticaria in the setting of transfusion may arise from
several mechanisms, including IgE-mediated allergic reactions, complement-mediated reactions,
1831
and other immunologic events. These reactions are discussed elsewhere. (See "Immunologic
transfusion reactions".)
Direct mast cell activation — Certain drugs, foods, and plants can cause urticaria due to mast cell
degranulation through a non-IgE-mediated mechanism. The most frequently implicated are narcotics,
muscle relaxants, vancomycin, and radiocontrast media. Some berries and nettle plants are
examples of plants and plant foods that cause direct mast cell activation.
● Narcotics – Opiate analgesics, such as morphine and codeine, cause direct mast cell activation.
Dextromethorphan, an opiate derivative ingredient in cough suppressant syrups, can also cause
urticaria [20].
● Muscle relaxants – Anesthetic muscle relaxants, including atracurium, vecuronium,

succinylcholine, and curare, may cause urticaria. Muscle relaxants can also cause IgE-mediated
anaphylaxis. Allergic reactions to these medications are reviewed in greater detail elsewhere.
(See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management".)
● Vancomycin – The "red man" syndrome is seen after rapid vancomycin infusion and presents as
diffuse erythema or flushing, sometimes with accompanying urticaria. The concomitant use of
opiates and vancomycin may increase the likelihood of a reaction. (See "Vancomycin
hypersensitivity".)
● Radiocontrast medium – Radiocontrast agents are associated with urticaria and angioedema.
(See "Diagnosis and treatment of an acute reaction to a radiologic contrast agent".)
● Certain foods – Tomatoes, strawberries, and a small number of other foods can cause
generalized urticaria or contact urticaria through nonimmunologic mechanisms, particularly in
young children [6]. These foods are sometimes referred to as "pseudoallergens." IgE-mediated
allergies to these foods are also possible.
● Stinging nettle – The nettle plant (Urtica dioica), after which the disorder "urticaria" was named,
is a common weed found in Europe, North and South America, and parts of Africa that causes
hives and a stinging sensation immediately following contact with the skin [21-23]. These
symptoms may be due to histamine in the nettle plant itself, in addition to mediators that cause
pain [24].
Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs (NSAIDs), such as

aspirin, ibuprofen, naproxen sodium, and others, can trigger urticaria and/or angioedema by two
distinct mechanisms:
1832
● Pseudoallergic/pharmacologic – NSAIDs cause urticaria in some individuals, presumably due to
underlying abnormalities in arachidonic acid metabolism. This form of NSAID reaction is called
a pseudoallergic reaction because the mechanism is nonimmunologic. NSAID pseudoallergy
can be seen with any agent (eg, aspirin, ibuprofen) that inhibits the cyclooxygenase 1 (COX-1)
enzyme and rarely occurs with agents that are very weak inhibitors of COX-1. Patients with
pseudoallergy usually tolerate acetaminophen and the selective cyclooxygenase 2 (COX-2)
inhibitors. Pseudoallergic reactions attributed to NSAIDs are discussed in more detail
separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on
'Pseudoallergic reactions'.)
● Allergic – A specific NSAID can also cause acute urticaria in patients who are allergic to that
one agent. These reactions are presumed to represent true, immunologic allergy. (See "NSAIDs
(including aspirin): Allergic and pseudoallergic reactions", section on 'Allergic reactions
(presumed IgE-mediated)'.)
Both pharmacologic and allergic reactions to NSAIDs can be severe. However, the management
differs. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on
'Management'.)
Scombroid syndrome — The ingestion of poorly preserved fish (tuna in most cases, but
sometimes mackerel or sardines) containing large amounts of histamine may cause acute
symptoms that resemble those of an IgE-mediated allergic reaction characterized by flushing,
urticaria, diarrhea, headache, and sometimes bronchospasm. (See "Scombroid (histamine)
poisoning".)
Uncommon causes — Uncommon causes of new-onset urticaria include various physical factors,
serum sickness, and hormone-associated disorders.
● Physical stimuli – Physical urticarial syndromes are forms of chronic urticaria that are triggered
by specific physical factors, such as cold exposure, sudden changes in body temperature,
pressure or vibration against the skin, exercise, exposure to sunlight, or other stimuli. These
disorders are reviewed separately. (See "Physical (inducible) forms of urticaria" and "Cold
urticaria".)
● Serum sickness – Serum sickness and serum sickness-like reactions to exogenous proteins or
medications may present with an urticarial rash accompanied by fever, polyarthralgias,
polyarthritis, and/or lymphadenopathy. This typically develops within one to three weeks after
administration of the causative agent. Proteinuria, edema, and abdominal pain may also be
present. These reactions are discussed elsewhere. (See "Serum sickness and serum sickness-
like reactions".)
1833
● Progesterone-associated urticaria – There are rare reports of progesterone-containing oral
contraceptives, hormone replacement therapy, or endogenous progesterone associated with
cyclic urticaria [25,26]. The disorder is sometimes called autoimmune progesterone dermatitis
[27-30]. Lesions usually appear during the second half of the menstrual cycle and resolve with
menstruation.
SYSTEMIC DISORDERS THAT MAY INCLUDE URTICARIA
Uncommonly, urticaria or urticaria-like lesions may be an early feature of a systemic disorder,

including the following:
● Urticarial vasculitis – Urticarial vasculitis should be suspected when individual lesions are
painful, are long-lasting (longer than 24 to 36 hours), appear purpuric or ecchymotic, or leave
residual ecchymosis or hyperpigmentation upon resolution (in the absence of trauma from
scratching) (picture 4 and picture 5 and picture 6). Vasculitis should also be suspected in
patients with urticaria accompanied by fever, arthralgias, arthritis, weight changes, bone pain, or
lymphadenopathy. Urticarial vasculitis may be a cutaneous or systemic disease, and it may
occur in the setting of another rheumatologic disorder or rarely, a malignancy. (See "Urticarial
vasculitis" and "Cutaneous manifestations of internal malignancy".)
● Mastocytosis – Mastocytosis and mast cell disorders are rare conditions in which patients
present with apparent allergic reactions and anaphylaxis to a variety of triggers. Characteristic
skin findings are helpful in diagnosis. These disorders are reviewed separately. (See
"Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical
manifestations".)
● Systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, celiac disease,

autoimmune thyroid disease, and other autoimmune diseases – Urticaria may be a presenting
manifestation or occur sporadically over time in patients with autoimmune conditions [31]. The
etiology of this remains unclear but may be due to direct mast cell activation via complement
receptors or due to the generation of autoantibodies that may result in anaphylactoid
degranulation. Screening for these disorders in the setting of an acute episode of urticaria is not
indicated, unless there are other preceding symptoms that suggest that one of these disorders
may be present.
● Cutaneous small vessel vasculitis – Some forms of cutaneous small vessel vasculitis can
appear urticarial during early stages. Urticarial lesions that are persistent in a single location for
>24 hours, have bruising, are painful, or are accompanied by systemic symptoms (eg, fever)
should raise a concern for vasculitis.
1834
• Urticarial vasculitis is a disorder characterized by urticarial lesions with vasculitic findings
on skin biopsy (picture 5). The disorder may be systemic or limited to the skin. (See
• Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) is a systemic vasculitis with

a prominent cutaneous component characterized by purpuric lesions, particularly involving
the lower extremities. The skin lesions can be urticarial initially, although the development
of systemic disease with arthralgias, abdominal pain, and renal involvement should prompt
investigation for this condition. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical
manifestations and diagnosis", section on 'Skin manifestations'.)
• Patients with lupus may also develop urticarial lesions that persist and become vasculitic.
Skin biopsy may show evidence of vasculitis. (See "Overview of cutaneous lupus
erythematosus".)
● Malignancies – Urticaria may also be seen with malignancies, especially immunoglobulin M

(IgM) and sometimes immunoglobulin G (IgG) paraproteinemias. The etiology is also unclear but
may be due to complement-mediated pathways. In these cases, the urticaria is persistent and
becomes chronic. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis,
pathogenesis, and natural history", section on 'Unclear association with malignancy'.)
The urticaria associated with systemic disorders is usually recurrent, persistent, and relatively
difficult to treat, so patients with these disorders typically present with chronic urticaria. Clinical
features that can help distinguish these disorders from uncomplicated chronic urticaria are reviewed
separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis,
and natural history", section on 'Differential diagnosis'.)
EVALUATION AND DIAGNOSIS
Urticaria is diagnosed clinically, based upon a detailed history and physical examination confirming
the presence of characteristic skin lesions [32-35].
Clinical history — The clinical history should determine the following:
● Were there other signs and symptoms of a generalized allergic reaction or anaphylaxis? Patients
may fail to report more subtle symptoms unless specifically asked. The clinician should ask
about chest tightness or difficulty breathing, hoarse voice or throat tightness, nausea, vomiting,
crampy abdominal pain, lightheadedness, and other symptoms of anaphylaxis (table 2). (See
"Anaphylaxis: Emergency treatment".)
1835
● Has the patient had hives previously in the past? Some children develop acute urticaria
repeatedly with infections. Adults may develop urticaria following nonsteroidal anti-
inflammatory drug (NSAID) ingestion but may not recognize the association until it has occurred
several times. Does the patient have other allergic disorders?
● Were there any symptoms or signs to suggest an underlying systemic disorder? Specifically, has
the patient recently had unexplained fever, weight loss, arthralgias, arthritis, or bone pain [36,37]?
Diseases that may include hives as part of the clinical presentation are reviewed separately.
(See 'Systemic disorders that may include urticaria' above.)
● Is a possible etiology apparent from the patient's history (table 1)? (See 'Etiologies' above.)
• Was the patient in his/her usual state of health when the hives appeared or has the patient
been ill recently with viral or bacterial infections? Has the patient experienced any recent
health events, such as musculoskeletal injuries for which he/she was taking NSAIDs or new
diagnoses requiring unfamiliar medications or treatments?
• The patient should be asked to review events in the hours before the urticaria appeared.
What had the patient ingested (foods, beverages, candy)? Was the patient involved in
exercise or physical exertion? Was the patient exposed to extremes of temperature or stung
by an insect? The answers may reveal clues to allergic or physical causes of urticaria.
• Patients should be questioned about any new medications or supplements in the preceding
days or weeks [38,39]. Were any medications taken in the hours before the urticaria
appeared?
• Inquiries should be made about recent travel (and symptoms of parasitic infection) and
sexual history. (See 'Infections' above.)
• A complete review of systems is valuable in the patient with new-onset urticaria.
Physical examination — Lesions should be visualized directly in order to make the diagnosis with
certainty, since the term "hives" is used nonspecifically by patients. If the patient has no lesions at
the time of evaluation, showing patients photographs of urticaria and asking if their lesions look
similar can be helpful, although the diagnosis will need to be confirmed at some point in the future
(picture 2).
Individual urticarial lesions usually appear and resolve completely within 24 hours. If the patient is
unsure of the duration of the lesions, a lesion can be circled with a pen and time to resolution noted.
Laboratory studies — Laboratory studies are typically normal in patients who lack any history or
physical findings to suggest an underlying disease process [3].
1836
● For patients presenting with new-onset urticaria (with or without angioedema) in whom the
clinical history and physical exam do not suggest an underlying disorder or urticarial vasculitis,
international, European, and British practice parameters state that laboratory testing is not
indicated [40-42]. American practice parameters state that a limited evaluation "may be
considered" in such patients, primarily for the purpose of detecting underlying disorders earlier
in the one-third of patients in whom urticaria will prove persistent (ie, initial presentation of
chronic urticaria) [43]. In this setting, complete blood count with differential, urinalysis,
erythrocyte sedimentation rate, and liver function tests are suggested. However, the author's
approach is to obtain these tests in patients with persistent symptoms.
● In patients in whom a specific etiology is suspected, laboratory studies and further evaluation
should be directed at establishing or excluding that cause. (See 'Etiologies' above.)
Tests for allergic causes — An allergic cause is possible if the clinical history reveals a specific
trigger to which the patient was exposed shortly before the onset of symptoms (usually within one to
two hours). If the history does suggest a possible allergy, serum tests for allergen-specific
immunoglobulin E (IgE) antibodies are appropriate, if commercially available. For example, if a
patient who does not normally eat seafood but did so at a special occasion develops hives within 10
minutes of eating a crab cake, it would be reasonable to obtain a crab-specific IgE test, particularly if
there were no other new foods ingested and the patient is avoiding seafood for fear of a repeat
reaction. However, the interpretation of allergy tests can require some expertise. A positive result is
suggestive, although not diagnostic, of allergy, and a negative result does not exclude allergy.
Because of this, we suggest that patients suspected of having an allergy be referred to an
allergist/immunologist for further evaluation when possible. Skin tests with fresh food, which should
be performed by an allergy specialist, is probably the most convenient, inexpensive, and sensitive
way to detect food hypersensitivity. (See 'Referral' below and "Overview of in vitro allergy tests".)
The conditions discussed in this section are those that may mimic various features of urticaria [44].
The presence or absence of pruritus is a helpful clinical feature that can be used to narrow the
differential.
Nonpruritic conditions — Nonpruritic conditions that may resemble acute urticaria include viral
exanthems, the skin changes of auriculotemporal syndrome, and Sweet syndrome.
● Viral exanthems – Viral exanthems are common in children and can occur with many different
infections, including erythema infectiosum (fifth disease), Epstein-Barr virus, enteroviruses, and
measles. However, viral exanthems are generally not pruritic and usually consist of
1837
erythematous maculopapular eruptions that persist for days. Fever is often present. The
macules are relatively fixed compared with urticarial lesions, which continually change, with new
lesions appearing as older lesions resolve. (See topic reviews on specific infections.)
● Auriculotemporal syndrome – Auriculotemporal syndrome is a nonpruritic flushing and/or

sweating of the skin over the cheeks or jawline (the areas supplied by the auriculotemporal
nerve) that occurs transiently after eating and may be mistaken for urticaria associated with
food allergy [45]. It can be seen in children or adults and may develop following damage to the
nerve secondary to forceps delivery, viral infection, surgery, or other local trauma. Unilateral
distribution is typical, although bilateral cases have been reported [46].
● Sweet syndrome – Sweet syndrome is an uncommon disease characterized by recurrent

episodes of painful, long-lasting inflammatory papules and plaques associated with fever,
arthralgias, and peripheral leukocytosis. There may be a history of a febrile illness one to three
weeks before the onset of skin lesions in some cases. (See "Sweet syndrome (acute febrile
neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
Pruritic conditions — Pruritic conditions that are more likely to be confused with urticaria are
discussed here. An overview of the causes of pruritic dermatoses is found separately. (See "Pruritus:
Etiology and patient evaluation".)
● Atopic dermatitis – Atopic dermatitis is a common disorder that presents initially as intensely
pruritic erythematous patches with papules and some scaling. In children, the face, scalp,
extremities, or trunk are typically involved, while the diaper area is spared. In older children and
adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly
involved. Other sites include the face, wrists, and forearms (picture 7). Erythematous areas of
involvement last for days or weeks and have ill-defined borders. Scaling and xerosis develop
with time. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and
diagnosis".)
● Contact dermatitis – Contact dermatitis refers to any dermatitis arising from direct skin
exposure to a substance. The dermatitis may either be allergic or irritant-induced. The latter is
more common. Contact dermatitis is an erythematous, papular dermatitis, often with areas of
vesiculation (picture 8). It is distributed in the areas of direct contact. (See "Contact dermatitis in
children" and "Irritant contact dermatitis in adults" and "Common allergens in allergic contact
dermatitis".)
● Drug eruptions – Drug eruptions, also called morbilliform or exanthematous drug eruptions, are
cutaneous drug reactions that closely mimic viral exanthems but occur in association with a
medication. These dermatoses may or may not be pruritic and begin as small macules and/or
1838
papules that become larger and confluent with time (picture 9). The individual lesions are
persistent, unlike urticaria. (See "Drug eruptions".)
● Insect bites – Insect bites produce individual lesions that persist for days in most cases (see
"Insect and other arthropod bites"). However, the stings of some insects can cause true urticaria
as part of a systemic allergic reaction. (See 'IgE-mediated allergic reactions' above.)
● Bullous pemphigoid – In older adults, bullous pemphigoid may start with pruritus, with or
without urticarial lesions. Blistering usually becomes evident eventually. (See "Clinical features
and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Bullous
pemphigoid'.)
● Erythema multiforme minor – Erythema multiforme minor is a syndrome characterized by

erythematous, iris-shaped macules and vesiculobullous lesions with a target appearance
(picture 10). The lesions may be painful or pruritic and distributed symmetrically on the extensor
surfaces of the extremities (particularly the palms and soles). Individual lesions last several
days, unlike urticaria. There may be accompanying fever and malaise. (See "Erythema
multiforme: Pathogenesis, clinical features, and diagnosis".)
● Plant-induced reactions – Poison ivy and poison oak can present with urticaria-like lesions
initially that evolve into vesicular lesions. (See "Poison ivy (Toxicodendron) dermatitis".)
TREATMENT
Initial treatment of new-onset urticaria (with or without angioedema) should focus on the short-term
relief of pruritus and angioedema, if present. Approximately two-thirds of cases of new-onset
urticaria will be self-limited and resolve spontaneously. The literature on management of acute
urticaria is sparse, probably because the condition is so often self-limited [47]. The agents discussed
below have mostly been evaluated in the treatment of chronic urticaria, and in some cases, their use
in acute urticaria is extrapolated from those studies, which are presented separately. (See "Chronic
spontaneous urticaria: Standard management and patient education".)
H1 antihistamines — H1 antihistamines may be divided into older, first-generation agents (eg,

diphenhydramine, chlorpheniramine, hydroxyzine) and newer, second-generation agents (eg,
cetirizine, loratadine, fexofenadine, others). Second-generation agents are preferred for both adults
and children.
Second-generation agents — The newer, second-generation H1 antihistamines are recommended

as first-line therapy by published guidelines from both allergy and dermatology expert panels [48,49].
These drugs are minimally sedating, are essentially free of the anticholinergic effects that can
1839
complicate use of first-generation agents, have few significant drug-drug interactions, and require
less frequent dosing compared with first-generation agents [50-54]. We know of no data
demonstrating that any specific agent is more effective than another for the treatment of acute
urticaria, although a few studies in patients with chronic urticaria suggest that cetirizine and
levocetirizine may be modestly more effective than other agents. (See "Chronic spontaneous
urticaria: Standard management and patient education", section on 'Agents and efficacy studies'.)
Some patients require higher than standard doses (shown below in parentheses) for control of
urticarial symptoms and may experience drowsiness at these higher doses. Caution is therefore
warranted until effects upon the individual are understood. The higher doses may have better
efficacy in some adults, although this has not been conclusively demonstrated. Studies of higher-
dose antihistamines for chronic urticaria are reviewed separately. (See "Chronic spontaneous
urticaria: Standard management and patient education", section on 'H1 antihistamines'.)
Treatment with H1 antihistamines results in clearance of the lesions in some patients, but in others,
treatment may only achieve flattening of the lesions and reduction in pruritus, with persistence of
erythematous macules. Patients in the latter group can begin to reduce medications after the
erythematous lesions clear.
Second-generation H1 antihistamines include the following:
● Cetirizine – Cetirizine demonstrates a rapid onset of action and some mast cell-stabilizing
activity. It can be mildly sedating, in a dose-dependent manner, although less so than first-
generation agents. It is available in both intravenous (in some countries) and oral formulations,
and the dosing is similar for either route of administration. Intravenous doses should be
administered over one to two minutes. The standard oral or intravenous dose of 10 mg once
daily is appropriate for adults and children aged 12 years and older (and may be increased to 10
mg twice daily in adults if needed).
Children six years of age and older can receive 5 mg or 10 mg. The usual dose for children aged
two to five years is 5 mg once daily. Smaller children aged six months to two years may be given
2.5 mg once daily (can be increased to 2.5 mg twice daily in children one year and older if
needed). The maintenance dose for patients with significant renal and/or hepatic insufficiency
should be reduced by one-half.
● Levocetirizine – Levocetirizine is an active enantiomer of cetirizine that produces effects

equivalent to cetirizine at about one-half of the dose. For adults and children 12 years and older,
the standard dose is 5 mg once daily in the evening (or up to 5 mg twice daily in adults if
needed) or 2.5 mg once daily in the evening for children aged 6 to 11 years. Levocetirizine is
unlikely to be effective as an alternative for patients who did not have an adequate response to
1840
cetirizine, and its sedative effects are similar to those of other second-generation antihistamines
[55]. Dose reductions are necessary in renal insufficiency.
● Loratadine – Loratadine is a long-acting, selective H1 antihistamine. The standard dose is 10 mg

once daily for ages six years and older, which is minimally sedating. It can be increased up to 10
mg twice daily in adults if needed. For children aged two to five years, the usual dose is 5 mg
once daily. For patients with significant renal and/or hepatic insufficiency, the usual dose is
administered every other day.
● Desloratadine – Desloratadine is the major active metabolite of loratadine and produces effects
equivalent to loratadine at about one-half the dose. For adults and children 12 years and older,
the standard dose is 5 mg once daily (or up to 5 mg twice daily in adults if needed).
For children aged 6 to 11 years, the dose is 2.5 mg once daily, and for those aged 1 to 5 years,
the dose is 1.25 mg once daily. A lower dose of 1 mg once daily is approved in the United States
for small children aged 6 months to 1 year. For patients with significant renal and/or hepatic
insufficiency, the usual dose is administered every other day.
● Fexofenadine – Fexofenadine is minimally sedating. The suggested dose is 180 mg daily for
ages 12 years and older (or up to twice daily in adults if needed) or 30 mg twice daily for children
aged 2 to 11 years. A lower dose of 15 mg twice daily is approved in the United States for small
children aged six months to two years. For patients with significant renal insufficiency, the adult
dose should be reduced to 60 mg once daily. It is best taken without food and specifically not
with fruit juices.
There are additional nonsedating antihistamines that are available in many countries, although not in
the United States:
● Ebastine – Ebastine is a nonsedating antihistamine that is licensed for use in children older than
12 years of age and adults. The usual dose is 10 mg daily, but it can be doubled to 20 mg daily if
needed, although not in patients with liver insufficiency. One study of patients with acute
urticaria found that 20 mg of ebastine was similar in efficacy to 5 mg of levocetirizine and
caused fewer adverse effects [56].
● Bilastine – Bilastine is a nonsedating antihistamine with efficacy similar to cetirizine and higher
than that of fexofenadine [57]. The initial dose is 20 mg daily for children older than 12 years of
age and adults. Bioavailability is reduced approximately 30 percent by grapefruit juice,
ketoconazole, or erythromycin, and it should not be taken with food. The drug minimally crosses
the blood-brain barrier (because it is a zwitterion), does not cause somnolence, and is not
affected by alcoholic beverages [58].
1841
● Rupatadine – Rupatadine antagonizes both histamine and platelet-activating factor (PAF)
receptors [59]. It is licensed at a dose of 10 mg daily for patients older than 12 years of age,
although it is safe in patients older than 2 years of age [60]. As is the case for bilastine, the drug
should not be taken with grapefruit juice, ketoconazole, or erythromycin, but (unlike bilastine) it
is not affected by food.
First-generation agents — The first-generation antihistamines include diphenhydramine,

chlorpheniramine, hydroxyzine, and others [61]. These agents are lipophilic and readily cross the
blood-brain barrier, causing sedating and anticholinergic side effects that may be dose-limiting in
some patients. Significant sedation and impairment of performance (eg, fine motor skills, driving
skills, and reaction times) occur in more than 20 percent of patients [62]. Anticholinergic side effects
include dry mouth, diplopia, blurred vision, urinary retention, or vaginal dryness. Patients should be
warned specifically about these adverse effects. Despite these adverse effects, patients at low risk of
complications (eg, young, healthy patients) may find a sedating H1 antihistamine at bedtime helpful,
especially when combined with a nonsedating H1 antihistamine during the day.
Some first-generation H1 antihistamines are available in parenteral preparations for use in patients
in whom a more rapid onset of action is desired, such as those who have presented to the
emergency department. Parenteral dosing of the first-generation agents is:
● Diphenhydramine – The dose in adults is 25 to 50 mg given by slow intravenous (IV)

administration or intramuscular (IM) injection every four to six hours as needed. Children may
receive 0.5 to 1.25 mg/kg (up to 50 mg per dose) IV/IM every six hours as needed.
OR
● Hydroxyzine – The dose in adults is 25 to 50 mg deep IM administration in adults every four to

six hours as needed. Do not administer intravenously. Children may receive 0.5 to 1 mg/kg (up to
50 mg per dose) IM every six hours as needed.
Pregnant and lactating women — Pregnant women may be treated initially with loratadine (10 mg
once daily) or cetirizine (10 mg once daily). There are reassuring human data for each of these drugs
in a large number of pregnant patients [63]. The first-generation agent chlorpheniramine, 4 mg orally
every four to six hours, may also be safely used in pregnancy [64,65]. Safety issues surrounding the
use of antihistamines in pregnancy are reviewed separately. (See "Recognition and management of
allergic disease during pregnancy", section on 'Oral antihistamines'.)
Lactating women may be treated with either cetirizine or loratadine (both are dosed at 10 mg once
daily), which are minimally excreted in breast milk and should not cause sedation or poor feeding in
the infant. (See "Pharmacotherapy of allergic rhinitis", section on 'Breastfeeding women'.)
1842
H2 antihistamines — There are very few data examining the use of H2 antihistamines for acute
urticaria, but the practice is supported by one randomized trial of 91 adults presenting to an
emergency department with acute allergic reactions [66]. Subjects received 50 mg IV
diphenhydramine with either placebo or 50 mg IV ranitidine. At two hours, the number of patients in
whom urticaria had resolved was statistically greater in the ranitidine group compared with the
placebo group (25 of 29 and 13 of 24, respectively). Options for H2 antihistamines include nizatidine,
famotidine, ranitidine (no longer available in the US), and cimetidine, although caution should be
used with cimetidine, since it can increase levels of other drugs. (See "Antiulcer medications:
Mechanism of action, pharmacology, and side effects".)
Studies of the use of H2 antihistamines in chronic urticaria are conflicting and are reviewed
elsewhere [67-69]. (See "Chronic spontaneous urticaria: Standard management and patient
education", section on 'H2 antihistamines'.)
Glucocorticoids — Glucocorticoids do not appear to be necessary for isolated urticaria. However, a

brief course (ie, usually a week or less) of systemic glucocorticoids may be added to antihistamine
therapy for patients with prominent angioedema or if symptoms persist beyond a few days.
Glucocorticoids do not inhibit mast cell degranulation but may act by suppressing a variety of
contributing inflammatory mechanisms.
A small number of trials have examined the utility of glucocorticoids in the management of acute
urticaria [70-72]. In the largest study, the addition of prednisone to levocetirizine did not speed
resolution of acute urticaria. In this randomized trial, 100 adults presenting to the emergency
department with urticaria of ≤24 hours duration without angioedema, anaphylaxis, or fever, were
treated with the H1 antihistamine levocetirizine (5 mg once daily for five days) plus either placebo or
prednisone (40 mg once daily for four days) and followed by phone for several days [72]. The primary
endpoint was complete relief of itching two days after the start of therapy, and secondary endpoints
included resolution of skin lesions, relapses, and adverse events. Most subjects had resolution of
itch by day 2, with a slightly lower percentage itch-free in the prednisone group (79 versus 67
percent). Similarly, by day 2, skin lesions had resolved entirely in 78 and 70 percent of those in the
placebo and prednisone groups, respectively. Thus, the addition of prednisone to levocetirizine did
not speed resolution of acute urticaria. Between one-quarter and one-third of patients experienced
relapse in both groups, generally within the first few days of therapy. Another smaller randomized
trial found that glucocorticoids were helpful when added to antihistamines, although the
antihistamine regimen used in that study (hydroxyzine 25 mg orally every four to eight hours) may
have been more difficult to adhere to [70].
Our approach is to treat all patients with H1 antihistamines, adding H2 antihistamines for more
severe symptoms and reserving oral glucocorticoids for those patients with prominent angioedema
1843
or persistent symptoms despite antihistamines.
The optimal agent and dose have not been determined for acute urticaria, but we typically
administer:
● In adults – Prednisone 30 to 60 mg daily, with tapering of the dose over five to seven days
● In children – Prednisolone 0.5 to 1 mg/kg/day (maximum 60 mg daily), with tapering of the dose
over five to seven days
Antihistamine therapy should be continued during and after the course of glucocorticoids because
some patients experience an exacerbation as the glucocorticoids are tapered or discontinued. If
symptoms do not recur over several days after stopping glucocorticoids, then antihistamines can be
discontinued also. For patients whose symptoms recur when medications are discontinued,
antihistamines should be reinstituted and used at the lowest effective dose. Repeated courses of
glucocorticoids should be avoided, as the risks of adverse effects outweigh the benefit for most
patients. (See 'Referral' below.)
REFERRAL
Patients who are suspected of having an allergic etiology causing new-onset urticaria, such as a
food or medication allergy, should be referred to an allergy specialist who will equip them with
epinephrine for self-injection when indicated. These issues are discussed in detail separately. (See
"Anaphylaxis: Emergency treatment", section on 'Discharge care'.)
It should be explained to patients that about one-third of cases of new-onset urticaria will prove
persistent and that if they continue to have ongoing symptoms after several weeks, they should seek
re-evaluation in a primary care setting. Patients with difficult-to-control symptoms may also be
referred to a dermatology or allergy specialist.
the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding
hereditary angioedema)".)
1844
● Basics topic (see "Patient education: Hives (The Basics)")
● Beyond the Basics topic (see "Patient education: Hives (urticaria) (Beyond the Basics)")
● Urticaria is common, affecting up to 20 percent of the population. Urticarial lesions are intensely
pruritic, circumscribed, raised, erythematous plaques, often with central pallor. Morphology and
size can vary (picture 2). Uncomplicated urticarial lesions are pruritic cutaneous plaques that
develop over minutes to hours and resolve in hours without residual markings. (See 'Clinical
manifestations' above and 'Epidemiology' above.)
● Urticaria is classified as acute or chronic. Acute urticaria is defined as periodic outbreaks of

urticarial lesions that resolve within six weeks, and two-thirds of all urticaria falls into this
category. (See 'Categorization of urticaria' above.)
● A presumptive trigger, such as common viral and bacterial infections, medications, food
ingestion, or insect sting, can sometimes be identified for new-onset urticaria. (See 'Etiologies'
above.)
● Occasionally, urticaria may be the presenting feature of another systemic disorder, such as
urticarial vasculitis, mastocytosis, or systemic lupus erythematous. There are specific clinical
features that should prompt an evaluation for these conditions. (See 'Systemic disorders that
may include urticaria' above.)
● The diagnosis of urticaria is made clinically. A careful history should be performed to exclude
possible anaphylaxis, identify a possible trigger, and determine if there are signs or symptoms to
suggest urticarial vasculitis or an underlying systemic disorder. If the history does not suggest a
1845
specific trigger or underlying systemic illness, then laboratory tests are usually normal and not
helpful. Some guidelines advocate obtaining a complete blood count with differential, urinalysis,
erythrocyte sedimentation rate, and liver function tests at initial presentation, while others
suggest testing only if symptoms persist. (See 'Evaluation and diagnosis' above.)
● In patients with mild symptoms of new-onset urticaria, we suggest treatment with a nonsedating
H1 antihistamine alone (Grade 2B). In patients at low risk of complications from anticholinergic
side effects (ie, young, healthy patients), use of a sedating H1 antihistamine at bedtime and a
nonsedating H1 antihistamine during the day is a reasonable alternative. (See 'H1
antihistamines' above.)
● In patients with moderate-to-severe new-onset urticaria, we suggest adding an H2 antihistamine

(Grade 2C). (See 'H2 antihistamines' above.)
● In patients with prominent angioedema or persistent symptoms despite an H1 and H2

antihistamine, we suggest adding a brief course of oral glucocorticoids (Grade 2C). We typically
administer prednisone (30 to 60 mg daily) in adults or prednisolone (0.5 to 1 mg/kg/day) in
children, tapered over five to seven days. (See 'Glucocorticoids' above.)
● Urticaria that persists beyond several weeks may represent the beginning of chronic urticaria, a
disorder that is reviewed separately. (See "Chronic spontaneous urticaria: Clinical
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Clifton O Bingham, III, MD, who contributed
to an earlier version of this topic review.
1846
GRAPHICS
Acute urticaria on the trunk
1847
Urticaria - Multiple images
Multiple images of urticaria are shown. Urticarial lesions may be rounded (F) or irregular
(A) in shape and uniform or mixed (G) in morphology. Individual lesions may be small (H) or
large (D). Urticaria are raised plaques, although they may appear flattened in patients taking
antihistamines (C). Although lesions are consistently erythematous, this may be difficult to
appreciate on darkly pigmented skin (I). Some urticaria show central clearing (E).
Panel B courtesy of Andrew Samel, MD.

Panels C, F, G, and H reproduced with permission from: Goodheart HP. Goodheart's Photoguide of
Common Skin Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright © 2003
Panel D courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV,
Nesbitt LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.
Panel E reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric
Emergency Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott
Williams & Wilkins.
Panel I reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
1848
Identifiable causes of urticaria
Infections
Viral
Parasitic
Bacterial
IgE-mediated allergic cases

Medications
Insects
Stinging (yellow jackets, bees, wasps, hornets, fire ants)
Biting (Triatoma [kissing bugs])
Foods
Blood products (urticarial transfusion reaction)
Latex (contact or inhaled)
Contact allergens (animal saliva, raw foods)
Aeroallergens (rare)
Food additives
Direct mast cell activation

Narcotics/opiates
Muscle relaxants (eg, succinylcholine)
Radiocontrast agents
Vancomycin
Physical stimuli
Dermatographism
Delayed pressure
Cold
Cholinergic
Vibratory
Aquagenic
Solar
Exertion/exercise
Miscellaneous mechanisms
Nonsteroidal anti-inflammatory drugs
Serum sickness
Transfusion reactions (distinct from IgE-mediated reactions)
Hormone-associated (progesterone)
Stinging nettle
IgE: immunoglobulin E.
1849
Symptoms and signs of anaphylaxis
Skin
Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end" (pilor erection)
Oral
Itching or tingling of lips, tongue, or palate
Edema of lips, tongue, uvula, metallic taste
Respiratory
Nose - Itching, congestion, rhinorrhea, and sneezing
Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor
Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis
Gastrointestinal
Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing)
Cardiovascular
Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations, tachycardia, bradycardia or other
dysrhythmia, hypotension, tunnel vision, difficulty hearing, urinary or fecal incontinence, and cardiac arrest
Neurologic
Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children may have sudden behavioral
changes (cling, cry, become irritable, cease to play)
Ocular
Periorbital itching, erythema and edema, tearing, and conjunctival erythema
Other
Uterine cramps in women and girls
Original figure modified for this publication. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161. Table used with the permission of
Elsevier Inc. All rights reserved.
1850
Symptoms and signs of anaphylaxis in infants*
Anaphylaxis signs that are

Anaphylaxis symptoms that infants Anaphylaxis signs in infants:
potentially difficult to interpret in
cannot describe Obvious but may be nonspecific
infants and why
General
Feeling of warmth, weakness, anxiety, Nonspecific behavioral changes, such as

apprehension, impending doom persistent crying, fussing, irritability, fright
Skin/mucus membranes
Itching of lips, tongue, palate, uvula, Flushing (may also occur with fever, Rapid onset of hives (potentially difficult to
ears, throat, nose, eyes, and so forth; hyperthermia, or crying spells) discern in infants with acute atopic
mouth-tingling or metallic taste dermatitis; scratching and excoriations, as
such, will be absent in young infants);
angioedema (face, tongue, oropharynx)
Respiratory
Nasal congestion, throat tightness; Hoarseness, dysphonia (common after a Rapid onset of coughing, choking, stridor,
chest tightness; shortness of breath crying spell); drooling, increased secretions wheezing, dyspnea, apnea, cyanosis
(common in infants)
Gastrointestinal
Dysphagia, nausea, abdominal Spitting up/regurgitation (common after Sudden, profuse vomiting
pain/cramping feeds), loose stools (normal in infants,
especially if breastfed); colicky abdominal
pain
Cardiovascular
Feeling faint, presyncope, dizziness, Hypotension; measured with an Weak pulse, arrhythmia,
confusion, blurred vision, difficulty in appropriate size blood pressure cuff, low diaphoresis/sweating, pallor,
hearing, palpitations systolic blood pressure for infants is collapse/unconsciousness
defined as less than 70 mmHg from age 1
month to 1 year and less than (70 mmHg +
[2 x age in years]) in the first and second
years of life; tachycardia, defined as greater
than 120 to 130 beats per minute from the
third month to second year of life inclusive;
loss of bowel and bladder control
(ubiquitous in infants)
Central nervous system
Headache Drowsiness, somnolence (common in Rapid onset of unresponsiveness, lethargy,

infants after feeds) or hypotonia; seizures
* More than one body system involved.
From: Simons FER. Anaphylaxis in infants: Can recognition and management be improved? J Allergy Clin Immunol 2007; 120:537. Table used with the
permission of Elsevier Inc. All rights reserved.
1851
Urticarial drug eruption
2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams &
Wilkins.
1852
Urticarial vasculitis
Urticarial patch with central ecchymosis.
1853
Annular patch with elevated borders.
1854
Discrete and confluent urticarial patches with unusual annular and semi-annular features.
1855
Atopic dermatitis
Severe atopic dermatitis in a 12-year-old girl showing in the typical location of the popliteal fossae.
Note the oozing of serous fluid from the most involved areas, plus the papular component and
erythema.
Courtesy of Scott Walsh, MD, FRPCP.
1856
Allergic contact dermatitis is characterized by an erythematous, papular dermatitis with

indistinct margins, distributed in areas of exposure.
Courtesy of James C Shaw, MD.
1857
Exanthematous (morbilliform) drug eruption
Drug-induced exanthems, such as this morbilliform eruption, often begin in dependent

areas and generalize.
Courtesy of Andrew Samel, MD.
1858
Erythema multiforme
Characteristic target lesions of the palm in erythema multiforme begin with a central
vesicle.
Courtesy of Nesbitt LT Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr (Eds),
Williams & Wilkins, Baltimore 1995.
http://www.lww.com
1859
Chronic spontaneous urticaria: Clinical manifestations,

diagnosis, pathogenesis, and natural history
Author: Sarbjit Saini, MD
INTRODUCTION
Chronic spontaneous urticaria (CSU) is defined by the presence of recurrent urticaria (also called
hives or wheals), angioedema, or both, for a period of six weeks or longer [1]. There are several
theories regarding the pathogenesis of CSU, none of which have been conclusively established. CSU
is a self-limited disorder in most patients, with an average duration of disease of two to five years,
although active CSU significantly impairs quality of life [1].
The clinical manifestations, epidemiology, diagnosis, theories of pathogenesis, and natural history of
CSU will be reviewed here. The management of CSU is discussed separately. (See "Chronic
spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous
urticaria: Treatment of refractory symptoms".)
TERMINOLOGY
The term "chronic spontaneous urticaria" (CSU) refers to patients with recurrent urticaria for six
weeks or longer well, as those with both urticaria and angioedema. Note that in a 2017 international
guideline, isolated idiopathic angioedema, without urticaria, was included in the definition of CSU for
the first time, provided that other angioedema disorders (especially those mediated by bradykinin)
have been excluded [1]. Therefore, CSU presents with an urticaria-predominant phenotype in
approximately one-half of patients, a mixture of urticaria and angioedema in about 40 percent, and
mainly angioedema in 10 percent. However, there are additional diagnostic considerations in patients
1860
with isolated angioedema, which are discussed in more detail separately. (See "An overview of
angioedema: Clinical features, diagnosis, and management".)
The term "spontaneous" is included to differentiate CSU from several forms of physical urticaria,
which are hives triggered by physical stimuli, such as heat, cold, pressure applied to the skin,
exercise, water, vibration, and sunlight. Physical urticaria is also called "inducible urticaria." Physical
urticaria syndromes are discussed separately. (See "Physical (inducible) forms of urticaria".)
Other terms for CSU include "chronic idiopathic urticaria" and the general term "chronic urticaria." We
favor the term CSU over the others, although it is not as familiar to nonspecialists.
EPIDEMIOLOGY
At any given time, CSU affects up to 1 percent of the general population in the United States, and the
prevalence is believed to be similar in other countries [2-4]. Both children and adults can develop
CSU, although it is more common in adults. Women are affected twice as often as men [3,5-11], and
the condition typically begins in the third to fifth decades of life [3,7,10].
The clinical manifestations of CSU may be limited to the skin, although some patients report
accompanying systemic symptoms.
Cutaneous signs and symptoms
Urticaria — Urticarial lesions (also called hives or wheals) have three typical features [1]:
● An area of central swelling of various size, usually with surrounding erythema

● An itching sensation
● A fleeting time course for an individual lesion (usually 30 minutes to 24 hours) with the skin
returning to normal without ecchymoses
Urticaria may be round, annular, or serpiginous (picture 1 and picture 2 and picture 3 and picture 4
and picture 5). Any area of the body may be affected. Areas in which clothing compresses the skin
(ie, under waistbands) or the skin rubs together (axillae) are sometimes affected more extensively.
Patients with intense pruritus may occasionally injure their skin by scratching, resulting in
excoriations (superficial erosions and crusts). The lesions may appear flattened if the patient is
currently taking H1 antihistamines.
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The pruritus of CSU may be severe enough to disrupt work, school, or sleep and is often most
noticeable at night. Patients whose symptoms have resolved sometimes have difficulty describing
urticarial lesions in a sufficiently detailed manner to assist in diagnosis. In this situation, showing
patients photographs of urticaria and asking if the lesions looked similar can be helpful.
Individual lesions usually appear, possibly enlarge or merge, and then resolve within 24 hours. If the
patient is having difficulty estimating how long an individual lesion lasts, he/she can trace a newly
developed lesion with a pen and monitor the time to resolution. Lesions lasting longer than 24 hours
and those that are painful or burning in nature or leave residual bruising are suggestive of a
vasculitic process. (See 'Differential diagnosis' below.)
Angioedema — Angioedema, if present, is defined as episodic submucosal or subcutaneous

swelling that is usually asymmetric in distribution and affects nondependent parts of the body, such
as the lips, cheeks, periorbital areas of the face, extremities, and genitals [12]. It typically develops
over minutes to hours and resolves gradually over one to three days, depending upon the initial
severity. Affected areas typically feel slightly painful, numb, or tingling, rather than pruritic.
In contrast, angioedema involving the throat, tongue, or lips, without urticaria, should prompt
consideration of drug-induced angioedema (such as that seen with angiotensin-converting enzyme
inhibitors), hereditary angioedema, or acquired C1 inhibitor deficiency. Episodic abdominal pain due
to angioedema of the intestinal mucosa is another distinguishing feature of these disorders. (See
"ACE inhibitor-induced angioedema" and "An overview of angioedema: Pathogenesis and causes".)
Systemic symptoms — A subset of patients with CSU report systemic symptoms, including
headache, fatigue, pain or swelling of joints, wheezing, flushing, gastrointestinal symptoms, and
palpitations [13,14]. In a study of 155 CSU patients treated at a university allergy clinic, 103 reported
systemic symptoms [13]. This subgroup had more severe and longer-lasting disease and
significantly higher baseline tryptase levels, compared with CSU patients without systemic
symptoms (5.1 versus 3.9 ng/mL, respectively). Although there was likely some referral bias in this
study toward patients with more severe disease, clinicians should inquire about systemic symptoms
in patients with CSU.
Note that in patients with urticaria or angioedema accompanied by fever or objective evidence of
joint inflammation, urticarial vasculitis should be considered. (See 'Differential diagnosis' below.)
ASSOCIATED CONDITIONS
CSU is associated with various atopic and autoimmune disorders. There is a possible association
with malignancies, although data are conflicting.
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Allergic diseases — Strong associations with atopic disorders, including food allergy, allergic rhinitis,
chronic rhinosinusitis, atopic dermatitis, and asthma were demonstrated in a large cohort study of
over 1 million Israeli adolescents [15]. These associations were not seen in the adult population,
when studied by the same researchers. Instead, an association with autoimmune conditions was
observed.
Autoimmune disorders — Various autoimmune conditions are more prevalent among patients with
CSU [5,16-19]. In the largest study, the prevalence of autoimmune disorders in nearly 13,000 patients
with CSU was compared with over 10,000 control patients [5]. The following autoimmune disorders
were more prevalent in patients with CSU: thyroid disorders, celiac disease, Sjögren syndrome,
systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus, with considerable
variability between males and females. Antinuclear antibodies were also more prevalent than in the
general population [5]. Among patients with CSU, an autoimmune disorder was more likely to be
diagnosed in the decade after the onset of CSU, rather than before it.
Thyroid disorders — In the larger study mentioned previously, hypothyroidism was diagnosed in
9.8 percent of CSU patients (versus 0.6 percent of controls) and hyperthyroidism in 2.6 percent
(versus 0.5 percent of controls) [5]. A population-based Korean study found that individuals with
autoimmune thyroid disease (Hashimoto thyroiditis and Graves' disease) had higher rates of CSU
compared with controls (hazard ratio [HR] = 1.5, 95% CI 1.3-1.7) [20].
Thyroid autoantibodies, specifically thyroid peroxidase antibodies or antimicrosomal antibodies, are

more prevalent among patients with CSU (12 to 30 percent), compared with members of the general
population (5 to 10 percent) [6,21-23]. However, the presence of thyroid autoantibodies does not
necessarily correlate with abnormal thyroid function, and the majority of patients with CSU who have
demonstrable thyroid autoantibodies have normal thyroid function [22]. The role of these
autoantibodies in CSU in patients with normal thyroid function is not clear. Their presence may
simply reflect an underlying tendency to develop autoantibodies [18]. However, even in the absence
of hypo- or hyperthyroidism, patients with thyroid autoantibodies are often poorly responsive to
standard therapies for CSU and have more persistent disease [18].
The pathogenesis of autoimmune thyroid disease is reviewed elsewhere. (See "Pathogenesis of

Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" and "Pathogenesis of Graves' disease".)
Based upon the association between CSU and thyroid autoimmunity, several studies have examined
the use of thyroid supplementation therapy in the treatment of CSU, with mixed results. These
studies are reviewed elsewhere. (See "Chronic spontaneous urticaria: Standard management and
patient education", section on 'Patients with thyroid autoantibodies'.)
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Unclear association with malignancy — The association between CSU (without vasculitis) and
malignancy is unclear. Guidelines do not suggest that malignancy screening be performed in
patients with CSU, unless indicated by specific abnormalities in the clinical history or physical exam
or the presence of unintended weight loss [1,24,25]. Studies that support this approach include the
following:
● No increased risk of malignancy was found in a study of 1155 Swedish patients with CSU, in
which subjects were followed by academic dermatologists for an average of 8.2 years [26]. The
incidence of malignant cancer during the period of observation was compared with the expected
number of cancers from the Swedish Cancer Registry, yielding a relative risk (RR) of 0.88 (95%
CI 0.61-1.12).
● In a systematic review of 6462 patients described in 29 studies, underlying diseases were

detected as an underlying cause of CSU in only 105 patients (1.6 percent) [16]. Within this group,
there were 60 cases of urticarial vasculitis, 17 patients with thyroid disease, 7 with lupus, and 16
with other connective tissue disorders. Three patients had a paraproteinemia, four had
polycythemia vera, and five had various malignancies (breast cancer, acute myeloid leukemia,
renal cell carcinoma, and two unidentified cancers). Therefore, few malignancies were detected
in this review, and no one type of cancer predominated.
In contrast to the two studies above, a possible association was detected in a study of 12,720
Taiwanese patients with CSU [27]. In this cohort, subjects were identified as having CSU based upon
the International Classification of Diseases (ICD)-9-CM code for urticaria, combined with use of an
antihistamine for at least six months over a two-year period. Patients with coexisting allergic
disorders that could require chronic antihistamines, patients receiving immunosuppressant drugs for
any reason, and those with pre-existing malignancies, rheumatoid arthritis, lupus erythematosus, or
Sjögren syndrome, were excluded. The rate of malignancies diagnosed in this cohort over an average
follow-up period of five years was compared with expected rates obtained from the Taiwan National
Cancer Registry. The standardized incidence ratio for patients with CSU was 2.2 (95% CI 2.0-2.4).
However, information about possible confounders (eg, smoking and alcohol use) was not included,
and patients may not have been systematically evaluated for signs or symptoms of underlying
disorders. In addition, the authors noted that there was no diagnostic code for urticarial vasculitis,
which is known to be associated with malignancy, so this diagnosis would not have been easily
distinguished from simple CSU. Therefore, this study may have overestimated cancer risk, although
the association warrants further evaluation.
A case report and literature review described 26 patients in whom CSU preceded the diagnosis of a
malignancy, usually by several months, and reported that treatment (ie, chemotherapy or surgical
1864
resection) led to resolution of the CSU in 88 percent of cases [28]. In three patients, return of urticaria
signaled a recurrence of the malignancy.
Until the association between chronic idiopathic urticaria and malignancy is better defined, it seems
logical to continue to perform additional testing only if indicated by the patient's clinical history and
physical exam.
EVALUATION AND DIAGNOSIS
CSU is diagnosed clinically based upon the episodic and transient appearance of characteristic
urticarial lesions, with or without angioedema, for a period of six weeks or longer. A detailed history
and physical examination form the basis of the evaluation [1,29-32]. Several practice parameters
have been published for the diagnosis of CSU [1,24,25,33,34]. The suggestions in this review are
consistent with these, although some variation exists among guidelines.
History — The clinical history is an important element of the evaluation. The history should include
the signs and symptoms associated with the lesions, duration of individual lesions, and
accompanying angioedema. If signs and symptoms are consistent with CSU, then questioning
should focus on identifying a possible underlying cause and on ensuring that the patient does not
have evidence of a more serious systemic disease.
● To exclude a specific cause, clinicians should question patients about any newly administered
drugs, including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal
therapies [35,36]. Inquiries should be made about recent travel, infections, changes in health
status, other atopic conditions, sexual history, and complete review of systems. No external
cause can be identified in 80 to 90 percent of adults and children with recurrent urticaria
persisting longer than six weeks once these known causes are excluded [37-40]. The various
identifiable causes of urticaria are discussed in more detail elsewhere. (See "New-onset
urticaria".)
● Patients should be thoroughly questioned about signs and symptoms of systemic disease, such
as fever, weight loss, arthralgias, arthritis, cold or heat sensitivity, abdominal pain, and bone pain
[17,41]. Occasionally, urticaria or urticarial vasculitis will be a presenting feature of an underlying
systemic disorder, such as systemic lupus erythematosus. Systemic diseases that can present
with urticaria accompanied by other signs and symptoms and disorders that involve urticarial
vasculitis are reviewed in more detail separately. (See "New-onset urticaria", section on
'Systemic disorders that may include urticaria' and "Urticarial vasculitis", section on 'Associated
conditions'.)
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Aggravating factors — Although not the sole cause of symptoms, certain factors aggravate CSU in
a substantial subset of patients (table 1). These include:
● Physical factors – Some patients with CSU have some flares that are triggered by physical
stimuli. As an example, heat (hot showers, extreme humidity) is a common trigger for many CSU
patients, and tight clothing or straps can also aggravate symptoms. In contrast, patients in
whom physical factors are the main trigger for symptoms are more appropriately diagnosed as
having a physical urticarial syndrome, such as cholinergic urticaria or delayed-pressure
urticaria. Physical urticarias are reviewed separately. (See "Physical (inducible) forms of
urticaria" and "Cold urticaria".)
● Anti-inflammatory medications – NSAIDs worsen symptoms in 25 to 50 percent of patients with

CSU [42].
● Stress – Patients often report more severe symptoms during periods of physical or psychologic
stress [43-50]. However, evidence that psychosocial factors are in some way causative is lacking
[51].
● Variations in dietary habits and alcohol – Although food allergy is a rare cause of CSU, some
patients will report that variations in diet, particularly rich meals or spicy foods, will aggravate
symptoms. Alcohol also aggravates symptoms in some. The interactions between diet and CSU
are discussed separately. (See "Chronic spontaneous urticaria: Standard management and
patient education", section on 'Dietary manipulations (controversial)'.)
Laboratory evaluation — Routine laboratory tests are unlikely to reveal abnormalities when the
clinical history does not suggest an underlying allergic etiology or the presence of systemic disease
[16,24,52-55]. Guidelines suggest initially obtaining a limited set of laboratories to screen for the
systemic disorders that may involve urticaria [1,56-58]. The author and editors agree with limited
testing and suggest the following:
● A complete blood count with differential – This is usually normal in patients with CSU [59].
Eosinopenia (ie, an absolute eosinophil count of <50 cells/microL) was present in approximately
10 percent of patients with CSU in one large study of 1259 patients, and was associated with
basopenia, more severe disease, autoimmunity, and poor response to treatment with second
generation antihistamines and omalizumab [59]. Eosinopenia is present in about 5 percent of
the general population, and has been linked to several disease states [60]. Eosinophil numbers
should be assessed when the patient has not recently received glucocorticoids, which cause a
rapid reduction in eosinophil counts.
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Eosinophilia should prompt evaluation for an atopic disorder or parasitic infection. (See
"Approach to the patient with unexplained eosinophilia".)
Basopenia has been associated with more severe disease [61]. (See 'Cellular defects theory'
below.)
● CRP or ESR – Both tests are normal in the majority of cases of CSU, although an elevation of
erythrocyte sedimentation rate (ESR) of a few points is also common in uncomplicated CSU [54].
Significant elevations in ESR or C-reactive protein (CRP) have been correlated with more severe
disease, quality of life impairment, and non-response to antihistamines [62]. Such elevations
should prompt further investigation for systemic diseases, such as autoimmune, rheumatologic,
infectious, or neoplastic diseases. Such an evaluation may include measurement of antinuclear
antibodies, cryoglobulins, hepatitis B and C serologies, total hemolytic complement, and a serum
protein electrophoresis. (See "Acute phase reactants" and 'Differential diagnosis' below.)
● TSH level – Routine measurement of thyroid-stimulating hormone (TSH) was not endorsed by
the 2017 international guidelines [1]. However, some clinicians measure TSH in adults with CSU
and also obtain thyroid autoantibodies (antithyroglobulin, antimicrosomal antibodies, or both),
while others do so only if the TSH level is abnormal [63]. Autoimmune thyroid disease is
uncommon in children with CSU [64].
The utility of more extensive laboratory testing in patients with CSU was analyzed in the systematic
review mentioned previously, which concluded that only ESR, complete blood count, and differential
were useful screening tests. This review analyzed 29 studies (including 6462 patients), in which
investigations for underlying medical disorders were performed [16]. Potentially causative internal
diseases were identified in only 1.6 percent of patients, and there was no association between the
number of tests ordered and the identification of an underlying disorder.
Investigational tests — Investigational tests include the autologous serum skin test, various tests
of basophil activation, and tests for autoantibodies to the immunoglobulin (Ig)E receptor or the Fc
region of IgE [1]. These tests are discussed separately. (See 'Theories of pathogenesis' below.)
Diagnosis — The diagnosis of CSU can be made in a patient with characteristic skin lesions of
urticaria and/or angioedema, which appear and resolve repeatedly over a period of six weeks or
longer. There should be no other signs of systemic illness, and laboratory testing is usually normal.
In patients with isolated angioedema, other angioedema disorders should be excluded.

Measurement of complement component 4 (C4) is indicated because depressed C4 levels should
prompt further evaluation for hereditary or acquired C1 inhibitor deficiency. In cases in which the
history suggests a possible diagnosis of hereditary or acquired C1 inhibitor deficiency (ie, lack of
1867
response to antihistamines or positive family history), C1 inhibitor antigen and functional levels
should also be measured. The evaluation of angioedema without urticaria is discussed elsewhere.
(See "An overview of angioedema: Clinical features, diagnosis, and management", section on
'Evaluation'.)
Skin biopsy — Skin biopsy is not routinely needed for the diagnosis of CSU. However, a 3 mm punch
biopsy of a newly formed lesion should be performed to exclude urticarial vasculitis in patients with
one or more of the following features:
● Individual lesions that persist beyond 24 hours, are painful rather than pruritic, have
accompanying petechial or purpuric characteristics, or leave residual pigmentation upon
resolution [32,65].
● An elevated CRP/ESR and/or systemic symptoms (eg, arthralgias, fever).
● Symptoms that are unresponsive to appropriate doses of antihistamines. (See "Chronic

spontaneous urticaria: Standard management and patient education", section on 'H1
antihistamines'.)
Biopsy should also be obtained in patients with any features suggestive of mastocytosis.
Mastocytosis is a rare disease that would be suspected in a patient in whom CSU was accompanied
by episodic signs and symptoms of systemic mast cell-mediator release, such as flushing,
abdominal cramping and diarrhea, wheezing, lightheadedness, or syncope. (See 'Differential
diagnosis' below and "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and
clinical manifestations".)
The biopsy sample should be obtained from a fresh lesion. Patients receiving glucocorticoids may
need to discontinue these medications for several days in order to allow new lesions to form. Biopsy
specimens should be submitted in formalin for routine hematoxylin and eosin staining. In addition, if
there is a strong clinical suspicion for urticarial vasculitis, a sample should be submitted in Michel's
media or freshly snap frozen for direct immunofluorescence microscopy. Also consider testing for
immunoglobulins in lesional skin when vasculitis is a consideration and in perilesional, noninvolved
skin when considering autoimmune blistering disease.
Biopsy findings — The biopsy findings of CSU vary somewhat among patients. Consistent
features include interstitial edema with a perivascular mixed infiltrate consisting of lymphocytes,
eosinophils, and in some areas, a few neutrophils or basophils. Lymphocytes are generally CD4+ T
lymphocytes. B lymphocytes are not usually seen [12]. Angioedema, if present, often shows a similar
infiltrate and is characterized by more prominent edema of the interstitial tissues.
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Neutrophil-predominant urticaria, without vasculitis, is a variant of CSU that is often refractory to
standard pharmacologic treatments. The significance of neutrophil-predominant urticaria, in terms of
preferred treatment or prognosis, is not known [66].
Findings that are not characteristic of CSU include the following:
● Several disorders in the differential diagnosis for CSU may also show a predominance of
neutrophils, such as Schnitzler syndrome, delayed-pressure urticaria, and cryopyrin-associated
periodic syndromes. Biopsies in these disorders may also mistakenly be interpreted as
leukocytoclastic vasculitis. (See 'Differential diagnosis' below.)
● Leukocytoclasis should not be present in CSU. Leukocytoclasis is the fragmentation of

neutrophils resulting in scattered nuclear fragments (nuclear dust) in the infiltrate, red blood cell
extravasation within the lumen of affected vessels or in the interstitium, and fibrinoid
degeneration of the endothelial cells resulting in a blunted vascular outline with fibrin deposits.
If leukocytoclasis is found, the diagnosis of leukocytoclastic vasculitis and associated
conditions should be considered. (See "Urticarial vasculitis", section on 'Histology' and
● Leukocytoclasis accompanied by a dense cellular infiltrate consisting almost entirely of

neutrophils, without evidence of vasculitis, should prompt evaluation for the rare disorder,
neutrophilic urticarial dermatosis. (See "Neutrophilic dermatoses".)
THEORIES OF PATHOGENESIS
None of the theories of pathogenesis of CSU have been fully established, and we do not suggest
routine performance of any of the tests mentioned in this section outside of research settings [1,67].
The best developed hypotheses include the autoimmune theory, theories involving histamine-
releasing factors, and the cellular defects theory.
Autoimmune theory — The concept that CSU could represent an autoimmune disorder arose from
the recognition that thyroid dysfunction and thyroid autoantibodies are more prevalent in patients
with CSU [5,17,21,22]. This led to a search for autoantibodies and other serum factors that could be
responsible for increased release of histamine from cutaneous mast cells and basophils. A European
taskforce panel of CSU experts published a statement in 2013 concluding that there was persuasive
but not conclusive evidence for the existence of autoimmune CSU as a specific disease entity [68].
The evidence suggesting that CSU may be an autoimmune disorder in some patients is reviewed
above. (See 'Autoimmune disorders' above.)
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The autologous serum skin test — One area of investigation suggesting that CSU is an
autoimmune disorder was introduced in the 1980s with the description of the autologous serum skin
test (ASST) [69]. The ASST is proposed to provide an in vivo assay of mast cell activation induced by
factors in the patient's serum. The ASST involves intradermal injection of the patient's own serum
[69,70]. In preparation for this test, patients must refrain from taking antihistamines for three to
seven days (depending upon the half-life of the specific drug), which can cause an exacerbation in
symptoms.
In up to one-half of patients with CSU, the intradermal injection of serum produces a wheal-and-flare
reaction (ie, area of cutaneous edema and erythema) at the site of injection within 30 minutes (note
that the time to maximal reaction is longer than 15 minutes seen in allergen skin testing) [71]. In vitro
tests of mast cell activation are lacking because mast cells are tissue-based cells that are not easily
collected or cultured. (See "Mast cells: Development, identification, and physiologic roles".)
The leading argument against the clinical significance of the ASST is that a positive test is not
unique to patients with CSU [72-74]. In one study, positive ASSTs were found in 53 percent of
patients with CSU, 20 percent of patients with nonallergic asthma/rhinitis, and 56 percent of healthy
controls [74]. In addition, the positivity of the ASST persists in patients with CSU, even when the
disorder is in clinical remission [75,76]. Finally, the ASST has not demonstrated clinical utility in
identifying patients who respond differently to treatment or whose disease follows a different clinical
course [64,77-79].
Autoantibodies — The sera of patients with CSU and positive ASSTs are capable of causing in
vitro histamine release from basophils collected from control subjects [69]. It was therefore
proposed that an autoantibody or other histamine-releasing factor was present in the serum of these
patients.
At least two candidate autoantibodies have been identified [70,75,80,81]:
● Human IgG molecules directed against the IgE receptor alpha subunit (anti-Fc-epsilon-R1-alpha)
● Human IgG molecules directed against the Fc region of IgE (anti-IgE)
The presence of IgG autoantibodies to the IgE receptor or the Fc region of IgE can be demonstrated
in as many as 30 to 50 percent of children and adults with CSU [12,68,82-86]. These autoantibodies
can trigger histamine release when incubated with normal basophils [80] and can activate mast cells,
possibly through a mechanism involving complement [12,40,87-91]. Assays are commercially
available for detecting anti-Fc-epsilon-RI-alpha antibodies (eg, the Chronic Urticaria Index) [92],
although the clinical utility of this test is not well-established, as discussed in the next section.
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Conflicting evidence — Similar to the ASST, the autoantibodies described above are not
specific to CSU. Anti-Fc-epsilon-RI-alpha antibodies have been identified in healthy subjects [93] and
in people with other autoimmune diseases, including pemphigus vulgaris, systemic lupus
erythematosus, dermatomyositis, and pemphigoid, suggesting that they may represent an
epiphenomenon [87,94-96]. In addition, the levels of autoantibodies in CSU do not appear to change
with the clinical activity of the disease [97], and the presence of these autoantibodies does not
predict more difficult-to-manage disease [78].
Also problematic is the fact that commercial assays for anti-Fc-epsilon-RI-alpha antibodies are
based upon basophil activation tests, for which there are no widely accepted standards across
laboratories. When more stringent basophil activation studies were performed with additional
controls, only 7 percent of CSU patients were found to have autoantibodies that triggered histamine
release, as opposed to the 30 to 50 percent found in earlier studies [98]. The technical difficulties of
studying basophils are reviewed below. (See 'Problems with basophil studies' below.)
Theories involving other serum or plasma factors — Several other factors in the serum or plasma
have been implicated in the pathogenesis of CSU because of an ability to activate mast cells or
basophils, either directly or indirectly. No single factor has been shown to be essential for a positive
ASST, and it remains unclear why serologic factors would activate only skin mast cells rather than
causing more generalized mast cell and basophil activation leading to anaphylaxis, yet patients with
CSU are not at increased risk for anaphylaxis.
● One study tested sera from patients with CSU and normal controls for the ability to induce
endothelial cell permeability [99]. Although neither group's sera alone induced endothelial cell
permeability, the majority of CSU sera caused mast cell degranulation when incubated with
different mast cell lines, one of which lacked IgE receptors. Supernatants from activated mast
cell cultures did increase endothelial cell permeability. This property persisted when the sera
were depleted of IgG and was unrelated to the ability of the sera to cause a positive ASST.
● The observation that many patients with CSU improve with anti-IgE therapy (omalizumab)
implies that there may be an abnormal IgE present, which recognizes an unknown antigen(s)
and activates mast cells and basophils. Studies of omalizumab for the management of
refractory CSU are reviewed separately. A variation on this theory proposes that there are
individuals with IgE against self-antigens, but there are limited data for this concept. (See
"Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
● Histamine-releasing factors in the plasma have also been proposed. Some patients with chronic
idiopathic urticaria demonstrate excessive or abnormal production of platelet-derived clotting
factors, such as thrombin, possibly resulting from activation of the extrinsic pathway of the
1871
clotting cascade [100-102]. In one study, the plasma of 28 patients with CSU contained higher
levels of the polypeptide F1+2, which is produced upon activation of prothrombin to thrombin,
compared with control plasma [100]. The levels of this peptide correlated with the severity of the
patients' urticaria. Thrombin, in turn, is capable of activating mast cells and basophils and also
increasing the permeability of blood vessels [103-105]. In addition, thrombin can stimulate the
generation of C5a, which has been shown to enhance IgG-dependent mast cell histamine
release in patients with CSU [91]. Other groups have also found abnormalities in the coagulation
system that correlate with CSU severity [106].
The identification of abnormalities in clotting factors lead to the autologous plasma skin test
(APST), a variant of the ASST in which sodium citrate-anticoagulated plasma is injected
intradermally [100]. However, the APST does not appear to provide information that is different
from that of the ASST [100,107-109]. Of note, one study showed that if a control solution of
0.105 mol/L sodium citrate was included as a negative control, then there were no patients with
positive APSTs who did not also have positive ASSTs [109].
The finding that the extrinsic pathway of the clotting cascade is activated in CSU is consistent
with reports of successful treatment with the anticoagulant warfarin in a small double-blind,
controlled study, as well as a case report of patients with CSU refractory to antihistamines [110-
112]. Subcutaneous heparin and the antifibrinolytic agent tranexamic acid were also reported to
be effective in small numbers of patients [113,114].
A review examined the literature for serum measures that could distinguish patients with CSU from
healthy subjects. Among the measures that showed promise were D-dimer, C-reactive protein, and
mean platelet volume [115]. Although promising, prospective studies will be needed to validate these
associations.
Cellular defects theory — The cellular defects theory generally proposes that patients with CSU have
defects in mast cell and/or basophil trafficking, signaling, and/or function. The following
observations support this concept:
● Mast cell numbers are normal in the skin of patients with CSU, although the cells release
histamine more readily than cells from healthy controls in response to compounds that trigger
nonimmunologic mast cell degranulation, such as 48/80 and codeine sulfate [116,117].
Functional studies of mast cells from patients with CSU are difficult to perform because mast
cells are tissue-based cells that are not easily collected or cultured. In 2015, a G-protein-coupled
receptor, MrgX2, was recognized as the receptor for 48/80 on mast cells [118]. It has also been
noted that the expression of this receptor is heightened in CSU skin tissue [119].
1872
● Peripheral blood basophil counts are low in patients with CSU and even lower with more severe
disease, a finding attributed to increased migration of basophils to the skin [61,120-123].
Evidence supports that basophil counts normalize on therapy with omalizumab [124,125]. (See
"Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
● Several groups have identified functional differences in basophils from patients with CSU.
Histamine release was reduced following in vitro activation through Fc-epsilon-RI, although not
with activation through other receptors [117,126,127], even though the cells contained normal
amounts of histamine [128,129]. Subsequently, two basophil phenotypes were identified in
patients with CSU: one type with an apparently normal response to Fc-epsilon-RI activation
("responders") and another type of basophil that does not respond to IgE-mediated activation
("nonresponders") [128,130]. These phenotypes are present in approximately equal numbers in
patients with CSU, unlike in normals where "nonresponders" comprise only about 10 to 15
percent of the population. The nonresponder phenotype demonstrates elevated intracellular
levels of regulatory proteins that normally inhibit signaling through Fc-epsilon-RI. Of note,
normalization in basophil responsiveness has been demonstrated in patients with CSU as their
symptoms improve, unlike levels of autoantibodies or ASST status [97,127]. CSU patients with
the responder phenotype have milder but more prolonged disease [61].
Problems with basophil studies — Basophils are notoriously difficult to study for the following
reasons:
● Different laboratories using different basophil donors will yield different results with the same
tested serum.
● Basophils from individual donors can show variability in response to the same serum over time.
● There are no standardized procedures for handling basophils for use in serum testing, including
uniform approaches to cell isolation, dilution of serum, or addition of a basophil priming cytokine
(ie, interleukin [IL]-3) to the assay mix.
● Basophils are typically obtained for study from peripheral blood, although it has not been
established that circulating basophils are fully representative of cutaneous basophils, and the
two populations may have different characteristics in this disorder.
Sometimes basophils from normal donors are used to test serum from CSU patients, although
histamine release may be due to several factors, such as activated complement, chemokines, or
even IL-3 in the tested sample. Thus, the readout of the assay itself represents a complex cellular
response that can be elicited through a variety of mechanisms.
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Other theories — Theories about infectious causes and food additives (pseudoallergens) continue to
draw periodic attention in the medical literature and lay news. However, the evidence for these
theories remains anecdotal. It is possible that various sources of chronic inflammation may
predispose susceptible patients to the development of CSU [131].
Infectious agents — Attempts have been made to associate some common chronic infections
with CSU, including Anisakis simplex [132], Helicobacter pylori [133-136], hepatitis A [137], and
hepatitis C [138]. However, case reports and small series have been conflicting [139].
A larger study illustrated the ambiguous relationship between chronic infections and CSU. In a large
meta-analysis of 22 studies including 1385 patients, spontaneous remission of CSU occurred more
often in patients who were negative for H. pylori compared to those who were positive (risk ratio 0.39;
95% CI 0.19-0.81) [140]. Among H. pylori-positive CSU patients, remission of urticaria was more likely
following antimicrobial therapy for H. pylori, regardless of whether eradication of the infection was
successful.
Foods and food additives — Allergies to foods or food additives are rarely identified as a cause of
CSU [141,142]. IgE-mediated food allergy is far more likely to present with acute urticaria as part of
generalized allergic reactions. Despite this, up to one-half of adult patients initially perceive a
relationship between food and episodes of urticaria. Patients' suspicion about the role of foods and
food additives is fueled by the fact that many will notice that dietary variations can cause temporary
fluctuations in CSU symptoms. In particular, rich meals, spicy or fermented foods, alcohol, and
dramatic changes in diet will often worsen the condition temporarily. This may be related to the
histamine content or innate histamine-releasing properties of these foods, as well as the vasodilatory
effects of alcohol and certain spices. However, when CSU is in remission, the same patients can eat
these foods without symptoms.
Dietary factors that can aggravate CSU and lists of foods that are potentially problematic are
discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient
education", section on 'Dietary manipulations (controversial)'.)
Studies of food additives as a cause of acute and chronic urticaria are reviewed separately. (See
"Allergic and asthmatic reactions to food additives", section on 'Patients with chronic urticaria'.)
Several systemic disorders can present with urticaria-like lesions in the context of other signs and
symptoms.
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● Urticarial vasculitis – Urticarial vasculitis should be considered when the hives are painful
rather than pruritic, last longer than 48 hours, leave residual bruising or pigmentation changes,
or recur whenever glucocorticoids are tapered (picture 6 and picture 7 and picture 8). Patients
with urticarial vasculitis may also report fever, chills, and arthralgias. Urticarial vasculitis may
occur in isolation or in patients previously diagnosed with other systemic inflammatory
diseases, such as Sjögren syndrome or systemic lupus erythematosus. Skin biopsy is indicated
if signs or symptoms of vasculitis are present. (See "Urticarial vasculitis".)
● Systemic lupus erythematosus – Urticaria and urticarial vasculitis are among the many reported
cutaneous manifestations of systemic lupus erythematosus (picture 9). However, patients with
lupus should have some of the other manifestations of this disease, such as fever, weight loss,
arthritis, lymphadenopathy, or renal, pulmonary, or cardiac manifestations. This disorder is
reviewed in detail elsewhere. (See "Overview of cutaneous lupus erythematosus".)
● Cryoglobulinemia – Cryoglobulinemia causing cold-induced urticarial or vasculitic lesions can

be seen in hepatitis B or C infection. Lesions are more prominent on the buttocks and lower
extremities. (See "Overview of cryoglobulins and cryoglobulinemia" and "Cryopyrin-associated
periodic syndromes and related disorders".)
● Schnitzler syndrome – Schnitzler syndrome has been described in patients with a monoclonal
IgM or IgG component (monoclonal gammopathy) who have associated fever, weight loss, bone
pain, adenopathy, and urticaria, presumably due to circulating immune complexes and
complement activation. (See "Cutaneous manifestations of internal malignancy" and "Urticarial
vasculitis", section on 'Differential diagnosis'.)
● Mast cell disorders – Mast cell disorders are characterized by the proliferation and
accumulation of tissue mast cells or excessive activity of these cells. The best characterized
disorders are systemic and cutaneous mastocytosis, which feature signs and symptoms
affecting multiple organ systems (table 2). Skin findings in mastocytosis consist either of
flushing and pruritus or a distinctive lesion called maculopapular cutaneous mastocytosis or
urticaria pigmentosa (picture 10). Patients with mast cell disorders can have urticaria in the
setting of other episodic symptoms, but recurrent hives most days of the week is not typical
[143]. (See "Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical
manifestations".)
● Polymorphic eruption of pregnancy – Polymorphic eruption of pregnancy (PEP, also called

pruritic urticarial papules and plaques and papules of pregnancy or PUPPP) is a pruritic
dermatitis affecting pregnant women, which typically presents as erythematous papules within
abdominal striae with periumbilical sparing (picture 11). The lesions then spread to the
1875
extremities and coalesce to form urticarial plaques. The face, palms, and soles are usually
spared. Lesions may also be target-like. PEP is reviewed elsewhere. (See "Dermatoses of
pregnancy".)
● Hypereosinophilic syndrome – Hypereosinophilic syndrome refers to a group of disorders

characterized by persistent overproduction of eosinophils that infiltrate and damage tissues.
Cutaneous symptoms can include recurrent urticaria, although angioedema or erythroderma are
more characteristic. The diagnosis requires persistent unexplained blood eosinophilia of
≥1500/microliter, signs and/or symptoms of eosinophil-mediated, end-organ dysfunction, and no
other apparent etiologies for eosinophilia, such as parasitic infection or allergic disease. (See
"Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)
● Cryopyrin-associated periodic syndromes – The cryopyrin-associated periodic syndromes

include syndromes that involve urticarial or urticaria-like skin eruptions: familial cold
autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem
inflammatory disorder. These are rare genetic disorders that are discussed in more detail
separately. (See "Cryopyrin-associated periodic syndromes and related disorders".)
The differential diagnosis of isolated angioedema is reviewed in detail separately. (See "An overview
of angioedema: Clinical features, diagnosis, and management", section on 'Differential diagnosis'.)
NATURAL HISTORY AND PROGNOSIS
CSU is an episodic and self-limited disorder in most patients. The average duration of disease is two
to five years [2,144]. In patients in whom no trigger or underlying disorder is identified, there is a rate
of spontaneous remission at one year of approximately 30 to 50 percent [39,145]. Remission rates in
children may be somewhat higher [146]. However, symptoms persist beyond five years in up to 30
percent of patients, and disease duration in this subgroup is not as well-studied [8,147,148].
In a representative prospective study, 139 patients with CSU of all severities were followed over a
period of five years [147]. Disease severity, the presence of angioedema, and various laboratory
parameters were assessed in relation to disease duration. CSU persisted beyond one and five years
in 70 and 14 percent of patients, respectively. A longer duration of symptoms was associated with
more severe disease, the presence of angioedema, and thyroid autoimmunity. This study also found
that a positive autologous serum skin test was associated with longer-lasting disease, although
other studies did not find this correlation [39].
Other studies have also found that more severe disease tends to last longer [144,146]:
1876
● In a retrospective analysis of 117 patients with CSU who were not controlled on a standard dose
of oral antihistamine, the remission rates (ie, no urticaria for one month in the absence of any
medication) were 12 and 28 percent at one and five years, respectively [146].
● In a prospective study of 228 patients with moderate-to-severe CSU, a correlation was observed
between the presence of systemic hypertension and more persistent symptoms [144]. Among
hypertensive patients, resolution was seen in 19 and 26 percent at two and five years,
respectively, compared with 37 and 46 percent in normotensive patients. The type of
antihypertensive medication administered did not appear to impact duration of urticaria. The
association with hypertension warrants further study.
Peripheral blood eosinopenia and basopenia may be biomarkers for more severe disease that is
refractory to antihistamines and omalizumab. (See 'Laboratory evaluation' above.)
● Basics topic (see "Patient education: Chronic hives (The Basics)")
1877
● Chronic spontaneous urticaria (CSU) is defined by the presence of urticaria (hives), angioedema,
or both for a period of six weeks or longer. It is estimated that about 1 percent of the adult
population develops CSU at some point in their lives. Adults are affected more often than
children, and women are affected more often than men. (See 'Terminology' above and
● The diagnosis of CSU is made clinically, based upon the episodic appearance of characteristic
urticarial lesions, with or without angioedema, on most days of the week, for a period of six
weeks or longer. No specific cause can be identified in 80 to 90 percent of adults and children
with CSU. A complete blood count with differential, a C-reactive protein (CRP) or erythrocyte
sedimentation rate (ESR), and possibly a thyroid-stimulating hormone (TSH) level are suggested
at diagnosis, although these laboratories are normal in most patients who lack signs and
symptoms of systemic disease. (See 'Evaluation and diagnosis' above.)
● Skin biopsy is not needed for routine diagnosis of CSU, although it is indicated to exclude
urticarial vasculitis if there are signs or symptoms consistent with a vasculitic process or in the
rare patients with features of mastocytosis. (See 'Skin biopsy' above.)
● Tests used in investigations of pathogenesis include the autologous serum and plasma skin
tests (ASST/APST), assays for autoantibodies directed against immunoglobulin (Ig)E or Fc-
epsilon-RI, and in vitro assessments of basophil function. However, these tests lack specificity
and prognostic value, are not standardized across laboratories, and are not recommended for
routine clinical use. (See 'Theories of pathogenesis' above.)
● Several theories regarding the pathogenesis of chronic idiopathic urticaria have been proposed,
although the data for each are incomplete, and none appear to be helpful for determining
treatment or prognosis. The best developed hypotheses involve histamine-releasing factors and
defects in basophil signaling and/or function. (See 'Theories of pathogenesis' above.)
● CSU is a self-limited disease in the vast majority of patients. Spontaneous remission occurs in
30 to 50 percent of patients by one year, and the average duration of disease is two to five years.
Up to 20 percent of patients still have symptoms persisting beyond five years. Those with more
severe symptoms tend to have longer-lasting disease. (See 'Natural history and prognosis'
above.)
1878
GRAPHICS
Urticaria on abdomen
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition. Philadelphia:
1879
Urticaria
Urticaria is characterized by circumscribed, raised, erythematous, and extremely pruritic

lesions. They typically appear in one area, resolve over the course of several hours, and
then reappear elsewhere. Individual lesions may enlarge and develop central pallor before
fading.
1880
Urticaria
Dermal vasodilatation occurs with no epidermal change (scale).
Wilkins.
1881
Giant urticaria
Very large erythematous annular lesion of the shoulder with central clearing. This patient
had several large lesions of this type, which could be confused with erythema migrans.
Courtesy of Lee T Nesbitt, Jr. The Skin and Infection: A Color Atlas and Text, Sanders CV, Nesbitt LT Jr
(Eds), Williams & Wilkins, Baltimore, 1995.
http://www.lww.com
1882
Urticaria
Reproduced with permission from: Berg D, Worzala K. Atlas of Adult Physical Diagnosis. Philadelphia:
1883
Factors that exacerbate chronic spontaneous urticaria (CSU)
Exacerbating factor Examples Alternate explanations to consider
Nonsteroidal anti-inflammatory drugs Urticaria may worsen in patients within Consider alternate diagnosis of NSAID
(NSAIDs) 24 hours after ingestion; some within 2 allergy or pseudoallergy if NSAIDs are
hours and others (particularly children) the only or predominant trigger for hives
up to 4 to 24 hours later. or angioedema.
Environmental conditions Heat. Consider alternate diagnosis of

Cold. cholinergic urticaria if hives are small (1
Sunlight. to 3 mm), surrounded by large areas of
erythema, and predominantly triggered
by changes in core body temperature
(eg, exercise, hot showers, sweating,
emotional factors).
Consider exercise-induced anaphylaxis
if hives only occur during exercise and
not with passive changes in core body
temperature.
Consider cold urticaria or cold-
associated inflammatory disorder if
hives are exclusively triggered by
exposure to cold.
Consider solar urticaria if hives appear
to be exclusively triggered by exposure
to sunlight.
Friction or pressure from clothing Hives may form under clothing straps, Consider diagnosis of delayed-pressure
in areas where tight clothing urticaria/angioedema if pressure on
compresses the skin, or in areas of skin is followed in 4 to 24 hours by
natural friction (axillae, between thighs). erythematous angioedema of affected
area. Patients with delayed-pressure
urticaria often have concomitant CSU.
Consider vibratory urticaria if hives
appear after exposure to vibration (eg,
after clapping, mowing lawn, holding
certain appliances).
Alcohol Hives may be more numerous or severe If alcohol is the sole or predominant
after drinking alcoholic beverages. trigger, consider nonspecific reaction to
histamine-releasing properties of some
alcoholic beverages, or rarely, allergy to
some component of the beverage.
Narcotic medications Hives may be more numerous or severe

and pruritus more pronounced after
taking narcotics.
Stress (emotional or physical) or sleep Hives can appear during stressful

deprivation events, and/or control of chronic hives
can be more difficult during stressful
periods or periods of reduced sleep.
Concomitant infections Hives can be more numerous or severe

during viral illnesses (eg, common
colds) or bacterial infections (eg,
sinusitis).
Menstruation or perimenstrual period Some women with CSU observe Consider alternate diagnoses of
fluctuations with their menstrual cycle. autoimmune progesterone dermatitis or
1884
other catamenial dermatoses if hives
only occur in perimenstrual periods or
lesions are not clearly urticarial.
Irregular use of antihistamines Regular and consistent dosing of

antihistamines is most effective in
controlling CSU. Erratic or as-needed
use may contribute to poor symptom
control.
1885
1886
1887
1888
Subacute cutaneous lupus erythematosus
Erythematous, annular plaques with scale.
1889
Clinical manifestations of cutaneous and systemic mastocytosis
Symptoms, physical findings, and

Symptoms due to acute and/or abnormalities of routine
Organ system affected
chronic mast cell-mediator release laboratories due to organ
infiltration
Skin Flushing, pruritus Multiple: Urticaria pigmentosa, plaque-like

or nodular lesions, diffuse skin
involvement, bullous eruptions, isolated
mastocytoma, or telangiectasias
Gastrointestinal tract Nausea, bloating, chronic diarrhea, Stomach and duodenal infiltration:
hyperacidity, gastroduodenal ulcer disease, Gastroduodenal ulcers (possibly, although
chronic abdominal pain, vomiting more clearly related to mediator release),
steatorrhea, malabsorption
Liver infiltration: Elevated transaminases,
portal hypertension, and ascites (only in
advanced forms of the disease)
Musculoskeletal* Adults: Fibromyalgia-like diffuse In mast cell sarcoma of the bone (rare),
musculoskeletal pain, pain in long bones, local symptoms (eg, pain, deformity,
osteoporosis, osteopenia, pathologic pathologic fracture) occur at the involved
fractures site
Cardiovascular Adults: Episodes of vasodilation,

tachycardia, hypotension, collapse
Infants: Apneic spells, cyanosis
Hematologic (lymph nodes, spleen, bone Lymph nodes and spleen:

marrow) Lymphadenopathy, splenomegaly (with
hematologic findings of hypersplenism:
nonimmune hemolytic anemia)
Bone marrow: Anemia (mild-to-moderate, in
approximately 50%), thrombocytopenia
(usually asymptomatic), eosinophilia
(approximately 25%), myeloproliferative or
myelodysplastic findings, fibrosis
Neurologic, psychiatric Adults: Anxiety, depression, headache,

mood changes, inability to concentrate,
hypersomnolence, irritability, "mixed
organic brain syndrome"
Children: Aggressive behavior
Systemic* Adults: Fatigue, cachexia
Signs and symptoms of both acute and chronic release of mast cell mediators are seen in patients with cutaneous and systemic forms
of mastocytosis. Episodic symptoms tend to occur in patterns that are characteristic for a given patient, but not all patients
demonstrate all of the signs and symptoms described in the table. In patients with cutaneous mastocytosis, mast cells infiltrate the
skin. In patients with systemic mastocytosis, mast cells may infiltrate the skin, gastrointestinal tract and liver, lymph nodes, spleen,
and bone marrow.
* Rare in children.
1890
Urticaria pigmentosa (maculopapular cutaneous mastocytosis)
Lesions of maculopapular cutaneous mastocytosis, also called urticaria pigmentosa, in an

adult patient with systemic mastocytosis.
Reproduced with permission from: Soter AN. J Invest Derm 1991; 96(3):S32. Copyright © 1991
Blackwell Science.
1891
Polymorphic eruption of pregnancy (pruritic urticarial papules and plaq
ues of pregnancy)
Erythematous plaques are present in areas of striae in this woman with polymorphic
eruption of pregnancy (PEP). This disorder is also called pruritic urticarial papules and
plaques of pregnancy (PUPPP).
1892
Chronic spontaneous urticaria: Standard management and

patient education
Author: David A Khan, MD
INTRODUCTION
Chronic spontaneous urticaria (CSU) is defined by the presence of recurrent urticaria (also called
hives or wheals), angioedema, or both, for a period of six weeks or longer [1]. Associated
angioedema occurs in approximately one-half of patients with CSU and usually affects the lips,
cheeks, periorbital areas of the face, extremities, and genitals [2,3].
This topic will discuss the initial and most commonly used therapies for CSU, as well as counseling
of individuals with this disorder. Treatment of CSU that is refractory to standard management and
the diagnosis, pathogenesis, and prognosis of CSU are presented separately. (See "Chronic
spontaneous urticaria: Treatment of refractory symptoms" and "Chronic spontaneous urticaria:
Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CSU
(such as delayed-pressure urticaria, cholinergic urticaria, or cold urticaria) are discussed separately.
(See "An overview of angioedema: Pathogenesis and causes" and "Urticarial vasculitis" and "Physical
(inducible) forms of urticaria" and "Cold urticaria".)
TERMINOLOGY
In this review, the term "chronic spontaneous urticaria" (CSU) refers to patients with isolated chronic
idiopathic urticaria (CIU), as well as those with both urticaria and angioedema. There are several
closely related terms that are used in the urticaria literature.
1893
Chronic idiopathic urticaria and chronic spontaneous urticaria — The terms "chronic urticaria,"
"chronic idiopathic urticaria," and "chronic spontaneous urticaria" have been used interchangeably.
"Chronic urticaria" is the most general term, although it has been used less in the literature over time
because it is nonspecific and sometimes is applied to patients with various forms of inducible
urticaria (ie, hives triggered by physical stimuli).
The term "chronic spontaneous urticaria" is preferred by the 2018 international guidelines [1]. CSU is
not triggered by identifiable factors, and the inclusion of "spontaneous" specifically excludes physical
urticaria syndromes or other inducible forms of urticaria.
Some studies distinguish between patients with and without positive autologous serum skin tests
(ASSTs) or other laboratory indicators of an autoimmune process [4]. The terms "chronic
autoimmune urticaria" or "autoantibody associated urticaria" are variably used. In this review, this
distinction is mentioned only if a study found a difference between these two patient groups. The
performance and interpretation of an ASST is reviewed separately. (See "Chronic spontaneous
urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on
'Autoimmune theory'.)
Inducible urticaria — Urticaria can be triggered by physical stimuli, such as heat, cold, pressure
applied to the skin, exercise, water, vibration, and sunlight. These disorders are referred to as
physical urticaria or "inducible urticaria." A patient can have only CSU or only inducible urticaria or a
combination of these disorders. Inducible urticaria syndromes are discussed in detail separately.
(See "Physical (inducible) forms of urticaria".)
GUIDELINES
Treatment guidelines and practice parameters for the management of chronic urticaria have been
published by professional allergy and dermatology groups worldwide [1,5-12]. In all cases,
management begins with a careful clinical history to detect and minimize aggravating factors,
followed by initial treatment with nonsedating, second-generation H1 antihistamines. If symptoms
persist, most guidelines suggest increasing the dose of H1 antihistamine, changing agents, or both.
When symptoms are refractory to these measures, guidelines differ somewhat as to the next steps
(algorithm 1) [13]. The approach described here is consistent with the American practice parameters
[5], although the recommendations of the international guidelines are noted also.
PATIENT EDUCATION
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CSU causes marked distress to patients because it is physically uncomfortable, waxes and wanes
unpredictably, interferes with work, school, and sleep, and is often difficult to treat [14]. The severity
and duration of symptoms vary among individuals, and the underlying cause is not known in most
cases. Furthermore, it can be misinterpreted by others to be infectious, and patients may stay home
to avoid embarrassment. All of these factors contribute to patient frustration and anxiety [15].
Reassurance — Patients with CSU are often frustrated and fearful, and reassurance is an important
component of successful management. There are several important concepts to relay to patients
with CSU:
● CSU is rarely a sign of another underlying disease. When it is, the hives are usually accompanied
by other systemic symptoms that are noticeable to the patient and/or the clinician.
● CSU is rarely permanent. Almost 50 percent of patients experience remission within one year
[16]. However, for those in whom the disorder persists beyond one year, approximately 14
percent will still have symptoms beyond five years [17,18].
● CSU is not an allergic reaction, and it rarely puts the patient at any acute risk. This can be
confusing to patients because acute urticaria and angioedema are manifestations of allergic
reactions, which can be life-threatening. However, CSU is limited to the skin and mucosal tissues
and does not involve other organ system as an allergic reaction can. Also, the angioedema that
sometimes accompanies CSU tends to be milder and rarely compromises the airway.
● CSU symptoms can be adequately controlled in the majority of patients.
Goal of therapy — It is helpful to explain to patients that treatments for CSU are intended to reduce or
eliminate symptoms for as long as the condition lasts, using one or more medications that do not
cause significant side effects for that individual. The majority of available therapies have not been
shown to cure CSU (although symptoms may be eliminated) or impact how long the underlying
disorder persists. In most patients, CSU spontaneously resolves in two to five years, although it may
recur or persist in a significant minority. (See "Chronic spontaneous urticaria: Clinical manifestations,
diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)
Avoidance of exacerbating factors — CSU, by definition, has no external cause or triggering stimulus
that explains all episodes. However, there are various factors that can exacerbate CSU. The
evaluation and diagnosis of persistent urticaria are reviewed separately. (See "Chronic spontaneous
urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Once the diagnosis of CSU/angioedema has been established, the clinician should begin educating
the patient about management, including avoidance of factors that can aggravate the condition
(table 1):
1895
● Physical factors – A substantial subset of patients with CSU have some flares that are triggered
by physical stimuli. Educating patients about this can help them avoid these stimuli or simply
make sense of their symptoms. As an example, heat (hot showers, extreme humidity) is a
common trigger for many CSU patients, and tight clothing or straps can also aggravate
symptoms. In contrast, patients in whom physical factors are the main trigger for symptoms are
more appropriately diagnosed as having inducible urticaria (previously referred to as a physical
urticarial syndrome), such as cholinergic urticaria or delayed-pressure urticaria. (See "Physical
(inducible) forms of urticaria" and "Cold urticaria".)
● Anti-inflammatory medications – Nonsteroidal anti-inflammatory drugs (NSAIDs) worsen

symptoms in many patients, and patients with CSU should be advised to avoid them, especially
if there is any concern they may be exacerbating their urticaria [1]. After the ingestion of NSAIDs,
patients may develop worsening of urticaria as quickly as 15 minutes or as delayed as 24 hours,
although most patients report symptoms within 1 to 4 hours. In a study of 68 children with CSU
and no history of previous reactions to NSAIDs, challenge-proven aspirin sensitivity was found
in 10 to 24 percent, most often manifesting as lip angioedema [19]. In adults with CSU, 20 to 40
percent will experience worsening symptoms after ingesting NSAIDs [20,21]. Once the NSAID is
stopped, most patients return to the baseline state in a few hours to two days, although some
may continue to have increased symptoms for up to two weeks [22-24].
● Foods – Patients may notice that some foods seem to aggravate their symptoms, although food
allergy is not a cause of CSU. The role of diet is reviewed below. (See 'Dietary manipulations
(controversial)' below.)
STEPWISE APPROACH TO TREATMENT
A stepwise approach is advocated by all major guidelines [1,5]. The approach of the 2014 American
practice parameters is similar, although not identical, to the 2018 international guideline and other
guidelines (algorithm 1) [1,6,12,13]. All doses mentioned in this section are for adults, unless
otherwise noted. More detailed information about dosing and efficacy for the agents discussed in
this section is found below. (See 'Agents and efficacy studies' below.)
Step 1 — For initial therapy, administer a second-generation antihistamine at standard therapeutic

dose (adult dosing shown) (see 'H1 antihistamines' below):
● Cetirizine, 10 mg once daily

● Levocetirizine, 5 mg once daily
● Fexofenadine, 180 mg once daily
● Loratadine, 10 mg once daily
1896
● Desloratadine, 5 mg once daily
Several other agents are available outside of the United States, including bilastine, ebastine,
olopatadine, and rupatadine. (See "New-onset urticaria", section on 'Second-generation agents'.)
Patients should also be counseled to avoid nonsteroidal anti-inflammatory drugs and any other
triggers relevant to that individual that can be avoided (table 1). (See 'Avoidance of exacerbating
factors' above.)
Step 2 — If step 1 does not control symptoms adequately within one to two weeks, therapy may be
increased by making one or more of the changes described below. There are no controlled studies
directly comparing these different interventions:
● Increase the dose of the second-generation antihistamine. This is the approach preferred by the
2018 international guidelines and the author [1]. In a systematic review, dosing up to four times
standard doses with desloratadine or levocetirizine has been shown to be helpful with pruritus,
although higher doses did not consistently reduce the number of wheals [25]. In addition, higher
doses do not appear to be more effective for all antihistamines. (See 'Up-dosing of second-
generation agents' below.)
A difference between the 2018 international guidelines and the 2014 American practice
parameters is the preference of the international guidelines to use a single antihistamine for up-
dosing [13]. In contrast, the American guidelines suggest combining two different second-
generation antihistamines when up-dosing. Comparative studies have not been done, although a
retrospective study suggested that more patients could be controlled by combining high doses
(eg, fourfold doses) of two antihistamines compared with high doses of single antihistamines
[26].
If up-dosing over the course of a few weeks does not control symptoms, international guidelines
suggest omalizumab as a next step based on clearly demonstrated efficacy (algorithm 1) [1].
American guidelines suggest that the agents described below may also be tried and may be
more practical in some settings. Omalizumab is discussed in detail separately. (See "Chronic
spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
● Add a different second-generation antihistamine. This can be particularly helpful for patients
who find cetirizine sedating.
● Add an H2 antihistamine, such as one of the following (adult dosing shown):
• Famotidine, 20 mg twice daily
• Cimetidine, 400 mg twice daily

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Studies of the efficacy of H2 antihistamines are discussed below. (See 'H2 antihistamines'
below.)
● Add a leukotriene-receptor antagonist (adult dosing shown):
• Montelukast, 10 mg once daily
• Zafirlukast, 20 mg twice daily
We usually add montelukast and allow at least four weeks to assess the impact. (See
'Leukotriene modifiers' below.)
● Add a first-generation H1 antihistamine at bedtime. (See 'Use of first-generation agents' below.)
• Hydroxyzine is commonly used in this setting, beginning (in adults) with 10 to 25 mg as a

single dose before bed. In children up to 12 years of age, we start with a dose of 0.5 mg/kg.
For children >12 years of age, 10 mg can be given initially.
• Doxepin (in adults) may be initiated at 10 or 25 mg given at bedtime. Doxepin is generally

avoided in children <12 years of age due to limited clinical experience. (See 'Use of first-
generation agents' below.)
• Cyproheptadine can be helpful for children, starting with a dose of 2 mg for children six
years of age and younger, 4 mg for older children, and increasing to 8 mg before bed.
Step 3 — If the measures in step 2 do not result in adequate control of symptoms, the dose of the
first-generation H1 antihistamine may be advanced gradually. It is also important to discontinue any
medications that were added in step 2 that did not appear to benefit the patient. International
guidelines do not advocate the use of sedating antihistamines, unless there are no other options [1].
The author finds these drugs convenient and helpful in some patients but avoids them in children
and older adults, particularly because of the association between dementia and anticholinergic
medications in that latter age group. (See "Risk factors for cognitive decline and dementia", section
on 'Medications'.)
● Hydroxyzine – Adults may be given 10 or 25 mg initially at bedtime and increased in weekly

increments, as tolerated. Total daily doses of up to 100 to 200 mg may be given, divided into
three or four doses in a 24-hour period. In children, the maximum single dose for children <6
years of age is 12.5 mg; for those 6 to 12 years of age: 25 mg; and for those >12 years of age:
100 mg. Children ≥6 years of age may be given up to 50 to 100 mg per day in divided doses.
● Doxepin – Doxepin (in adults), may be initiated at 10 or 25 mg and increased in weekly

increments to 100 to 150 mg, given once at bedtime or alternatively in divided doses throughout
1898
the day. Doxepin is generally avoided in children <12 years of age due to limited clinical
experience.
Step 4 — Patients whose symptoms are not controlled by step 3 therapies or who are intolerant of
dose advancement of first-generation H1 antihistamines are considered to have refractory CSU [5].
There are several therapies that may be considered for such patients, including omalizumab,
cyclosporine, and various anti-inflammatory and immunosuppressive agents. These are presented
separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
Systemic glucocorticoids for short-term control — Systemic glucocorticoids may be required

periodically to gain temporary control of symptoms during severe exacerbations of urticaria that
significantly impair quality of life [1]. These rescue courses of glucocorticoids may be required at any
point in therapy and are generally added on to the medications that the patient is already taking.
However, long-term (eg, months to years) treatment with systemic glucocorticoids should be
avoided. (See 'Systemic glucocorticoids' below.)
The optimal dose and duration of glucocorticoids used for CSU exacerbations has not been
systematically studied, and recommendations vary among urticaria specialists. In addition, patients
differ in their responsiveness to glucocorticoids in both the dose and duration of treatment required
to control symptoms. The following are example regimens:
● We typically give prednisone at a dose of 40 mg daily (in the morning, with food) for two to three
days. Once symptoms are controlled, the dose should be tapered down to 10 mg daily or less,
which can typically be done in increments of 10 mg.
● Other experts suggest a prednisone dose of 35 to 40 mg initially, given once daily (with food) for
five to seven days, followed by tapering by 5 mg every two to three days. Occasionally, patients
require higher initial doses or longer courses (eg, three weeks).
Rebound worsening of urticaria may occur with tapering or discontinuation of systemic

glucocorticoids. If this occurs, we return to the last effective dose and then try to taper again more
gradually. Some authors suggest that once the dose has been reduced to 20 mg daily, the frequency
of administration may be changed to every other day, and then the dose tapered further.
ASSESSING CONTROL OF SYMPTOMS
Control of symptoms should be assessed at each visit.
Validated questionnaires — Questionnaires have been developed and validated for monitoring
patients with urticaria. We favor the four question Urticaria Control Test (UCT) for both accuracy and
1899
simplicity (table 2) [27]. Answers are assigned a value of 0 to 4, from most severe to least severe,
such that a higher score indicates better symptom control. Scores can range from 0 to 16. A score of
<12 on the UCT identifies patients with poorly controlled chronic urticaria, and a score of ≥12
identifies those with well-controlled symptoms. An improvement in 3 points is a minimal response
[28]. A different tool, the Urticaria Activity Score (UAS7) is favored by the international guidelines,
although it requires the patient to complete the questionnaire over seven days prior to evaluation
[29].
Maintenance therapy — Many patients with CSU require multiple medications to control symptoms
fully. Once symptoms have come under control, the patient should be maintained on those agent(s)
for a period of time before withdrawal of medications is considered.
For the majority of patients, we generally recommend three months of good control prior to tapering
therapies. The optimal duration of maintenance therapy in a variable disease like CSU has not been
studied, and we would alter this suggestion for specific situations. For example, patients whose
symptoms were easily and completely controlled with one or two agents may begin to taper therapy
after one or two months of well-controlled symptoms. We extend the period of control further than
three months for patients with one or more of the following characteristics:
● Symptoms that were present for years, were very severe, or were difficult to control
● Concomitant physical urticarias, which tend to be longer-lasting than simple CSU
● Symptoms that are mostly controlled but still present at a low level
Discontinuing therapy — At any point in therapy, we discontinue agents that have been deemed
ineffective, including antihistamines in patients who are completely antihistamine-resistant. In
patients responsive to antihistamine therapy, we gradually reduce antihistamine doses every two to
four weeks, beginning with first-generation agents. Other agents can be tapered in a similar fashion.
In patients dependent upon systemic glucocorticoids, we reduce the dose as quickly as possible
once their urticaria has been stabilized.
WHEN TO REFER
Patients with CSU should be referred for specialist care in the following circumstances:
● An underlying disorder is suspected (refer to an allergist/immunologist or other appropriate

specialist).
● Signs or symptoms suggest urticarial vasculitis, such as urticarial lesions that have a purpuric
quality, leave residual ecchymotic markings, or are accompanied by fever or joint pain (refer to a
specialist capable of performing skin biopsies).
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● Symptoms are not controlled with steps 1, 2, or 3 or the patient is requiring repeated or
prolonged treatment with glucocorticoids (refer to an allergist/immunologist or dermatologist).
(See "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
AGENTS AND EFFICACY STUDIES
Most patients with CSU are initially treated with antihistamines, often in conjunction with limited
courses of oral glucocorticoids for refractory symptoms. However, long-term systemic
glucocorticoids are associated with significant adverse effects, and persistent symptoms should be
treated instead with other immunosuppressive, anti-inflammatory, or steroid-sparing agents.
The different medications used in the management of CSU and studies of efficacy are discussed in
this section.
H1 antihistamines — H1 antihistamines are the cornerstone of pharmacotherapy for CSU and control
symptoms to at least some degree in most patients [6,30-33]. Patients show variable responsiveness
to antihistamines. Eosinopenia (ie, an absolute eosinophil count of <50 cells/microL) with or without
basopenia was found in one large study to be a marker of more severe disease and poor response to
second generation antihistamines [34]. (See "Chronic spontaneous urticaria: Clinical manifestations,
diagnosis, pathogenesis, and natural history", section on 'Laboratory evaluation'.)
Several randomized, placebo-controlled trials have demonstrated that both the first- and second-
generation H1 antihistamines reduce the major symptoms of CSU (ie, pruritus, wheal [hive]
formation, and disruption of sleep and daily activities) [2,35-41]. A systematic review concluded that
nonsedating antihistamines improve quality of life for patients with CSU [42]. The magnitude of
effect is difficult to generalize, although in various reports, 50 to 95 percent of patients achieved
satisfactory disease control with one or a combination of antihistamines, without other agents
[32,43-45].
The newer second-generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine,

desloratadine) are preferred because they are as effective and better tolerated (ie, less sedative and
anticholinergic effects) than moderate doses of the older, first-generation antihistamines (eg,
hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine) [46,47]. A systematic review of
randomized trials concluded that there was insufficient evidence to make recommendations for any
specific second-generation agent over another when each was used at approved doses [48]. In the
absence of additional data, it is the author's practice to initiate therapy with cetirizine in most
patients. Of note, most patients require higher than approved doses, and the data addressing "up-
dosing" are reviewed below. (See 'Up-dosing of second-generation agents' below.)
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Rupatadine is a newer second-generation antihistamine (not available in the United States) that also
has antiplatelet-activating factor effects. Randomized trials comparing levocetirizine and rupatadine
have shown that rupatadine is more effective and better tolerated [49,50]. Olopatadine (not available
in the United States) is also promising [51].
Up-dosing of second-generation agents — Doses of second-generation antihistamines as high as

four times the standard dose are advocated in American and most other guidelines [1,6,32,52,53].
The effectiveness of this approach varies between studies. One study estimated overall efficacy of
the second-generation agents and found that the standard dose of second-generation antihistamines
controlled symptoms in only 18 percent of patients with CSU, whereas doses as high as four times
the standard dose achieved control of symptoms in 74 percent [54]. Consistent with this, a
systematic review found that higher doses were helpful in controlling pruritus, although not wheal
number, in approximately 63 percent of patient who did not respond adequately to standard dose
therapy [25].
Not all agents are more effective at higher doses. The evidence for higher doses is strongest for
levocetirizine and desloratadine, mixed for cetirizine, and weak for fexofenadine [25,35,44,55,56]. The
author most commonly starts with cetirizine (10 mg twice daily) or levocetirizine (5 mg twice daily) in
patients who have already failed once daily. If symptoms continue, doses can be increased up to four
times daily at one- to two-week intervals. One difference between the 2018 international guidelines
and recommendations from American experts is that the international guidelines discourage use of
more than one different nonsedating antihistamine, while this is relatively common practice in the
United States, and studies comparing the two approaches are lacking [1].
Studies of specific agents include the following:
● Levocetirizine and desloratadine may be more effective at higher doses and do not cause
clinically significant sedation. In a randomized trial of 80 patients referred to a tertiary center for
refractory CSU, subjects were assigned to either levocetirizine or desloratadine [44]. Subject
were initially treated with 5 mg of either drug, and doses were doubled at weekly intervals if
symptoms had not responded (with response defined as being symptom-free for the last three
days of the interval), up to maximal doses of 20 mg by week 3. If subjects did not respond to 20
mg of one drug, they were then changed to 20 mg of the other during week 4. Increased
somnolence was not observed with either agent.
Response rates were slightly higher to levocetirizine than desloratadine. Among those patients
who responded (as defined above), improvement was achieved in 52, 65, and 74 percent with 5,
10, and 20 mg of levocetirizine, respectively, and 41, 56, and 63 percent with the same doses of
desloratadine. There were seven subjects who did not respond to 20 mg of desloratadine but did
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respond to 20 mg of levocetirizine. There were no patients who responded to desloratadine after
failing levocetirizine. Approximately 15 percent failed to respond to the highest doses of either
drug, and overall, only about one-half of patients achieved complete control of symptoms by the
conclusion of the trial.
Of note, there was no placebo arm in this trial, and there were 13 patients who became
symptom-free on standard 5 mg doses of either medication, raising the issue of whether these
"refractory" subjects had been adherent with previous therapies. Despite these limitations, this
study suggests that higher doses of either desloratadine or levocetirizine may be more effective
than standard doses. In addition, the approach of doubling the dose stepwise in patients whose
symptoms are not controlled appears to be safe and well-tolerated. Another open-label study of
levocetirizine reported similar results [56].
● Studies of cetirizine up-dosing for CSU are conflicting and methodologically less rigorous, and
information about sedation at higher doses is lacking. A small observational study evaluated 21
CSU patients with inadequate responses after one to two weeks of cetirizine 10 mg daily [57].
Cetirizine was increased to 10 mg twice daily for an additional one to two weeks, and then
subjects were randomized to continue at a dose of either 20 mg daily or reduce to 10 mg daily
for an additional two weeks. Both groups had improved urticarial scores on cetirizine 20 mg
daily, but only the group that remained on the higher dose had continued improvement, with
worsening symptoms in the group whose cetirizine dose was reduced. Thus, this study
suggests that the higher dose is more effective. However, in another small observational study,
increasing cetirizine from 10 mg once daily to 10 mg three times daily improved disease control
in only 1 of 22 patients [55].
● Fexofenadine has not been shown to be more effective at doses higher than 60 mg twice daily. A
multicenter randomized trial of 418 patients treated with fexofenadine at doses of 20 mg, 60 mg,
120 mg, or 240 mg twice daily found that the three higher doses provided better disease control
than the lowest dose (which was below the lowest recommended adult dose), but there were no
significant differences in effectiveness among the higher doses [35]. Another study of very
similar design, also using fexofenadine 20 mg, 60 mg, 120 mg, or 240 mg twice daily, found no
difference in efficacy among the three highest doses [58]. A caveat of these studies is that the
patients enrolled were not considered refractory to recommended doses of second-generation
antihistamines.
● An open-label study of 29 adults with CSU refractory to other antihistamines evaluated up-
dosing of bilastine (not available in the United States) at 20, 40, and 80 mg daily [59]. The dose
of bilastine was doubled every two weeks, and at each step, significantly more patients achieved
1903
control of their symptoms. However, at the 80 mg dose, 11 patients still had moderate disease
activity, consistent with studies of other second-generation antihistamines.
Importance of a regular regimen — Most clinicians prescribe nonsedating H1 antihistamines to

be taken regularly and advise patients to minimize day-to-day changes in their medication regimen,
and clinical trials demonstrating the efficacy of H1 antihistamines in this disorder involve regularly
dosed antihistamines. However, in reality, the symptoms of CSU fluctuate, and patients may try
taking their medications only as needed. A small number of studies have evaluated the efficacy of
as-needed antihistamines and found it to be inferior to regular administration.
● In a study of over 100 patients with CSU, subjects were randomized to desloratadine 5 mg daily
with placebo if needed for symptom control or to placebo daily with desloratadine as needed for
symptom control [60]. At four and eight weeks, there was a statistically significant difference in
quality of life scores in favor of regular desloratadine.
● In a double-blind trial of 29 patients with CSU, a single dose of desloratadine (either 5 or 20 mg)
had relatively little effect on existing wheals [61].
Thus, patients should be encouraged to take their prescribed regimen of H1 antihistamines regularly
for maximal benefit.
Use of first-generation agents — The use of first-generation antihistamines is suggested by the

American practice parameters as an option for adults when second-generation antihistamines do
not provide adequate control, although not by international guidelines [12]. The first-generation
antihistamines are similarly effective compared with newer second-generation antihistamines but
with more adverse effects.
In children younger than two years of age, first-generation, sedating antihistamines should be
avoided, as these drugs can cause paradoxical agitation, and over-the-counter cold remedies
containing them have been linked to a small number of deaths in this age group. (See "The common
cold in children: Management and prevention", section on 'Over-the-counter medications'.)
The primary concern with first-generation agents is sedation and performance impairment, and
clinicians should inform patients specifically about this side effect [62]. First-generation
antihistamines, including hydroxyzine, doxepin, and diphenhydramine, can enhance the QTc-
prolonging effect when combined with other QTc-prolonging agents (eg, antiarrhythmic drugs,
macrolides, fluoroquinolones) (table 3). Therefore, combinations of such drugs should be avoided
(when possible), particularly in patients at elevated risk (eg, those with congenital long QT syndrome,
electrolyte abnormalities, recent myocardial infarction, or uncompensated heart failure). High doses
of doxepin are potentially cardiotoxic and should be avoided in susceptible individuals with heart
1904
disease. It is the author's approach to use extra caution in older adults chronically taking first-
generation antihistamines at doses greater than 50 mg daily and to obtain a baseline
electrocardiogram in such individuals. (See "Acquired long QT syndrome: Definitions, causes, and
pathophysiology", section on 'Medications'.)
Studies of first-generation antihistamines in adults at usual doses have shown tolerance to

performance impairment after three to five days of therapy [63-65]. Studies in patients with CSU
given higher doses are lacking, although many patients with CSU seem to tolerate high doses
without difficulty. Based upon this information, some authors suggest a gradual titration of first-
generation antihistamines. As an example, hydroxyzine can be started at 10 to 25 mg daily and
increased in 10 to 25 mg increments every five to seven days to a maximum of 25 to 50 mg four
times daily [66,67].
Another approach is to administer first-generation antihistamines as a single dose in the evening, in

combination with a second-generation antihistamine given in the morning [30,67]. However, in a
randomized, double-blind crossover study of 24 patients with CSU, this approach (ie, 15 mg
levocetirizine in the day, with 50 mg hydroxyzine at night) was compared with second-generation
agents alone (10 mg levocetirizine twice daily) for periods of five days [68]. Wheals and pruritus were
reduced by both treatments, and sleep quality was similar. However, daytime somnolence was
statistically reduced in patients in the levocetirizine monotherapy group but remained unchanged
from baseline in the hydroxyzine group. The clinical relevance of this change is unknown, and the
assessment of daytime somnolence was not validated. In addition, given the long half-life of
hydroxyzine, five days is likely an insufficient time to study its efficacy or tolerance. Furthermore, the
initial starting dose of 50 mg of hydroxyzine is higher than is typically recommended. The American
practice parameters recommend dose advancement of evening doses of first-generation
antihistamines in patients who have failed higher doses of second-generation antihistamines and/or
H2 antihistamines and leukotriene-receptor antagonists, while the international guidelines do not
[1,5].
H2 antihistamines — Patients whose symptoms are not adequately controlled on H1 antihistamines

alone may experience modest improvement with the addition of an H2-antagonist antihistamine,
although data are conflicting, and international guidelines do not include H2 antihistamines as an
option [1,12]. If not effective, the H2 antagonist should be discontinued.
A meta-analysis concluded that there was insufficient evidence upon which to make
recommendations about the use of H2 antihistamines in CSU because the available studies were old
and at risk for bias [69]. Most of the studies demonstrating benefit used the combination of
hydroxyzine and cimetidine [70-73]. These two drugs are metabolized by the same liver enzymes,
and the benefit may be due to increased serum concentrations of one or both drugs, rather than a
1905
true synergistic effect [74,75]. However, the combined use of ranitidine (no longer available in the US)
and terfenadine (no longer available), which are not metabolized by the same liver enzymes, was
shown to be helpful in another study [76]. In contrast, improved symptom control was not observed
by combining cetirizine with either cimetidine [77] or ranitidine (no longer available in the US) [78].
Thus, until more conclusive data are available, a trial of H2 antihistamines can be considered as
additive therapy in patients whose symptoms do not respond adequately to H1 antihistamines alone,
but if no improvement is noted within two to four weeks, other therapies should be considered.
Systemic glucocorticoids — Systemic (usually oral) glucocorticoids are effective in controlling

symptoms in most patients with CSU. However, administration beyond several weeks is not justified
for a disorder that in itself has an excellent long-term prognosis, since glucocorticoids have
predictable and significant adverse effects. Further, there is no evidence that glucocorticoids have a
disease-modifying effect. A retrospective study found that the addition of glucocorticoids to
antihistamines during the initial weeks of treatment did not hasten the time required to achieve
control of symptoms, compared with treatment with antihistamines alone [79]. We view
glucocorticoids as rescue therapy that should be used to attain temporary control of severe
symptoms. (See "Major side effects of systemic glucocorticoids".)
Most guidelines suggest that oral glucocorticoids be considered as a temporary additive therapy for
patients with symptoms refractory to one or more antihistamines at full dose, for the purpose of
gaining control of severe symptoms [1,6,31,32]. Optimal dosing has not been formally studied,
although our approach is described above. In many cases, symptoms recur as glucocorticoids are
tapered or discontinued, and these agents are not believed to alter the long-term course of the
disease. (See 'Systemic glucocorticoids for short-term control' above.)
Leukotriene modifiers — Leukotrienes are believed to be involved in the pathogenesis of urticaria.

Activated mast cells generate and release leukotrienes in addition to histamine, and intradermally-
injected leukotriene D4 causes a strong wheal-and-flare response [80-82]. Antileukotriene
medications include the leukotriene-receptor antagonists, montelukast and zafirlukast, as well as the
5-lipoxygenase inhibitor, zileuton. Amongst these agents, montelukast is the most commonly used
for CSU. We do not recommend the use of zileuton in CSU given the absence of controlled studies,
higher cost, need for laboratory monitoring, and potential adverse effects (eg, liver toxicity). The 2018
international guidelines excluded leukotriene modifiers from the stepwise approach based on limited
evidence of efficacy [1].
In unselected populations of patients with CSU, the data in support of leukotriene modifiers are
relatively weak:
1906
● Montelukast (10 mg once daily), either alone or in combination with antihistamines, has
demonstrated efficacy in randomized-controlled trials [71,83-86]. However, not all trials were
positive [87,88], and one found montelukast to be less effective than desloratadine for 160
patients with relatively mild CSU [89].
● Studies of zafirlukast are mixed as well. In a double-blind, placebo-controlled, crossover study,

52 patients with CSU were randomized to 20 mg zafirlukast twice daily or placebo for 12 weeks
[90]. There was no statistical difference between zafirlukast and placebo. In another randomized
trial, the combination of zafirlukast and cetirizine was superior to cetirizine alone in patients with
a positive autologous serum skin test (ASST) but not in patients with a negative ASST [91].
Patients with CSU that is exacerbated by ingestion of aspirin or other nonsteroidal anti-
inflammatory drugs (NSAIDs) may respond more predictably to antileukotriene medications,
since abnormal leukotriene regulation is believed to be important in the pathogenesis of this
type of urticaria [92,93]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic
reactions".)
● Case reports described the use of montelukast to block acute urticaria secondary to NSAIDs
[94,95], and another report described a patient with NSAID-exacerbated CSU who responded to
both zafirlukast and zileuton [92].
● Two small randomized trials found montelukast to be superior to cetirizine and placebo in
patients with NSAID-exacerbated CSU [83,84].
Topical agents — Routine use of topical agents for CSU is discouraged, as they rarely result in
sustained improvement. Some of these agents include emollients that contain menthol, phenol, or
pramoxine, which are substances that are benign but minimally effective. Others contain high-
potency topical corticosteroids, which can cause dermal atrophy, or topical antihistamines (eg,
doxepin-containing preparations), which can cause contact sensitization [96].
OTHER THERAPIES
Vitamin D — A small number of studies have examined the impact of vitamin D supplementation on
chronic urticaria [97-100]. In a prospective, double-blinded study, 42 subjects with CSU were
randomized to high (4000 international units daily) or low (600 international units daily) vitamin D3
supplementation for 12 weeks and also received a standardized three-drug regimen (cetirizine,
ranitidine [no longer available in the US], and montelukast) and a written action plan. Three-drug
therapy decreased total urticaria symptom severity (USS) scores by 33 percent in the first week.
There was a further significant decrease (40 percent) in total USS scores in the high but not low
1907
vitamin D3 treatment group by week 12. Sleep quality and pruritus scores improved in the high-dose
group. However, serum 25-hydroxyvitamin D levels did not correlate with USS scores, and there was
no reduction in medication use between the high and low supplementation groups. Therefore, the
clinical significance of vitamin D supplementation remains unclear, although it may be an option for
patients who wish to minimize other medications or prefer nontraditional therapies.
Dietary manipulations (controversial) — We do not routinely advise CSU patients to modify their diets
for the purpose of controlling CSU symptoms, because adherence to the proposed diets is difficult,
benefit has not been demonstrated in controlled trials, and dietary modifications are not supported
by most guidelines [5]. A 2019 systematic review concluded that the quality of the evidence in
support of dietary interventions including pseudoallergen-free and low histamine diets for CSU was
low [101]. The most recent international guidelines state these diets are "controversial and as yet
unproven" [1]. However, if a patient is very motivated to try these diets, we do not object. A
pseudoallergen-free diet avoids naturally occurring aromatic compounds in certain foods such as
many fruits and vegetables, seafood, and artificial preservatives (table 4). It is recommended that a
trial of a minimum of two to three weeks is required to see benefit.
It is particularly important to explain to patients that an undiscovered allergy to food or food

additives is not likely to be responsible for their symptoms. Immunoglobulin (Ig)E-mediated food
reactions are not a cause of CSU, and testing for food allergy is not necessary [5]. (See "Chronic
spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section
on 'Foods and food additives' and "Allergic and asthmatic reactions to food additives", section on
'Patients with chronic urticaria'.)
SPECIAL POPULATIONS
Children — CSU can occur in infants and children, and the approach to therapy is the same as that in
adults, although avoidance of first-generation, sedating antihistamines is particularly emphasized [1].
Nonsedating antihistamines that have been shown to be safe in children include cetirizine,
levocetirizine, loratadine, desloratadine, fexofenadine, and outside the United States, bilastine and
rupatadine [1,102-108]. Most are available in orally-dissolving or chewable tablets or syrups for ease
of administration. While up-dosing second-generation antihistamines has been recommended in
guidelines for children with CSU, the safety and efficacy of this approach has not been well-studied
[109].
Pregnant or lactating women — Pregnant women with urticaria with/without angioedema should be
treated with the least amount of medication possible. Most patients can be treated with second-
generation H1 antihistamines alone, with occasional short courses of oral glucocorticoids for severe
1908
flares. Among second-generation antihistamines, cetirizine (10 mg once daily), levocetirizine (5 mg
once daily), and loratadine (10 mg once daily) may be considered the antihistamines of choice in
pregnancy [110,111]. No studies have evaluated the safety or efficacy of high-dose antihistamines in
pregnancy. We have used twofold higher doses of single agents or two separate antihistamines at
approved doses after a careful discussion with the patient about these issues. Omalizumab has been
used safely for refractory CSU in pregnant women, as discussed separately. (See "Chronic
spontaneous urticaria: Treatment of refractory symptoms", section on 'Safety'.)
Additional information on the safety of antihistamines, leukotriene-modifying drugs, and other agents
in pregnancy and lactation is discussed separately. (See "Recognition and management of allergic
disease during pregnancy".)
Patients with concomitant hypertension — For patients with concomitant hypertension,

dihydropyridine calcium channel blockers may help with both disorders. These drugs appear to
reduce the proliferation of stimulated T lymphocytes and inhibit mast cell-mediator release [112,113].
A small, randomized-controlled crossover trial of 10 patients with chronic idiopathic urticaria treated
with nifedipine (up to 20 mg three times daily) demonstrated benefit in seven patients, with mild
adverse effects [114]. Other evidence consists of case reports.
Advantages of this agent include a relatively rapid therapeutic response, familiarity of clinicians with
this class of drug, and wide availability. Thus, a trial of calcium channel blockers may be reasonable
for patients who can tolerate the hemodynamic effects or for those with concomitant hypertension.
In addition, there is preliminary evidence that the presence of systemic hypertension is associated
with longer chronic urticaria duration, as discussed separately. (See "Chronic spontaneous urticaria:
Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and
prognosis'.)
Patients with thyroid autoantibodies — Thyroid autoimmunity, as determined by the presence of

elevated levels of thyroid peroxidase antibodies or antithyroglobulin antibodies, is found in patients
with CSU at a greater than expected frequency [115-117]. However, the patient's thyroid status does
not necessarily correlate with the presence of urticaria, and patients with CSU/angioedema and
evidence of thyroid autoimmunity may be euthyroid, hypothyroid, or hyperthyroid [115,118]. (See
"Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural
history".)
Patients with thyroid autoantibodies and laboratory evidence of clinical hypothyroidism may benefit
from thyroid-hormone replacement [119]. In contrast, the treatment of euthyroid patients with CSU is
controversial. There are several reports of apparent success treating euthyroid patients with thyroid
hormone at doses that suppress the level of thyroid-stimulating hormone [115,116,118,120-122]. A
1909
proposed mechanism of action is reduction in complement activation by the complement controller
domain of thyroperoxidase [123]. We have seen some euthyroid patients with thyroid autoantibodies
respond to thyroxine therapy without adverse effects, but the results are mixed and unpredictable. If
this therapy is used, the uncertain benefits must be balanced with potential risks of iatrogenic
hyperthyroidism and osteoporosis [124].
subjects by searching on "patient education" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Hives (The Basics)" and "Patient education: Chronic hives
(The Basics)")
● Patients with chronic spontaneous urticaria (CSU) are often frustrated and anxious. Although no
external cause is identified in most patients, numerous factors can aggravate the condition
(table 1). Understanding these triggers and learning to avoid those that are relevant to the
individual patient are critical components of successful management. Education should begin
1910
as soon as the diagnosis is made. (See 'Patient education' above and 'Information for patients'
above.)
● We recommend H1 antihistamines as initial therapy for all patients with CSU (Grade 1A). We
recommend less-sedating, second-generation agents (eg, cetirizine, levocetirizine, fexofenadine,
loratadine, desloratadine), rather than older first-generation agents (eg, hydroxyzine,
diphenhydramine, chlorpheniramine, or mizolastine) (Grade 1B). (See 'H1 antihistamines' above
and 'Step 1' above.)
● Up to one-half of patients may not achieve complete control of symptoms using standard doses
of second-generation H1 antihistamines alone. For these patients, a stepwise approach to
increasing therapy is appropriate. As doses are increased or different agents are introduced, it is
important to discontinue any that have not been beneficial, so that medications do not
accumulate. There are minor differences in the stepwise approaches advocated by American
and European expert panels (algorithm 1). (See 'Stepwise approach to treatment' above.)
● For patients whose symptoms persist, we suggest one or more of the following interventions,
which have not been compared in head-to-head studies (Grade 2C) (see 'Step 2' above):
• Increasing the dose of the second-generation H1 antihistamine to up to four times the

standard dose (after which, international guidelines suggest adding omalizumab)
• Adding a different second-generation antihistamine
• Adding an H2 antagonist
• Adding a leukotriene-receptor antagonist
• Adding a first-generation H1 antihistamine at bedtime
● For patients whose symptoms persist, we suggest increasing the dose of first-generation H1
antihistamine gradually (Grade 2C). The patient should be informed about sedation and
anticholinergic side effects. (See 'Step 3' above.)
● Systemic glucocorticoids should be reserved for short-term control of refractory symptoms.

(See 'Systemic glucocorticoids for short-term control' above.)
● Patients whose symptoms persist despite step 3 therapy or who are intolerant of dose
advancement of first-generation H1 antihistamines are considered to have refractory disease.
There are several therapies that may be considered for such patients, including omalizumab and
various anti-inflammatory and immunosuppressive agents. These are discussed separately.
(See 'Step 4' above and "Chronic spontaneous urticaria: Treatment of refractory symptoms".)
1911
● Once symptoms are controlled, we continue the drug(s) required for control for a minimum of
one to three months before attempting to taper doses or discontinue medications. We extend
this maintenance period even longer in patients whose symptoms were particularly difficult to
suppress. (See 'Maintenance therapy' above.)
1912
GRAPHICS
Comparison of international and American urticarial guidelines
The approach of the 2018 international guideline (left side) and the earlier American practice parameter (right side) are
compared.
EAACI: European Academy of Allergology and Clinical Immunology; WAO: World Allergy Organization; AAAAI: American Academy
of Allergy, Asthma, and Immunology; ACAAI: American College of Allergy, Asthma, and Immunology; sgAH: second-generation
antihistamine; LTRA: leukotriene-receptor antagonist; fgAH: first-generation antihistamine.
* Different spellings as used in the respective guideline.
Reproduced from: Zuberbier T, Bernstein JA. A comparison of the United States and international perspective on chronic urticaria
guidelines. J Allergy Clin Immunol Pract 2018; 6:1144. Illustration used with the permission of Elsevier Inc. All rights reserved.
1913
Factors that exacerbate chronic spontaneous urticaria (CSU)
Exacerbating factor Examples Alternate explanations to consider
Nonsteroidal anti-inflammatory drugs Urticaria may worsen in patients within Consider alternate diagnosis of NSAID
(NSAIDs) 24 hours after ingestion; some within 2 allergy or pseudoallergy if NSAIDs are
hours and others (particularly children) the only or predominant trigger for hives
up to 4 to 24 hours later. or angioedema.
Environmental conditions Heat. Consider alternate diagnosis of

Cold. cholinergic urticaria if hives are small (1
Sunlight. to 3 mm), surrounded by large areas of
erythema, and predominantly triggered
by changes in core body temperature
(eg, exercise, hot showers, sweating,
emotional factors).
Consider exercise-induced anaphylaxis
if hives only occur during exercise and
not with passive changes in core body
temperature.
Consider cold urticaria or cold-
associated inflammatory disorder if
hives are exclusively triggered by
exposure to cold.
Consider solar urticaria if hives appear
to be exclusively triggered by exposure
to sunlight.
Friction or pressure from clothing Hives may form under clothing straps, Consider diagnosis of delayed-pressure
in areas where tight clothing urticaria/angioedema if pressure on
compresses the skin, or in areas of skin is followed in 4 to 24 hours by
natural friction (axillae, between thighs). erythematous angioedema of affected
area. Patients with delayed-pressure
urticaria often have concomitant CSU.
Consider vibratory urticaria if hives
appear after exposure to vibration (eg,
after clapping, mowing lawn, holding
certain appliances).
Alcohol Hives may be more numerous or severe If alcohol is the sole or predominant
after drinking alcoholic beverages. trigger, consider nonspecific reaction to
histamine-releasing properties of some
alcoholic beverages, or rarely, allergy to
some component of the beverage.
Narcotic medications Hives may be more numerous or severe

and pruritus more pronounced after
taking narcotics.
Stress (emotional or physical) or sleep Hives can appear during stressful

deprivation events, and/or control of chronic hives
can be more difficult during stressful
periods or periods of reduced sleep.
Concomitant infections Hives can be more numerous or severe

during viral illnesses (eg, common
colds) or bacterial infections (eg,
sinusitis).
Menstruation or perimenstrual period Some women with CSU observe Consider alternate diagnoses of
fluctuations with their menstrual cycle. autoimmune progesterone dermatitis or
1914
other catamenial dermatoses if hives
only occur in perimenstrual periods or
lesions are not clearly urticarial.
Irregular use of antihistamines Regular and consistent dosing of

antihistamines is most effective in
controlling CSU. Erratic or as-needed
use may contribute to poor symptom
control.
1915
Urticaria control test
Patient name: Date (dd/mm/yyyy): _____ /_____ /_____
Date of birth (dd/mm/yyyy): _____ /_____ /_____
Instructions: You have urticaria. The following questions should help us understand your current health situation. Please read through
each question carefully and choose an answer from the five options that best fits your situation. Please limit yourself to the last four
weeks. Please do not think about the questions for a long time, and do remember to answer all questions and to provide only one answer to
each question.
0 points 1 point 2 points 3 points 4 points Scoring
1. How much have you suffered from the Very Much Somewhat A little Not at
physical symptoms of urticaria (itch, hives much all
[welts], and/or swelling) in the last four
weeks?
2. How much was your quality of life affected by Very Much Somewhat A little Not at
the urticaria in the last four weeks? much all
3. How often was the treatment for your urticaria Very Often Sometimes Seldom Not at
in the last four weeks not enough to control often all
your urticaria symptoms?
4. Overall, how well has your urticaria been Not at A little Somewhat Well Very
under control in the last four weeks? all well
Total
points:
Original figure modified for this publication. From: Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria Control Test: A
patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol 2014; 133:1365. Illustration used with the permission of
Elsevier Inc. All rights reserved.
1916
Some reported causes and potentiators of the long QT syndrome*
Congenital Acquired (continued)

Jervell and Lange-Nielsen syndrome (including Antihistamines
"channelopathies")
Astemizole §, bilastine ¶, hydroxyzine, terfenadine §
Romano-Ward syndrome
Antineoplastic drugs ◊
Idiopathic
High risk: Arsenic trioxide, ivosidenib, lenvatinib,
Acquired vandetanib
Moderate risk: Ceritinib, crizotinib, dasatinib,
Metabolic disorders
encorafenib, gilteritinib, inotuzumab ozogamicin,
Hypokalemia midostaurin, nilotinib, osimertinib, ribociclib,
toremifene, vemurafenib
Hypomagnesemia
Hypocalcemia Analgesic, anesthetic, and sedative drugs
Starvation Anesthetic/sedative: Chloral hydrate, propofol
Anorexia nervosa Opioids: Buprenorphine ¥, hydrocodone, loperamide ‡ (in

overdose), methadone
Liquid protein diets
Bronchodilators (beta-2 agonists)
Hypothyroidism
Arformoterol, albuterol, formoterol, levalbuterol,
Bradyarrhythmias indacaterol, olodaterol, salmeterol, terbutaline, vilanterol
Sinus node dysfunction Diuretics
AV block: Second or third degree Via electrolyte changes (especially hypokalemia or
Androgen deprivation therapy (GnRH agonist/antagonist hypomagnesemia)
therapy or bilateral surgical orchiectomy) Gastrointestinal drugs ◊
Antiarrhythmic drugs Antidiarrheal: Loperamide ‡ (in overdose)
Quinidine, procainamide, disopyramide Antiemetics:
Flecainide, pilsicainide ¶, propafenone Moderate risk: Droperidol, ondansetron (risk with IV
use greater than oral)
Amiodarone Δ, dronedarone, vernakalant ¶
Low to moderate risk: Amisulpride (IV antiemetic
Sotalol dose), granisetron, dolasetron, hydroxyzine,
Dofetilide, ibutilide tropisetron ¶
Antianginal drugs Promotility:

High risk: Cisapride (restricted availability)
Ranolazine, ivabradine ¶
Moderate risk: Domperidone ¶
Anticholinergic drugs (antimuscarinics)
Low to moderate risk (rare reports): Metoclopramide
Solifenacin, tolterodine
Proton pump inhibitors: Chronic use leading to
Anti-infective drugs ◊ hypomagnesemia (rare)
Antimalarial: Neurologic drugs
High risk: Delamanid ¶, quinidine, quinine
Low to moderate risk: Apomorphine, deutetrabenazine,
Moderate risk: Chloroquine, halofantrine, piperaquine
donepezil, ezogabine, fingolimod, ozanimod †,
Lower risk: Hydroxychloroquine (rare reports, noted pimavanserin, tetrabenazine
in labeling)
Psychotropic drugs
Antituberculous:
Antipsychotics: ◊
High risk: Bedaquiline
High risk: Chlorpromazine, IV haloperidol,
Azole antifungals: ziprasidone
Moderate risk: Fluconazole, voriconazole Moderate risk: Amisulpride (oral) ¶, clozapine,
Low to moderate risk: Itraconazole flupentixol ¶, haloperidol (oral), olanzapine,
quetiapine, risperidone, thioridazine
Clofazimine (moderate risk)
Low to moderate risk: Asenapine, iloperidone,
Fluoroquinolones (systemic): paliperidone, periciazine ¶, pimavanserin
¶
1917
Moderate risk: Gemifloxacin ¶, levofloxacin,
Tricyclic and tetracyclic antidepressants (TCAs):**
moxifloxacin, sparfloxacin ¶
Moderate risk: Clomipramine, doxepin, and
Low to moderate risk: Ciprofloxacin, norfloxacin,
imipramine
ofloxacin
Selective serotonin reuptake inhibitors (lower risk than
Foscarnet (low to moderate risk)
TCAs): Citalopram, escitalopram, fluoxetine (less than
HIV antiretrovirals: citalopram)
Moderate risk: Saquinavir Others:
Low to moderate risk: Efavirenz, lopinavir-ritonavir, Atomoxetine, trazodone, valbenazine
rilpivirine
Vasodilator drugs
Macrolide antibiotics:
Bepridil §, cilostazol
Moderate risk: Azithromycin, erythromycin,
clarithromycin Other drugs and herbs
Low to moderate risk: Roxithromycin, telithromycin Miscellaneous: Anagrelide, alfuzosin, cocaine, eliglustat,
Pentamidine (IV), moderate risk gadobenate dimeglumine, lofexidine, mifepristone,
papaverine (intracoronary), pasireotide, probucol §,
Pentavalent antimonials (antiparasitic/antiprotozoal): terlipressin ¶
Moderate risk: Meglumine antimoniate, sodium
Herbs: Cinchona (contains quinine), licorice extract
stibogluconate
(glycyrrhizin) in overuse leading to electrolyte changes
Telavancin (low to moderate risk)
Other factors
Myocardial ischemia or infarction, especially with

prominent T-wave inversions
Intracranial disease
HIV infection
Hypothermia
Toxic exposure: Organophosphate insecticides
This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or
isolated association(s) with QTc prolongation that appear to be safe in most patients, but may need to be avoided in patients with
congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the Credible
Meds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of
acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool.
AV: atrioventricular; IV: intravenous.

* The list of medications and other factors capable of prolonging the QTc represents an evolving area of clinical research. In some cases of long
QTc, two or more factors may be involved.
¶ Not available in the United States.
Δ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text
within UpToDate topic reviews of acquired long QT syndrome.
◊ Classifications based upon US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic
Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision
2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf.
The use of other classification criteria may lead to some agents being classified differently by other sources.
§ Removed from market in most countries due to adverse cardiovascular effects.
¥ Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable
alternative for patients with methadone-associated QTc prolongation. Refer to clinical topic reviews.
‡ Over-the-counter; available without a prescription.
† Not associated with significant QTc prolongation in healthy persons. Refer to clinical topic for potential adverse cardiovascular (CV) effects in
patients with CV disease.
** Several of the cyclic antidepressants have not been adequately tested for QTc prolongation risk.
Data from:
1. Nielsen J, Graff C, Kanters J, et al. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs 2011; 25:473.
2. Li E, Esterly J, Pohl S, et al. Drug-induced QT interval prolongation: Considerations for clinicians. Pharmacotherapy 2010; 30:684.
3. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/.
4. Lexicomp Online. Copyright ©1978-2020 Lexicomp, Inc. All Rights Reserved.
1918
1919
Pseudoallergen-free diet for chronic spontaneous urticaria: Prohibited foodstuffs
Foodstuff Comments
Additives E100-E1518, preservatives or artificial colors, gelling agents, thickening matter, humectant, emulsifiers, flavor
potentiators, antioxidants, separating agents, sweeteners, baking agents, modified starches, foaming agents,
stabilizers, flavoring agents.
Spices and herbs Salt and chives allowed. Avoid all others.
Egg products Eggs, pasta made with eggs, cake, biscuits, mayonnaise.
Meat and Smoked meats, seafood.

seafood
Vegetables Tomatoes, artichokes, peas, mushrooms, spinach, rhubarb, olives, sweet peppers.
Fruit Fresh fruits, dried fruits, fruit juices.
Breads Breads with additional grains, herbs, or other such added ingredients. Packaged bread is preferable to bakery
breads because the ingredients are listed on the label.
Miscellaneous, Alcohol, herbal teas, margarine, sesame, potato chips, chewing gum, candy.
candies
Adopting a diet free of pseudoallergens is an alternative approach to managing chronic spontaneous urticaria. All of the items listed
above should be avoided. Patients may eat fresh or deep-frozen forms of any foods that are not listed above, without any additives.
Chemical and common names for additives listed by E number above may be found online at www.food.gov.uk/safety-hygiene/food-
additives.
UpToDate experts rarely suggest that patients with chronic spontaneous urticaria attempt to follow a pseudoallergen-free diet because
it is very restrictive. However, there may be patients who are interested in this information.
Adapted from: Magerl M, Pisarevskaja D, Scheufele R, et al. Effects of a pseudoallergen free diet on chronic spontaneous urticaria: a prospective trial.
Allergy 2010; 65:78.
1920
Chronic spontaneous urticaria: Treatment of refractory

symptoms
Author: David A Khan, MD
INTRODUCTION
Chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, is defined by the
presence of urticaria (hives) on most days of the week, for a duration of six weeks or longer [1].
Associated angioedema occurs in about 40 percent of patients. Standard management of CSU
primarily involves second-generation H1 antihistamines, often at higher than usual doses and in
combination with H2 antihistamines and leukotriene modifiers. Short courses of systemic
glucocorticoids to control severe exacerbations may be needed. This review discusses the treatment
of patients whose symptoms are not controlled over time using these standard therapies.
Therapeutic options for patients with refractory CSU will be reviewed here, as well as the evidence in
support of the efficacy of each treatment. Standard management, as well as the diagnosis,
pathogenesis, and prognosis of CSU, are reviewed separately. (See "Chronic spontaneous urticaria:
Standard management and patient education" and "Chronic spontaneous urticaria: Clinical
Urticarial vasculitis and specific physical forms of chronic urticaria, such as delayed-pressure
urticaria, cholinergic urticaria, or cold urticaria, are discussed separately. (See "Urticarial vasculitis"
and "Physical (inducible) forms of urticaria" and "Cold urticaria".)
REFERRAL
1921
Patients with recurrent urticaria with or without angioedema that continues to recur for a period of
six weeks or longer and cannot be adequately controlled with higher doses of second-generation H1
antihistamines should be referred to an allergy or dermatology specialist. These patients are at risk
for receiving repeated courses of oral glucocorticoids. However, long-term systemic glucocorticoids
have potentially severe side effects and do not appear to induce lasting remission or alter the natural
history of CSU. Thus, it is preferable to limit glucocorticoid use to short periods of the minimally
effective doses and to refer the patient for consideration of more advanced treatments before he/she
has been exposed to months of glucocorticoid therapy. (See "Major side effects of systemic
glucocorticoids".)
In some cases, immunosuppressant or anti-inflammatory drugs are needed, and it is important for
the treating specialist to be knowledgeable about potential adverse effects and monitoring when
administering the agents discussed in this topic. Consultation with additional specialists (eg,
rheumatologists) may be appropriate, depending on the medication, as well as the experience and
comfort level of the treating specialist.
OVERVIEW
Available data indicate that H1 antihistamines at higher than standard doses will adequately control
CSU symptoms in approximately one-half of patients, and a small number will get additional benefit
from the other well-tolerated and low-risk supplementary therapies (eg, H2 antihistamines and
montelukast). The efficacy of H1 antihistamine therapy for CSU is reviewed separately. (See "Chronic
antihistamines'.)
The options for refractory CSU include omalizumab, cyclosporine, and several additional drugs that
have either anti-inflammatory or immunosuppressant effects. The recommendations in this topic
review are generally consistent with guidelines from international societies [1-4]. Deviations from the
recommendations in the guidelines are noted.
When introducing these more advanced treatments, antihistamines and other standard agents that
were clearly helpful to the patient are typically continued. Any medications of uncertain benefit
should be discontinued so that medications do not accumulate.
Goal of therapy — The goal of therapy in patients with refractory CSU is to achieve a level of
symptom control and improvement in quality of life that is acceptable to the patient, while
minimizing therapy-related side effects. Patients differ in their preferences. Some want to pursue
complete remission, while others would rather minimize medications and accept a low level of
ongoing symptoms. In addition, it should be kept in mind that although CSU can be a disabling
1922
disorder, it does not lead to permanent organ damage, and it ultimately resolves in the majority of
patients, with or without treatment. Thus, a treatment that appears to be inducing serious adverse
side effects is not warranted. The natural history of CSU is reviewed separately. (See "Chronic
spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section
on 'Natural history and prognosis'.)
Choice of initial intervention — For patients whose symptoms cannot be adequately controlled by
higher-dose antihistamines, international guidelines recommend the addition of omalizumab, a
monoclonal antibody against immunoglobulin (Ig)E, as the most appropriate next intervention [1].
Omalizumab is preferred because of both proven efficacy and also safety relative to
immunosuppressant or anti-inflammatory drugs. However, the high cost of omalizumab is a concern
in all health care systems and will limit the use of this therapy in many settings. (See 'Omalizumab'
below.)
We agree with international guidelines that omalizumab is the most appropriate therapy for patients
who do not respond to higher-dose H1 antihistamine therapy [1]. However, we typically give up-
dosing of antihistamines a trial period of at least several weeks to fully assess effectiveness,
whereas the international guidelines suggest that the trial period for antihistamines can be as short
as one month (algorithm 1). Up-dosing of antihistamines is reviewed separately. (See "Chronic
spontaneous urticaria: Standard management and patient education", section on 'Up-dosing of
second-generation agents'.)
Several studies have examined potential biomarkers to predict response to various therapies for
refractory CSU, but none can be recommended for routine clinical use [5]. The most promising
developments have been in identification of possible biomarkers to predict responsiveness to
omalizumab [6-8]. (See 'Predicting responsiveness' below.)
OMALIZUMAB
Omalizumab is a monoclonal antibody directed against IgE, which was approved in the United States
in 2014 for the treatment of patients 12 years of age and older with CSU that is not controlled with
standard-dose H1 antihistamine therapy [9]. (See "Society guideline links: Urticaria and angioedema
(excluding hereditary angioedema)".)
Predicting responsiveness — Studies have identified potential biomarkers that may predict
responsiveness to omalizumab therapy, but none predict a response well enough to inform the
decision to treat. No specific laboratories are required before omalizumab is initiated for CSU.
1923
Possible predictors of a better response include higher baseline serum IgE levels [7,10], a greater
than twofold increase in IgE after four weeks of treatment compared with baseline IgE [7], higher
baseline levels of high-affinity IgE receptor (Fc-epsilon-RI) on blood basophils, and greater reduction
of Fc-epsilon-RI on basophils after four weeks of treatment [8]. However, serum IgE levels predict
basophil IgE receptor levels, so these biomarkers are interconnected, and further study is needed.
Efficacy — A meta-analysis of seven randomized trials (1312 patients) demonstrated that

omalizumab significantly reduced the weekly itch and wheal scores relative to placebo in patients
with CSU not responsive to standard doses of H1 antihistamines (eg, cetirizine 10 mg daily) [11-19].
The most effective dose was 300 mg every four weeks, at which 36 percent of patients had a
complete response (urticaria activity score of 0). Adverse event rates and specific events were
similar with omalizumab and placebo. Other analyses of multiple studies showed that omalizumab
improved sleep beginning after the first dose and provided substantial improvements in quality of life
[20,21].
One trial included in the meta-analysis was particularly informative because it closely approximated
common clinical practice. The GLACIAL trial evaluated 335 patients whose symptoms were not
controlled with H1 antihistamines (up to four times the standard dose) plus H2 antihistamines,
antileukotriene agents, or the combination [15]. Subjects were randomized to omalizumab (300 mg
monthly) or placebo. Baseline medications were continued unchanged throughout the study period
and the four-month follow-up period. The primary endpoint was a change in mean weekly itch
severity scores (on a scale from 0 to 21, with a minimally important difference of 5) at the end of 12
weeks. Clinical efficacy was apparent by one week in the omalizumab group. Mean itch scores
decreased a clinically meaningful amount only in the omalizumab group, and the difference between
the two groups was statistically significant. A minimally important difference in symptoms was
achieved by 70 and 40 percent of subjects in the omalizumab and placebo groups, respectively. At
12 weeks, 34 and 5 percent of subjects were itch- and hive-free in the omalizumab and placebo
groups, respectively. Once omalizumab was stopped, subjects' symptoms gradually returned during
the observation period and were similar to placebo at the end of the study. Thus, the addition of
omalizumab to the combination of maximally-dosed H1 antihistamines (with or without H2
antihistamines, antileukotriene agents, or both) will control symptoms in another 30 to 35 percent of
patients, and the combination of maximal antihistamine therapy plus omalizumab will achieve
satisfactory control of CSU in approximately 80 percent of patients.
Long-term impact — Omalizumab has not been shown to have a long-term disease-modifying
effect, so patients may relapse when omalizumab is tapered or discontinued [22]. However, CSU is a
disorder that remits or resolves in the majority of patients within a few years even untreated, so it can
be difficult to assess the impact of therapy on natural history. (See "Chronic spontaneous urticaria:
1924
Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and
prognosis'.)
Safety — Among all nonantihistamine therapies with proven efficacy for refractory CSU, omalizumab
is the best studied, most widely used therapy and has a very low incidence of serious adverse
effects. It has been used safely in pregnant women and is the treatment of choice for refractory CSU
during pregnancy [23,24]. The adverse effects of omalizumab are discussed separately. (See "Anti-
IgE therapy", section on 'Adverse effects'.)
Monitoring — No specific laboratory monitoring is required for patients receiving omalizumab for
CSU.
Our approach
Initial dosing — We initiate omalizumab at a dose of 300 mg injected subcutaneously every four
weeks based on studies of efficacy that evaluated different dosing approaches [11,16]. We continue
nonsedating H1 antihistamines initially and then taper as tolerated if the patient responds well to
omalizumab. Patients must be prescribed an epinephrine autoinjector because anaphylaxis is
reported, although not at rates any higher than with other biologic therapies. (See "Anti-IgE therapy",
section on 'Anaphylaxis'.)
Expected response — In an analysis of multiple trials intended to evaluate the extent and time
course of the response to omalizumab, approximately 60 percent of patients had a meaningful
reduction in symptoms by week 12 [25]. Benefit was frequently seen in the first month, and a majority
of patients responded within four months (three doses). Approximately 40 percent of patients
became asymptomatic (ie, complete response) by week 12 and about 45 percent by week 24 (in the
longer studies). Thus, the analysis suggested that there is a group of early responders (<1 month)
and a smaller group who respond later. Overall, a period of 16 weeks should be sufficient to identify
patients who will benefit.
A meta-analysis was performed on 67 observational studies (randomized trials were excluded) in an

effort to describe the "real-world" benefits and risks of omalizumab therapy [26]. In contrast to a
meta-analysis of randomized trials, such an analysis provides an estimate of the effects of therapy
combined with possible placebo effect (see 'Efficacy' above). Outcomes were expressed as
improvement in the weekly Urticaria Activity Score (UAS7), which ranges from 0 to 42, with higher
scores indicating more severe symptoms. Omalizumab therapy was associated with a reduction in
UAS7 scores of 26 points (95% CI 28-23 points). Approximately 72 percent of patients had a
complete response, and approximately 18 percent had a partial response. The rate of adverse events
was 4 percent, with three patients experiencing anaphylaxis.
1925
Dose adjustment and duration of therapy — The optimal duration of therapy has not been
determined, and patients may relapse when omalizumab is tapered or discontinued [22]. Approaches
to tapering therapy have not been studied extensively, although an algorithm has been proposed by
one group [27]. The approach of the author and section editors is described here. We consider the
severity of disease and duration of CSU, with a more gradual step-down approach for patients with
very severe or long-term CSU. For example, in a patient with a history of refractory CSU for many
years (eg, ≥3 years) who responds to omalizumab, we would treat for a minimum of one year before
considering tapering.
● If the patient has complete resolution of symptoms and no breakthrough symptoms for two to
three months, the dose may be lowered (to 150 mg), and the interval between injections can be
gradually lengthened. If a patient has no symptoms for a period of time on 150 mg every eight
weeks, therapy can be stopped. Other experts (including the author) maintain a dose of 300 mg
monthly, prolong the interval by one week per cycle, and discontinue therapy if the patient's
disease remains controlled with eight-week intervals [28].
● If the patient has complete resolution of symptoms and no breakthrough symptoms for two to
three months, the approach of the author and other experts is to lengthen the interval between
doses by one week per cycle. If the patient's symptoms remain controlled with eight-week
intervals, therapy can be discontinued [28]. Another approach is to lower the dose gradually.
These two approaches have not been formally compared.
● For patients with partial responses to omalizumab at 300 mg, there is anecdotal evidence that
some may have further improvement with higher doses (450 or 600 mg every four weeks) or
more frequent doses (eg, 150 mg every two weeks) [12,13,29]. A response to the increased dose
should be evident after three doses.
● If the patient has minimal or inadequate control of symptoms despite the addition of
omalizumab, therapy should be discontinued after a four-month trial and other options explored.
● Patients who were treated in the past and stopped therapy but then had a subsequent
recurrence of CSU have been reported to respond to omalizumab again, suggesting that
resistance does not develop readily in most patients [22,30,31].
OTHER THERAPIES
For patients who have not achieved adequate relief with the combination of higher-dose H1
antihistamines and omalizumab or do not have access to omalizumab, several other therapies can
1926
be tried, including cyclosporine, tacrolimus, mycophenolate, dapsone, sulfasalazine, and
hydroxychloroquine [32-34].
Alternative non-US Food and Drug Administration (FDA)-approved agents for CSU can be divided into
two groups: "immunosuppressant" agents and "anti-inflammatory" agents, although there is
considerable overlap between the latter two groups of drugs.
● The term "immunosuppressant" is applied to drugs that have more potent immunosuppression
activity and greater potential toxicity, as well as more evidence for efficacy. We have categorized
the calcineurin inhibitors and mycophenolate mofetil in this way.
● "Anti-inflammatory" denotes a class of agents with predominantly anti-inflammatory activities,

which have low potential toxicity and less proven efficacy for CSU. We have applied this term to
dapsone, sulfasalazine, and hydroxychloroquine.
With the immunosuppressant and anti-inflammatory drugs described in this section, therapy is
generally continued for a period of several months once control of symptoms has been achieved. We
favor a longer duration of therapy before attempting to taper for patients with longstanding CSU.
In the author's experience, serious adverse effects that require discontinuation of therapy are rare,
and he has not observed any permanent complications from use of these agents [32].
Choice of agent — Of the drugs that have been studied in CSU, some have the advantage of a rapid
onset of action, such as cyclosporine and tacrolimus, which can be helpful for patients with
significant impairment in quality of life or side effects from glucocorticoids. The international
guidelines emphasize cyclosporine over other agents, but the authors and editors of this topic
consider a wider range of options [1,32]. There is insufficient evidence on which to base a strong
preference for one drug over another.
Cyclosporine — Cyclosporine (and tacrolimus) has several desirable properties, including rapid onset
(sometimes within days) [35-38], a degree of efficacy comparable with prednisone [4,39], and the
possibility of lasting remission after treatment is discontinued [38,40,41]. Cyclosporine has the most
supporting data. However, cyclosporine has potentially serious adverse effects (ie, hypertension and
renal insufficiency) as well as unpleasant cosmetic effects with long-term use (ie, hirsutism and
gingival hyperplasia), although these are less common at the doses used for CSU, which are
significantly lower than the doses used for most other indications [42]. Cyclosporine should be
avoided in patients with chronic kidney disease or poorly controlled hypertension.
Calcineurin inhibitors block the calcium-dependent release of and responsiveness to histamine,

leukotriene C4, and other mediators in mast cells and several cell types [43]. These agents also have
1927
anti-T lymphocyte activity [44]. Cyclosporine may also disrupt tumor necrosis factor-alpha activity
and secondarily inhibit neutrophil accumulation [45].
Efficacy — A 2018 systemic review identified 18 studies, including two randomized-controlled

trials of cyclosporine for CSU [46]. Early studies described significant improvement with relatively
high doses (5 to 6 mg per kg daily), but patients often discontinued therapy because of adverse
effects, with relapse of their urticaria [39,47]. Most subsequent studies have used lower doses (eg, 2
to 4 mg per kg daily), as well as the strategy of starting high and tapering down to the lowest
effective dose [36,37,40,48-52]. Pediatric studies also used the lower dose range [53].
In a representative trial, 30 patients with CSU refractory to standard doses of antihistamine were
randomized to cyclosporine (4 mg per kg daily) or placebo for four weeks [54]. Initial nonresponders
were offered open-label cyclosporine for four weeks. Eight of 19 (42 percent) receiving cyclosporine
improved, compared with none receiving placebo. In addition, 11 of 17 initial nonresponders
responded after an additional four weeks of open-label treatment. Mild adverse effects were
common in this study (29 of 30 subjects).
Dosing — The optimal dose of cyclosporine for CSU has not been determined. As recommended
by the authors of the aforementioned systematic review, we also suggest starting with a dose of 3
mg per kg, divided into two doses. For most adults, this is 100 to 150 mg twice daily. Cyclosporine is
available in modified and nonmodified formulations. We prefer using modified cyclosporine, as it
exhibits increased bioavailability and less erratic absorption. Some patients respond within one week
or two, and most patients who will respond improve within three months.
Blood pressure, blood urea nitrogen, and creatinine should be monitored monthly, and fasting lipids
should be monitored initially and yearly for patients who remain on therapy. [55]. Serum levels may
be followed to ensure that the dose is not excessive, although we do not find this useful, because the
optimal therapeutic level for CSU has not been defined, high levels are rare with the low doses we
suggest, and drug levels do not seem to correlate with effectiveness in CSU.
Mild adverse effects include paresthesias, gastrointestinal symptoms, and headache and are dose-
related. Dose reduction may eliminate these. Severe side effects are uncommon and should prompt
discontinuation. These include hypertension and renal insufficiency. Cyclosporine is contraindicated
in patients with uncontrolled hypertension. (See "Pharmacology of cyclosporine and tacrolimus".)
The optimal duration of therapy with cyclosporine is not known. We typically treat patients at a dose
required for complete or near-complete control of urticaria for three months and then taper the dose
over several months, as tolerated. In the majority of patients, six to nine months of treatment is
adequate, although some require long-term therapy (two or three years) at the lowest effective dose
[56].
1928
Tacrolimus — Data in support of the use of tacrolimus in CSU are limited [57,58]. Despite this, the
author prefers tacrolimus over cyclosporine because of an apparent lower rate of problematic side
effects with it. In particular, tacrolimus does not cause the hirsutism and gingival hyperplasia that
can be seen with cyclosporine. However, like cyclosporine, it should be avoided in patients with
chronic kidney disease or poorly controlled hypertension. Baseline laboratories including renal
function are required prior to starting calcineurin inhibitors.
We start tacrolimus at a dose of 1 mg twice daily for one to two weeks and then increase by 1 to 2
mg increments every few weeks, up to a maximum of 3 mg twice daily. In our experience, most
patients respond to doses ≤4 mg daily of tacrolimus. Higher doses with monitoring of drug levels can
be used in patients who partially respond or have no response to lower doses. Similar to
cyclosporine, monitoring of renal function is recommended to avoid renal toxicity [59-64].
The largest study of tacrolimus was a retrospective review of 36 patients treated with 45 distinct
courses [58]. Remission (ie, no urticaria for >1 month after treatment was discontinued, with no need
for other medications) occurred in 25 percent of courses, complete response occurred (no
symptoms >1 month while on tacrolimus) in 30 percent of courses, and partial response was seen in
23 percent of courses. An additional 23 percent of courses had no improvement with tacrolimus. The
mean length of therapy was 9.2 months. Therapy was generally well-tolerated, with gastrointestinal
symptoms in eight patients, mild hypertension in three patients and reversible elevations in serum
creatinine in four patients.
Mycophenolate — Mycophenolate mofetil acts as an antimetabolite selectively for lymphocytes and

also impairs expression of adhesion molecules and secondary leukocyte migration [65]. Although
unrelated to the calcineurin inhibitors, mycophenolate has some of the same properties with fewer
reported adverse effects. However, it works more gradually than the calcineurin inhibitors, and it is
rare to see an effect within days.
Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased by 500 mg
twice daily at monthly intervals if needed, up to a maximal dose of 2000 mg twice daily. We rarely
exceed 4000 mg daily. If there has been no improvement after one month of 2000 mg twice daily, we
discontinue it.
It is generally well-tolerated. The most common problems are gastrointestinal symptoms and
leukopenia. Complete blood counts (CBCs) should be performed after the first one to two weeks of
therapy and then once every six to eight weeks thereafter if no cytopenias are noted. (See
"Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
Very few studies are available on the use of mycophenolate in CSU:
1929
● An open series evaluated nine patients with "severe" CSU, defined as symptoms unresponsive
over a six-week period to antihistamines and/or more than two week-long courses of oral
glucocorticoids. Patients were treated with mycophenolate (1000 mg twice daily) for 12 weeks,
without dose escalation [66]. Six patients experienced marked improvement in urticaria scores,
all patients were able to discontinue glucocorticoids by the end of the 12-week trial, and
improvement persisted for at least six months after discontinuation.
● In another series of 19 patients, the majority of whom failed other alternative therapies, doses
ranging from 1 to 6 grams (divided into twice daily dosing) were administered [67]. Time to initial
response ranged from 1 to 9 weeks, and complete control of symptoms was achieved in 60
percent, after a mean treatment period of 14 weeks. Subjects who tapered off the drug
subsequently had remissions lasting between 2 and 16 weeks at the conclusion of the study.
Gastrointestinal adverse effects occurred in 53 percent of subjects.
Sulfones (dapsone and sulfasalazine) — The sulfone medications dapsone and sulfasalazine have
both been studied in CSU. Dapsone is a sulfone antimicrobial agent. Sulfasalazine is an anti-
inflammatory 5-aminosalicylic acid (5-ASA) derivative. The author prefers dapsone over
sulfasalazine but prefers sulfasalazine for patients with underlying anemia. Both dapsone and
sulfasalazine can be combined with hydroxychloroquine. (See 'Combined with a sulfone' below.)
Dapsone — Dapsone may provide benefit in CSU by suppressing prostaglandin and leukotriene
activity, interfering with release or function of neutrophil lysosomal enzymes [68,69], disrupting
integrin-mediated neutrophil adhesiveness [70], inhibiting neutrophil recruitment and activation
signals [71], and scavenging oxygen-free radical intermediates [72]. Dapsone has traditionally been
thought to be helpful in cutaneous diseases in which neutrophils play a prominent role [73]. Some
cases of CSU have a neutrophil-rich infiltrate on biopsy, although whether this histopathologic finding
predicts response to dapsone in patients with CSU is unproven.
Prior to initiating dapsone therapy, we check a CBC, liver function tests, and glucose-6-phosphate
dehydrogenase (G6PD) levels. Dapsone can cause severe hemolytic anemia in patients with G6PD
deficiency, and it is contraindicated in patients with this disorder. We also avoid this agent if the
patient is already anemic or has any abnormalities in hepatic function. The various diagnostic tests
for G6PD deficiency are discussed separately. (See "Drug-induced hemolytic anemia" and "Diagnosis
and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Diagnostic
evaluation'.)
In adults, we start dapsone with a dose of 100 mg daily. In two weeks, we obtain a CBC and liver
function tests and repeat these monthly for three months and then less often. A 10 to 20 percent
decline in hemoglobin (1 to 2 grams/dL) or hematocrit is common, even in patients who do not have
1930
G6PD deficiency, and we do not stop therapy unless the decrease exceeds 25 percent. The dose can
be reduced once there is a clear clinical response. A four-week trial is usually sufficient to determine
effectiveness.
Peripheral neuropathy, clinically significant methemoglobinemia, agranulocytosis, and drug-allergic

reactions, such as drug reaction with eosinophilia and systemic symptoms/drug-induced
hypersensitivity syndrome (DRESS/DiHS), are rare but serious reactions that warrant immediate
discontinuation of dapsone [74,75]. (See "Methemoglobinemia".)
Studies indicating that dapsone is effective for the treatment of CSU include two small, randomized
trials [76,77]. In the more rigorous trial, 22 patients with antihistamine refractory CSU showed
improvement in itch and urticaria scores in patients taking dapsone, 100 mg daily [76]. In all
responders, efficacy was apparent within the first week. Three patients had complete resolution of
CSU with dapsone [77].
A larger retrospective review included 79 patients with CSU refractory to four times the standard
dose of nonsedating antihistamines [78]. Some had additionally failed one or more other agents (ie,
glucocorticoids, omalizumab, cyclosporine, mycophenolate mofetil, leukotriene inhibitors, H2
antagonists, and/or nifedipine). Improvement was seen in 62 patients in a mean of 1.1 months, with
the mean maximal dose of 118 mg daily. In addition, 29 of these individuals had complete resolution
after a mean of 5.2 months. Dapsone was tapered down after 2 months of controlled symptoms, and
10 patients had sustained remission, for periods up to 16 months. However, two patients developed
serious adverse effects (DRESS/DiHS and methemoglobinemia).
The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did not
respond significantly to antihistamines in the past, we taper these first, and then the dapsone is
reduced over a period of several months, as tolerated.
Sulfasalazine — We choose sulfasalazine instead of dapsone for patients with underlying anemia
and sometimes initiate therapy with the combination of sulfasalazine and hydroxychloroquine. (See
'Combined with a sulfone' below.)
Mechanisms of action with possible relevance in CSU include alteration of adenosine release [79],
decreased leukotriene and prostaglandin synthesis, inhibition of IgE-mediated mast cell
degranulation [80], attenuation of neutrophil respiratory burst [81], and inhibition of early-phase
events in the proliferation and differentiation of B lymphocytes [82]. Sulfasalazine is metabolized to
sulfapyridine and 5-ASA within the gastrointestinal tract, and most of the 5-ASA is degraded locally
in the colon without much systemic distribution. Thus, the sulfapyridine may be largely responsible
for its therapeutic activity in patients with CSU.
1931
In adults, sulfasalazine therapy can be initiated with 500 mg once or twice per day for one week and
then gradually increased to 1 gram twice per day.
Overall, sulfasalazine is well-tolerated by most patients. Side effects include nausea, headache, mild
or transient leukopenia, and transaminitis. Rare reports of agranulocytosis exist. Folate supplements
should be coadministered to women who are pregnant or could potentially conceive. Drawbacks
include the advisability of gradual dose escalation, which may prolong the time to clinical response,
as well as the need for laboratory monitoring.
Laboratory monitoring with a CBC, liver function tests, and urinalysis is performed every month for
the first three months and then less often. A four- to six-week trial is usually sufficient to determine
effectiveness. British guidelines recommend monitoring with CBC, blood urea nitrogen, creatinine,
electrolytes, and liver function tests monthly during the first three months and then every three
months thereafter [55]. Other guidelines suggested weekly or every other week blood counts and
transaminases during the first month. Monitoring in patients with rheumatologic diseases is
reviewed in greater detail elsewhere. (See "Sulfasalazine: Pharmacology, administration, and adverse
effects in the treatment of rheumatoid arthritis", section on 'Dosing and monitoring'.)
Observational studies suggest that sulfasalazine is useful as an add-on to standard therapies for
patients with refractory symptoms [83-87]:
The largest study was a retrospective chart review of 39 patients with CSU refractory to
antihistamines and other therapies treated with sulfasalazine as an add-on therapy [83]. These
patients had relatively recalcitrant disease and had CSU on average for 5.5 years prior to starting
sulfasalazine, during which one-third required daily glucocorticoids and 10 percent had received
other immunomodulators (dapsone, cyclosporine, mycophenolate). Sulfasalazine treatment was
added to existing therapies starting with 500 mg daily and increased by 500 mg per week to 2000 mg
daily (and up to 3000 mg daily in 15 patients) if tolerated, and laboratories remained normal. Using
this approach, 84 percent of patients improved within three months. The percentage becoming
asymptomatic on sulfasalazine on the background of antihistamines was 32 and 51 percent by three
and six months, respectively. The average duration of sulfasalazine therapy was 74 weeks. Nine of
10 steroid-dependent patients were able to discontinue glucocorticoids. Once the patient's
symptoms were controlled, sulfasalazine was gradually withdrawn, while antihistamines were
continued throughout in most patients and withdrawn last. Eleven patients remained asymptomatic
after sulfasalazine was discontinued, requiring only antihistamine therapy. Five patients (16 percent)
failed therapy, either due to a drug adverse effect (one) or lack of improvement. There were two
serious adverse events (neutropenia and leukopenia and rhabdomyolysis of uncertain association),
although both patients recovered fully after the drug was discontinued.
1932
The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did not
respond significantly to antihistamines in the past, we taper these first, and then the sulfasalazine is
reduced over a period of several months, as tolerated.
Hydroxychloroquine — Hydroxychloroquine is an anti-inflammatory drug and antimalarial agent. The

relative safety and low cost of hydroxychloroquine makes it a reasonable agent in the treatment of
refractory CSU. The major disadvantage is a relatively slow onset of action. This can be countered by
starting hydroxychloroquine in combination with dapsone or sulfasalazine. (See 'Combined with a
sulfone' below.)
Mechanisms of action include suppression of T lymphocyte activation [88] and disruption of antigen
processing and other cellular processes by alkalinization of intracellular vacuoles in macrophages
and other antigen-presenting cells [89]. Hydroxychloroquine has not been shown to induce lasting
remission [34].
In adults, we start with a dose of 200 mg twice per day. A three-month trial is usually required to
determine effectiveness. Hydroxychloroquine rarely causes serious side effects. The most common
adverse reactions are related to the gastrointestinal tract (nausea), skin (various macular lesions),
and central nervous system (headache).
Ophthalmologic problems, including corneal deposits (reversible) and retinopathy (potentially vision
threatening), are possible but rare with the low daily doses of hydroxychloroquine used in CSU. The
issue of ophthalmologic screening is reviewed separately. (See "Antimalarial drugs in the treatment
of rheumatic disease", section on 'Routine eye examinations'.)
There are limited data on efficacy. In the best available study, 18 patients with CSU were treated with
a combination of therapies for CSU (H1 antihistamines, H2 antihistamines, glucocorticoids, and
doxepin) and randomized to receive either hydroxychloroquine (5 mg/kg daily) or no additional drug
[90]. After three months of treatment, patients in the hydroxychloroquine arm demonstrated
improved quality of life. Hydroxychloroquine was well-tolerated, and there was a trend (not reaching
significance) toward reduced medication use and urticarial activity.
Combined with a sulfone — A treatment strategy used successfully by the author to circumvent
the long latency time of hydroxychloroquine is to start either dapsone or sulfasalazine at the same
time. If the patient responds within a few weeks, the hydroxychloroquine can be discontinued, as it
was unlikely to have been responsible for the improvement. If no benefit is apparent with dual
therapy after four to six weeks, then the hydroxychloroquine is likely responsible for the
improvement, and the other agent (dapsone or sulfasalazine) may be discontinued. This approach
has not been formally studied.
1933
INVESTIGATIONAL AGENTS
Other biologics are under investigation for the treatment of refractory CSU, including the high-affinity
anti-IgE monoclonal antibody ligelizumab [91] and the anti-IL-4 and IL-13 monoclonal dupilumab
[92,93].
A phase 2, dose-finding randomized trial compared ligelizumab at three doses (24 mg, 72 mg, and
240 mg) to omalizumab (300 mg) or placebo, all given monthly, in over 338 adults with moderate to
severe CSU despite H1 antihistamines at usual or high doses, in combination with H2 antihistamines
and leukotriene antagonists [91]. The primary endpoint was complete control of hives at week 12,
which was achieved in 30, 51, and 42 percent of the ligelizumab treated subjects, compared with 26
percent of those receiving omalizumab and none in the placebo group. Ligelizumab was well
tolerated, with mild to moderate injection site reactions being the main treatment-related adverse
reaction. Higher doses of ligelizumab had a more prolonged effect after discontinuation with loss of
complete response occurring 10.5 weeks after discontinuation of the 240 mg dose.
RARELY USED THERAPIES
There are additional agents that have been reported to be useful in the management of CSU,
although each has significant limitations, including one or more of the following:
● High cost combined with limited evidence of benefit (eg, immune globulin)
● Limited evidence of benefit (eg, colchicine, methotrexate [94], methylxanthines, phototherapy)
● The potential for serious adverse effects (eg, methotrexate, tumor necrosis factor [TNF]-
inhibitors, cyclophosphamide, antifibrinolytics, anticoagulants, androgens)
Phototherapy: Phototherapy (eg, either psoralen plus ultraviolet A [PUVA] or narrow band UVB and
UVA) have been shown to have modest clinical benefit in CSU [95-98]. In a randomized trial of 50
patients with CSU refractory to H1 antihistamines (escalated to fourfold the standard dose for at
least three months) and requiring repeated courses of oral glucocorticoids, subjects received either
PUVA or narrow band UVB for 90 days [99]. There was no placebo group. Subjects in both treatment
groups had statistically and clinically significant improvement, with greater improvement in the UVB
group, and the authors noted that most responders had continued benefit for up to one year.
However, very few patients had complete control of hives, and adverse effects included tanning and
xerosis of the skin. In addition, the mean IgE was quite high in this population of patients from India
(403 to 721 international units/mL), raising questions regarding the generalizability of the findings.
1934
Phototherapy is a reasonable option for patients able to commit to frequent visits or for those
intolerant to systemic medications. Skin that is directly irradiated improves most dramatically,
suggesting local mediators and cells as primary targets. Histamine release from mast cells may also
be reduced [100]. It has also been used in the management of solar urticaria and other physical
urticarias. Phototherapy and its longer-term adverse effects are discussed in greater detail
separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "Physical (inducible)
forms of urticaria", section on 'Solar urticaria'.)
There are several other agents with weak evidence of efficacy in CSU.
● Sirolimus (rapamycin) was reported to be effective in two of three patients in a case report [101].
The patients had previously failed multiple alternative therapies, including montelukast,
dapsone, hydroxychloroquine, colchicine, olsalazine, and mycophenolate mofetil.
● Immune globulin (given intravenously or subcutaneously) may be an option in patients in whom

an immunomodulator would be preferable to an immunosuppressive agent, such as those with a
history of malignancy. It is an immunomodulatory agent that alters cell adhesion,
immunoregulatory molecules, complement function, cytokine levels, autoantibody production,
and anti-idiotypic networks [102]. Dosing has varied in past trials. The optimal dose, number of
infusions to administer, and schedule for CSU are unknown and have ranged from a single dose
of 2 grams per kg to 0.15 grams per kg, given monthly [103-110]. Similar to omalizumab, barriers
to use include expense, approval by insurance carriers, and inconvenience. (See "Overview of
intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse
effects".)
● Tumor necrosis factor (TNF)-inhibitors, including etanercept, adalimumab, and infliximab, have
been studied in the treatment of CSU because TNF-alpha has been shown to be upregulated in
the epidermis in lesional and nonlesional skin of CSU patients relative to controls [111]. We
would consider TNF-inhibitors in patients who have failed omalizumab, calcineurin inhibitors,
and anti-inflammatory agents. Reports of effectiveness are limited [112,113]. In the largest
series, 25 patients with CSU refractory to omalizumab, cyclosporine, prednisone, and
azathioprine were treated with adalimumab or etanercept for 3 to 35 months, with responses in
10 of 17 and 5 of 8, respectively [113]. Sixty percent obtained complete or near-complete control
of symptoms. One patient experienced a severe adverse effect (polyneuropathy).
Optimal dosing of TNF-inhibitors for CSU is unknown, but doses similar to those for other
cutaneous diseases have been used. As with omalizumab, barriers to use include expense and
inconvenience. TNF-inhibitors have several adverse effects, including injection-site or infusion-
1935
related reactions, infectious complications, and others. (See "Tumor necrosis factor-alpha
inhibitors: An overview of adverse effects".)
● Methotrexate reduces neutrophil accumulation in inflamed skin [114], diminishes activated

leukocyte adhesiveness and other adenosine-mediated anti-inflammatory properties [115],
decreases leukotriene synthesis [116], and alters cytokine activity [117]. Adverse effects can be
serious, and frequent monitoring is advised. These issues are reviewed elsewhere. (See "Major
side effects of low-dose methotrexate".)
Evidence of efficacy in CSU is limited to case reports and small series [118-123]. The doses of
methotrexate required ranged from 5 to 25 mg/week. Effects were typically observed after four
weeks of therapy. The authors do not state whether patients could be removed from therapy.
Negative studies also exist [109].
● Colchicine may act to relieve CSU by suppressing leukotriene generation or by decreasing

leukocyte adhesiveness and migration, but our clinical experience with it has been disappointing
[124,125]. It has a favorable safety profile at recommended doses, minimal requirements for
monitoring, and a generally rapid onset of action. However, evidence of benefit in patients with
CSU is limited to anecdotal reports and retrospective series [126-128]. The single available
randomized-controlled trial evaluated 12 patients with delayed-pressure urticaria and failed to
demonstrate any effect compared with placebo [129].
● Cyclophosphamide has generally been reserved for patients in whom multiple other alternative
agents have failed. It is believed to act on plasma cells to reduce autoantibody production in
autoimmune CSU [130]. Evidence of efficacy is limited to case reports of patients with positive
autologous serum skin tests who had failed multiple other therapies, including cyclosporine
[131-133]. In one report, improvement began four weeks into the initial infusions and continued
to complete resolution by six months [131]. The patient continued to be asymptomatic 12
months after the last infusion. Cyclophosphamide use is limited by expense, inconvenience,
need for monitoring, and risk of serious adverse effects (including delayed secondary neoplasia
and hemorrhagic cystitis).
● Several anticoagulants and antifibrinolytic agents have been studied in CSU because the
inflammatory pathways believed relevant to urticaria/angioedema are interconnected with
pathways of coagulation and fibrinolysis [134,135]. Agents acting on different points in these
pathways theoretically shunt mediators along altered routes and reduce prourticarial factors.
Antifibrinolytic agents (aprotinin and tranexamic acid) have long been used to treat disorders of
angioedema, and their utility in some patients with CSU was first noted in the 1970s [136-139].
1936
The anticoagulants warfarin and heparin were also studied in CSU [135,140-146]. However, the
risks of these agents generally outweigh the potential benefits.
● Methylxanthines have also been used to treat CSU [147,148]. A double-blind, placebo-controlled
study of 134 CSU patients evaluated theophylline 200 mg twice daily for six months followed by
200 mg once daily for six months, as add-on therapy to cetirizine [148]. Both groups experienced
large improvements in all symptoms assessed, and the theophylline group had statistically
significant improvement in overall urticaria scores. However, pruritus did not improve.
subjects by searching on "patient education" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Chronic hives (The Basics)")
● Chronic spontaneous urticaria (CSU) is considered refractory when symptoms are not controlled
by higher-dose, nonsedating H1 antihistamines in combination with other standard therapies (ie,
additional H1 antihistamines, H2 antihistamines, and/or antileukotriene drugs). (See "Chronic
spontaneous urticaria: Standard management and patient education".)
1937
● Patients with refractory CSU should be referred to an allergy or dermatology specialist for
consideration of advanced therapies, rather than receiving repeated courses of oral
glucocorticoids. (See 'Referral' above.)
● With the exception of omalizumab, the effectiveness of the other therapies discussed in this
review is supported by low-quality evidence, and the approach presented is largely based on
clinical experience. In addition, there are no biomarkers or clinical features that are useful in
selecting one therapy over another for a specific patient. (See 'Overview' above.)
● For patients with CSU who have significant symptoms despite maximal doses of nonsedating
H1 antihistamines in combination with other standard therapies (additional H1 antihistamines,
H2 antihistamines, and/or antileukotriene drugs), we recommend adding omalizumab therapy in
preference to other agents, with the understanding that the cost of this medication may be
prohibitive in many settings (Grade 1A). We initiate omalizumab at a dose of 300 mg injected
subcutaneously every four weeks. (See 'Omalizumab' above.)
● For patients who have not achieved adequate relief with the combination of higher-dose H1
antihistamines and omalizumab or do not have access to omalizumab, we suggest a calcineurin
inhibitor (ie, cyclosporine or tacrolimus) (Grade 2C). We start cyclosporine at a dose of 3 mg per
kg, divided into two doses daily or tacrolimus at 1 mg twice per day. Blood pressure, blood urea
nitrogen, and creatinine should be monitored. (See 'Cyclosporine' above and 'Tacrolimus' above.)
● Other generally well-tolerated therapies include mycophenolate, dapsone, sulfasalazine, and

hydroxychloroquine. (See 'Other therapies' above.)
1938
GRAPHICS
Comparison of international and American urticarial guidelines
The approach of the 2018 international guideline (left side) and the earlier American practice parameter (right side) are
compared.
EAACI: European Academy of Allergology and Clinical Immunology; WAO: World Allergy Organization; AAAAI: American Academy
of Allergy, Asthma, and Immunology; ACAAI: American College of Allergy, Asthma, and Immunology; sgAH: second-generation
antihistamine; LTRA: leukotriene-receptor antagonist; fgAH: first-generation antihistamine.
* Different spellings as used in the respective guideline.
Reproduced from: Zuberbier T, Bernstein JA. A comparison of the United States and international perspective on chronic urticaria
guidelines. J Allergy Clin Immunol Pract 2018; 6:1144. Illustration used with the permission of Elsevier Inc. All rights reserved.
1939
An overview of angioedema: Pathogenesis and causes

Author: Bruce Zuraw, MD
Section Editor: Sarbjit Saini, MD
INTRODUCTION
Angioedema is self-limited, localized swelling of the skin or mucosal tissues, which results from
extravasation of fluid into the interstitium due to a loss of vascular integrity. Angioedema may occur
in isolation, accompanied by urticaria, or as a component of anaphylaxis.
The pathogenesis and causes of angioedema will be reviewed here. The clinical features, diagnosis,
differential diagnosis, and management of acute angioedema are discussed separately. (See "An
overview of angioedema: Clinical features, diagnosis, and management".)
EPIDEMIOLOGY
Data regarding the epidemiology of angioedema are limited, although it affects both adults and
children and is not a rare disorder. In a retrospective review of all hospital admissions in New York
State over 13 years, angioedema was the second most common "allergic" disease to necessitate
hospitalization, exceeded only by asthma [1]. In this study, the number of angioedema
hospitalizations per year more than doubled during the study period, suggesting that the prevalence
may be increasing.
African Americans were disproportionately affected, as they accounted for 42 percent of the
admissions for angioedema, but only 16 percent of the state's population.
The epidemiology of specific forms of angioedema, such as hereditary angioedema (HAE) due to C1
inhibitor (C1INH) deficiency, is discussed separately. (See "Hereditary angioedema: Epidemiology,
clinical manifestations, exacerbating factors, and prognosis".)
1940
PATHOGENESIS
Angioedema results from a loss of vascular integrity that allows fluid to move into tissues. Exposure
of the vasculature to inflammatory mediators causes dilation and increased permeability of
capillaries and venules. Fluid collects asymmetrically in the areas in which the vasculature has been
altered, and these areas (eg, face, larynx, bowel wall) are not typically gravitationally dependent.
Angioedema differs from the edema associated with cardiovascular, renal, and liver disease (eg,
heart failure, renal failure, venous obstruction). Edema is usually due to an alteration in Starling's
forces, such as an increase in intracapillary pressure or a reduction in the plasma oncotic pressure
(ie, any cause of severe hypoalbuminemia) in the presence of normal vasculature. Edema affects
gravitationally dependent parts of the body and fluid collects symmetrically in those areas. (See
"Pathophysiology and etiology of edema in adults".)
CAUSES
The known causes of angioedema can be subdivided into three groups, depending on the underlying
mechanism (table 1):
● Mast cell-mediated etiologies, in which angioedema results from release of mast cell-derived
mediators that increase vascular permeability. Mast cell-mediated angioedema is associated
with urticaria and/or pruritus in most cases.
● Bradykinin-mediated etiologies, in which angioedema results from the generation of bradykinin,

leads to increased vascular permeability. These forms of angioedema are not associated with
urticaria and/or pruritus and are diagnosed and treated differently from other types of
angioedema. (See "An overview of angioedema: Clinical features, diagnosis, and management".)
● Etiologies of unknown mechanism.
Mast cell-mediated etiologies — Mast cell-mediated angioedema is associated with urticaria and/or
pruritus in many instances. This form of angioedema is pathologically similar to urticaria, although it
takes place in the deeper levels of the dermis and subcutaneous tissues, most often involving the
face or mouth. Mast cells can be activated via several mechanisms (table 2). Activated mast cells
release inflammatory mediators, including histamine, heparin, leukotriene C4, and prostaglandin D2,
which cause dilation of venules in the dermis and enhance venule permeability with resultant tissue
edema. (See "Mast cells: Development, identification, and physiologic roles" and "Mast cells: Surface
receptors and signal transduction" and "Mast cell-derived mediators".)
1941
Mast cell-mediated angioedema is treated with antihistamines and sometimes glucocorticoids.
However, if angioedema is encountered in the setting of anaphylaxis, epinephrine is the most
important intervention. The treatment of mast cell-mediated angioedema is discussed in detail
separately. (See "An overview of angioedema: Clinical features, diagnosis, and management".)
Allergic reactions — Acute angioedema, with or without other symptoms of allergic reactions, may
be triggered by foods, drugs, latex, exercise, the stings of various insects, and a growing list of other
uncommon allergens (table 3). Angioedema is a common component of anaphylaxis, and since
anaphylaxis is treated differently from isolated angioedema (ie, with epinephrine), the clinician must
be vigilant for other signs and symptoms of anaphylaxis (such as urticaria, pruritus, flushing, throat
tightness, bronchospasm, and hypotension) in patients presenting with angioedema.
The classic type of allergic reaction results from immunoglobulin E (IgE)-mediated, Gell and Coombs
type I hypersensitivity (table 4). The reaction typically occurs within minutes to two hours following
exposure to the trigger. However, some IgE-mediated allergic reactions are delayed in onset, such as
allergic reactions to certain meats (lamb, beef, and/or pork) that can lead to reactions with prominent
angioedema, beginning two to six hours after ingestion [2]. (See "Anaphylaxis: Acute diagnosis" and
"Food-induced anaphylaxis" and "Allergy to meats".)
Isolated angioedema is a relatively uncommon presentation of an allergic reaction. In a series of 112

patients with penicillin allergy confirmed by skin testing, only 1 patient had experienced isolated
angioedema without urticaria during the presenting allergic reaction [3]. However, it can occur.
Examples include reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). (See 'Aspirin and
NSAIDs' below.)
Direct mast cell release — Mast cells can be nonspecifically stimulated to release their
proinflammatory mediators by certain medications and pharmaceuticals, such as opiates and
radiocontrast media. This type of angioedema is accompanied by urticaria in most cases. IgE is not
involved, and skin testing or in vitro testing is rarely helpful. (See "Diagnosis and treatment of an
acute reaction to a radiologic contrast agent".)
Aspirin and NSAIDs — Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and
ibuprofen, can cause acute urticaria/angioedema and can exacerbate chronic urticaria/angioedema.
There are six known types of hypersensitivity reactions to NSAIDs, which are often difficult to
distinguish from one another based on clinical history alone (table 5). (See 'Chronic urticaria with or
without angioedema' below and "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)
The more common type of NSAID reaction is believed to be due to the pharmacologic properties of
the medications on mast cells. NSAIDs inhibit the enzyme cyclooxygenase 1 (COX-1), which
mediates the generation of prostaglandins from arachidonic acid within mast cells and other
1942
leukocytes. NSAID administration results in increased formation of proinflammatory mediators,
leading to angioedema in susceptible individuals. NSAIDs that nonselectively inhibit both COX-1 and
COX-2 enzymes (aspirin, ibuprofen, and most others) can potentially induce this effect, and patients
often react to multiple agents. Selective COX-2 inhibitors, such as celecoxib, are tolerated by most
patients who have reacted to nonselective NSAIDs [4], although rare exceptions are reported [5].
Management of patients with these reactions is reviewed separately. (See "NSAIDs (including
aspirin): Allergic and pseudoallergic reactions", section on 'Types 1 to 4: Treatment options'.)
NSAIDs can also cause rare IgE-mediated allergic reactions, and these are typically triggered by a
single agent. The diagnostic approach to NSAID reactions is reviewed separately. (See "NSAIDs
(including aspirin): Allergic and pseudoallergic reactions".)
Chronic urticaria with or without angioedema — Chronic urticaria refers to urticaria that continues
to recur for a period of six weeks or longer [6]. Angioedema is present in at least one-half of patients
with chronic urticaria [7].
Chronic urticaria may persist over months to years and is more common in women, particularly
between the ages of 40 and 50 years. In most cases of chronic urticaria/angioedema, a specific
cause cannot be identified. This disorder is reviewed in more detail separately. (See "Chronic
spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history" and
"Chronic spontaneous urticaria: Standard management and patient education".)
Bradykinin-mediated etiologies — Angioedema can occur due to vasodilation and increased vascular
permeability resulting from other inflammatory mediators, especially bradykinin. Angioedema can
result from either overproduction of bradykinin or inhibition of bradykinin degradation. Mast cells are
not believed to be involved in this form of angioedema, and pruritus and urticaria are absent.
Bradykinin-mediated angioedema, unlike histamine-mediated angioedema, frequently affects the
gastrointestinal mucosa, leading to bowel wall edema and presenting with episodes of abdominal
pain, nausea, vomiting, and/or diarrhea.
Perturbations in kinin pathways resulting directly from the actions of medications (eg, angiotensin-
converting enzyme [ACE] inhibitors) or from deficiencies of C1 inhibitor (C1INH) are the main
recognized causes of bradykinin-mediated angioedema. The treatment of bradykinin-induced
angioedema is discussed separately. (See "An overview of angioedema: Clinical features, diagnosis,
and management".)
Bradykinin-mediated angioedema does not respond to epinephrine, antihistamines, or

glucocorticoids. Instead, this type of angioedema is treated with drugs that act on the bradykinin
pathway (eg, icatibant, ecallantide, lanadelumab), preparations of C1INH concentrate (human), or
plasma replacement (depending on the cause).
1943
ACE inhibitors — Angiotensin-converting enzyme (ACE) inhibitors account for approximately 30
percent of all angioedema cases presenting to emergency departments in both community and
tertiary care settings [8,9]. ACE inhibitors impair bradykinin degradation (figure 1). Angioedema
related to ACE inhibitors most often affects the lips, tongue, mouth, larynx, pharynx, and subglottic
tissues. Urticaria and itching are absent. ACE inhibitors can also cause intestinal edema, and the
sudden onset of abdominal pain, nausea, and sometimes vomiting in an older adult should prompt
inquiries about the use of ACE inhibitors. The epidemiology, pathophysiology, diagnosis, and
management of patients with ACE inhibitor-induced angioedema is discussed separately. (See "ACE
inhibitor-induced angioedema".)
The risk of angioedema with the use of angiotensin-II receptor blockers (ARBs), such as losartan,
valsartan, and telmisartan, appears to be considerably lower than with ACE inhibitors [10-12]. The
development of angioedema following therapy with ARBs is surprising, since these drugs are not
thought to affect kinin metabolism directly (figure 1). The administration of ARBs to a patient with
past ACE inhibitor-induced angioedema is discussed separately. (See "ACE inhibitor-induced
angioedema".)
ACE inhibitors and ARBs may also unmask deficiencies of C1INH [13-16].
DPP-4 inhibitors — Dipeptidyl peptidase-4 (DPP-4) inhibitors (ie, gliptins) can also inhibit
degradation of bradykinin and substance P, and have been associated with an increased risk of
angioedema, especially when used together with immunosuppressive drugs or ACE inhibitors [17].
(See "ACE inhibitor-induced angioedema", section on 'Dipeptidyl peptidase-4 inhibitors'.)
Hereditary and acquired angioedema due to C1 inhibitor deficiency — Angioedema can occur in
patients with abnormalities in the level or function of the regulatory serpin C1 inhibitor (C1INH,
previously referred to as C1 esterase inhibitor), leading to increased generation of bradykinin due to
contact system (also known as plasma kallikrein-kinin system) activation. Angioedema in these
disorders typically asymmetrically affects the face, lips, tongue, throat, ears, hands and feet, bowel
wall, and genitalia and does not characteristically occur in dependent parts of the body. Clinical
manifestations and diagnosis are reviewed in detail separately. (See "Hereditary angioedema:
Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Acquired C1
inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
Summarized briefly, both hereditary and acquired forms of C1INH deficiency exist, with similar
clinical manifestations. The main differences between the two conditions are the age of presentation
and the underlying health of the patient:
● Patients with hereditary angioedema (HAE) typically present in childhood or early adolescence
with angioedema, including recurrent abdominal attacks. Angioedema may follow trauma,
1944
infection, dental procedures, or emotional stress. There is typically an increasing frequency and
severity of episodes with the onset of puberty. Exposure to estrogens, either through
contraception, hormone replacement therapy, or pregnancy, may trigger attacks. These patients
are otherwise healthy.
● In contrast, the acquired form typically occurs at an older age, and most patients have an
associated lymphoproliferative disorder or autoimmune diathesis. (See "Acquired C1 inhibitor
deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on
'Associated disorders'.)
The swelling with both forms of C1INH deficiency can range in severity during a given episode from
a minor inconvenience to life-threatening laryngeal edema. Overall, there is a significant risk of
morbidity and mortality from angioedema attacks.
Hereditary angioedema with normal C1 inhibitor — Familial angioedema with an autosomal

dominant inheritance pattern but normal C1 inhibitor levels has been identified [18]. The clinical
presentation of angioedema in these patients resembles but is subtlety different than HAE due to
C1INH deficiency. (See "Hereditary angioedema with normal C1 inhibitor".)
Specifically, these patients tend to be somewhat older at onset of swelling and have a greater ratio of
orofacial swelling to abdominal swelling than HAE due to C1INH deficiency. Four subtypes of HAE
with normal C1INH are currently recognized:
● HAE-FXII, defined by mutations involving coagulation factor XII

● HAE-Plasminogen, defined by a mutation in the plasminogen gene
● HAE-Angiopoietin-1, defined by a mutation in the angiopoietin-1 gene
● HAE-Unknown, which is the terminology used when patients meet the HAE with normal C1
inhibitor diagnostic criteria but have no recognized mutation
Fibrinolytic agents — Angioedema without urticaria has been reported following fibrinolysis with
streptokinase and alteplase in patients treated acutely for stroke and thrombosis [19,20]. The
swelling associated with fibrinolytic agents is likely bradykinin mediated, as plasmin has been
reported to activate coagulation factor XII of the contact system [21]. This complication is discussed
separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use",
section on 'Angioedema'.)
Etiologies of unknown mechanism — There are several recognized causes of angioedema for which
mechanisms are not defined (table 1). The treatment of these disorders is reviewed separately. (See
"An overview of angioedema: Clinical features, diagnosis, and management".)
1945
Idiopathic angioedema — "Idiopathic angioedema" is the term applied to recurrent episodes of
angioedema without urticaria, for which no explanation can be found after a thorough evaluation to
exclude allergic disorders, drug reactions, and defects in complement pathways. Idiopathic
angioedema may be divided into idiopathic histaminergic angioedema and idiopathic
nonhistaminergic angioedema. The diagnosis and management of idiopathic angioedema are
presented separately. The former is often associated with chronic spontaneous urticaria or inducible
forms of urticaria (ie, physical urticaria). Idiopathic nonhistaminergic angioedema may represent
new probands with HAE-Unknown because the penetrance of HAE with normal C1INH can be
relatively low. (See "An overview of angioedema: Clinical features, diagnosis, and management",
section on 'Recurrent, idiopathic angioedema'.)
Infections — Infections have been associated with angioedema in children, although this is not
well described in adults. In a prospective study of 95 consecutive children with isolated angioedema
(without urticaria or anaphylaxis) referred to an allergy clinic, angioedema was associated with
infection in 19 (21 percent) [22]. Identified infections included the common cold (17 patients),
streptococcal pharyngitis, and urinary tract infection. Infection was the most commonly associated
disorder, followed by allergic etiologies. (See 'Causes in children' below.)
Calcium channel blockers — Both dihydropyridines (eg, amlodipine, nifedipine) and

nondihydropyridines (eg, diltiazem and verapamil) have been associated with angioedema, either of
the skin or small bowel [23-27]. However, no mechanism has been proposed.
Other drugs — Other drugs that have been reported to cause angioedema without urticaria include
sirolimus, everolimus, amiodarone, metoprolol, risperidone, paroxetine, and etanercept and other
biologic agents [28-36]. Inhaled cocaine has been implicated in uvular angioedema [37-40].
Herbal medicines — Several herbal medicines have been associated with angioedema, including
garlic, sanyak, and Ecballium elaterium [41-43].
Other rare causes — Other rare causes of angioedema include selected disorders with
eosinophilia and urticarial vasculitis.
● Disorders with eosinophilia – Angioedema is associated with a peripheral eosinophilia in two

disorders, the hypereosinophilic syndromes (HES) and Gleich syndrome.
• Approximately 15 percent of patients with the HES have angioedema, and this diagnosis
should be considered in patients with dramatic elevations in peripheral eosinophil counts
(eg, ≥1500 eosinophils/microliter) [44,45]. The mechanisms of the angioedema in this
disorder may involve the direct release of vasodilatory mediators from eosinophils or may
1946
reflect the activation of cutaneous mast cells by eosinophil-derived mediators. (See
"Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)
• The entity of episodic angioedema with eosinophilia (Gleich syndrome) is characterized by

recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, elevated serum
immunoglobulin M (IgM), and leukocytosis with marked blood eosinophilia [46-49]. The level
of blood eosinophilia parallels disease activity. The etiology of this syndrome is unknown
but has been associated with upregulation of C5a receptors on eosinophils during episodes
of disease [50]. Gleich syndrome is now considered a type of HES, although the absence of
cardiac damage or other end-organ involvement and the episodic nature of the symptoms
distinguish this condition from other forms of HES. (See "Hypereosinophilic syndromes:
Clinical manifestations, pathophysiology, and diagnosis", section on 'Episodic angioedema
with eosinophilia (Gleich syndrome)'.)
● Urticarial vasculitis – Angioedema may be observed in patients with hypocomplementemic

urticarial vasculitis, in which immunoglobulin G (IgG) anti-C1q is often identified [51,52]. The
urticarial lesions of urticarial vasculitis are variably painful, ecchymotic, and purpuric and often
leave residual bruising upon resolution. Systemic disease and fever may be present. (See
CAUSES IN CHILDREN
There are very few studies of angioedema in children (other than hereditary angioedema [HAE]), and
isolated angioedema (ie, without urticaria or anaphylaxis) appears to be uncommon in this age
group. One study reported on 95 children referred to an allergy clinic and followed prospectively [22].
Most had more than one episode. In 51 percent, no cause could be identified. In the remaining one-
half, the most common associations were common infections (21 percent), followed by various
allergic disorders (14 percent), the presence of thyroid autoimmunity with normal thyroid function (8
percent), and nonsteroidal anti-inflammatory drugs (NSAIDs) (6 percent). One-third of the children
required ongoing treatment with antihistamines, and all improved with this intervention. (See
'Infections' above.)
1947
● Basics topic (see "Patient education: Angioedema (The Basics)" and "Patient education:
Angioedema caused by ACE inhibitor medicines (The Basics)")
SUMMARY
● Angioedema is self-limited, localized swelling of the skin or mucosal tissues. Angioedema may
occur in isolation, accompanied by urticaria, or as a component of anaphylaxis.
● Angioedema results from a loss of vascular integrity, allowing fluid to move into the interstitial
tissues, due to the presence of inflammatory mediators. (See 'Pathogenesis' above.)
● The causes of angioedema can be divided into three groups based on the underlying
mechanism (table 1) (see 'Causes' above):
• Mast cell-mediated angioedema, such as that seen in allergic reactions and reactions to
nonsteroidal anti-inflammatory drugs (NSAIDs). (See 'Mast cell-mediated etiologies' above.)
• Bradykinin-mediated angioedema, such as that induced by angiotensin-converting enzyme

(ACE) inhibitors, hereditary angioedema and acquired C1 inhibitor (C1INH) deficiency. (See
'Bradykinin-mediated etiologies' above.)
• Causes with unknown mechanisms, such as idiopathic angioedema and angioedema

associated with viral infections in children. (See 'Etiologies of unknown mechanism' above.)
ACKNOWLEDGMENT
1948
The editorial staff at UpToDate would like to acknowledge Clifton O Bingham, III, MD, who contributed
to an earlier version of this topic review.
1949
GRAPHICS
Causes of angioedema classified by mechanism
Known or presumed
Mechanism Examples
pathophysiology
Activation of mast cells IgE-mediated mast cell activation (type I Allergic reactions to foods, drugs, latex,
Clinical characteristics – Often associated hypersensitivity) insect stings, other allergens
with pruritus and urticarial. Direct mast cell activation Opioids, radiocontrast agents
May present as part of an allergic reaction Perturbations in arachidonic acid Aspirin and other NSAIDs
or anaphylaxis. metabolism
Immunologic and other non-IgE-mediated Idiopathic histaminergic angioedema, often

mast cell activation associated with chronic spontaneous
urticaria or inducible urticaria
Generation of bradykinin Inhibition of enzymes involved in ACE inhibitors, DPP-4 inhibitors

Clinical characteristics – Not associated degradation of bradykinin
with pruritus or urticaria. Deficiency or dysfunction of complement Hereditary angioedema (also known as
May present with abdominal symptoms C1 inhibitor due to mutation hereditary C1 inhibitor deficiency or
due to bowel wall edema. dysfunction)
Deficiency or dysfunction of complement Acquired C1 inhibitor deficiency

C1 inhibitor often due to anti-C1 inhibitor
antibody or an underlying malignancy
Defects in several genes have been Hereditary angioedema with normal C1

implicated, including those for coagulation inhibitor
factor XII, plasminogen, and angiopoietin-1.
Other cases are idiopathic.
Unknown pathophysiology Idiopathic nonhistaminergic angioedema

Clinical characteristics – Variable. Infections (especially in children)
Sometimes associated with urticaria. Drugs – Calcium channel blockers,
fibrinolytic agents, herbal medicines, other
hypereosinophilic syndrome
Gleich syndrome
IgE: immunoglobulin E; NSAIDs: nonsteroidal anti-inflammatory drugs; ACE inhibitors: angiotensin-converting enzyme inhibitors.
1950
Major causes of mast cell-mediated angioedema
IgE-dependent allergic reactions

Foods
Drugs (antibiotics, local anesthetics, hormones)
Stinging insects
Latex
Contact (fresh fruits and vegetables, animal saliva)
Direct mast cell-mediator release

Opiates
Muscle relaxants (succinylcholine, curare)
Perturbations in arachidonic acid metabolism within mast cells

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
1951
Causes of anaphylaxis
Allergens (IgE-dependent immunologic mechanism)

Foods, especially peanut, tree nut, crustacean shellfish, finned fish, milk, egg
Insect stings (eg, Hymenoptera venom) and insect bites (eg, kissing bugs)
Medications (eg, antibiotics, NSAIDs)
Biologic materials, including allergen immunotherapy, monoclonal antibodies, chemotherapy agents, and vaccines*
Natural rubber latex
Food additives, including spices, insect-derived colorants (eg, carmine), and vegetable gums
Inhalants (rare; eg, horse dander, cat dander, grass pollen)
Human seminal fluid (rare trigger of anaphylaxis in women)
Occupational allergens (eg, stinging insects, natural rubber latex)
Immunologic triggers (IgE-independent mechanism)

IgG dependent (rare; eg, to high-molecular-weight dextran, infliximab)
Coagulation system activation (eg, heparin contaminated with oversulfated chondroitin sulfate)
Idiopathic anaphylaxis
Consider the possibility of a hidden or previously unrecognized trigger
Consider the possibility of a mast cell activation syndrome, including systemic mastocytosis
Nonimmunologic triggers (direct activation of mast cells and basophils)

Physical factors (eg, exercise ¶, cold, heat)
Medications (eg, opioids, NSAIDs)
Alcohol (ethanol; may augment, rarely induces)
Any food, insect sting or bite, or medication or biologic can potentially trigger anaphylaxis. Novel or unusual allergen triggers include
storage mite-contaminated flour and saliva from kissing bugs. They also include mosquitoes, pigeon ticks, green ants, and pharaoh
ants and venoms from jellyfish, scorpions, and snakes. Medications include taxanes, platins, and other chemotherapy drugs, biologic
agents, including monoclonal antibodies, such as rituximab, cetuximab, infliximab, and, uncommonly, omalizumab. Some triggers,
such as radiocontrast media, insect venoms, and medications (such as NSAIDs) can act through more than one mechanism.
IgE: immunoglobulin E; NSAID: nonsteroidal antiinflammatory drug; IgG: immunoglobulin G.

* Reactions to vaccines are rare and typically involve an excipient, such as gelatin, rather than microbial content.
¶ Often involves a cofactor, such as a food, medication (eg, an NSAID), or exposure to cold air or water.
1952
Gell and Coombs classification of immunologic drug reactions
Type Description Mechanism Clinical features
I IgE-mediated, Antigen exposure causes IgE-mediated activation of Anaphylaxis

Immediate reaction immediate-type mast cells and basophils, with release of vasoactive Angioedema
(within one hour) hypersensitivity substances, such as histamine, prostaglandins, and
Bronchospasm
leukotrienes.
Urticaria (hives)
Hypotension
II Antibody-dependent An antigen or hapten that is intimately associated Hemolytic anemia

cytotoxicity with a cell binds to antibody, leading to cell or tissue Thrombocytopenia
injury.
Neutropenia
III Immune complex Damage is caused by formation or deposition of Serum sickness

disease antigen-antibody complexes in vessels or tissue. Arthus reaction
Deposition of immune complexes causes
complement activation and/or recruitment of
neutrophils by interaction of immune complexes
with Fc IgG receptors.
IV Cell-mediated or delayed Antigen exposure activates T cells, which then Contact dermatitis
hypersensitivity mediate tissue injury. Depending upon the type of T Some morbilliform
cell activation and the other effector cells recruited, reactions
different subtypes can be differentiated (ie, types IVa
Severe exfoliative
to IVd).
dermatoses (eg,
SJS/TEN)
AGEP
DRESS/DiHS
Interstitial nephritis
Drug-induced hepatitis
Other presentations
IgE: immunoglobulin E; Fc IgG: Fc portion of immunoglobulin G; SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis; AGEP: acute
generalized exanthematous pustulosis; DRESS/DiHS: drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity
syndrome.
Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18:515.
1953
Pseudoallergic and allergic reactions to nonsteroidal anti-inflammatory drugs (NSAIDs)
Timing of onset of Patient

Type Eliciting NSAID Signs and symptoms
signs/symptoms comorbidities
Pseudoallergic NSAID reactions:

Elicited by multiple NSAIDs (including aspirin) in a susceptible patient
Related to the pharmacologic ability of NSAIDs to inhibit COX-1 enzyme
Type 1 Multiple (including Common: Delayed: 30 minutes to Asthma (present in

aspirin) Severe rhinitis, nasal three hours after most but not all
obstruction ingestion or patients)
Bronchospasm administration Chronic
Conjunctival injection rhinosinusitis with
nasal polyposis
Facial flushing
(patients usually
Uncommon:
have extensive
Throat sinusitis on CT and
tightness/laryngospasm often report
Nausea/vomiting anosmia)
Diarrhea AERD*
Hypotension
Type 2 Multiple (including Urticaria and/or angioedema 30 to 90 minutes Chronic urticaria

aspirin) (patients may report
being able to tolerate
NSAIDs when urticaria
is in remission)
Type 3 Multiple (including Urticaria and/or angioedema 30 to 90 minutes None

aspirin)
Type 4 Multiple (including Symptoms affecting both the Variable depending upon Some patients have
aspirin) respiratory tract and skin. the type of reaction: 30 AERD and
Includes patients with AERD to 90 minutes experience systemic
who develop cutaneous reactions with
symptoms in the context of cutaneous
respiratory reactions. symptoms
Other patients have
no underlying
conditions
Allergic NSAID reactions:

Elicited by a single NSAID (or rarely by more than one agent with very similar structure) in a susceptible patient
Not reported with aspirin
Presumed to be IgE-mediated
Type 5 A single NSAID (not Cutaneous: Urticaria, pruritus, Variable: Minutes to a None
aspirin) angioedema few hours after
ingestion/administration
Type 6 A single NSAID (not Anaphylaxis (probably a more Variable: Minutes to a None
aspirin) severe form of type 5) few hours after
ingestion/administration
COX-1: cyclooxygenase, isoform 1; CT: computed tomography; AERD: aspirin-exacerbated respiratory disease; IgE: immunoglobulin E.
* AERD refers to the triad of asthma, chronic rhinosinusitis with nasal polyposis, and aspirin (or NSAID)-induced type 1 pseudoallergic
reactions.
1954
Actions of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers on angiotensin and kinin pathways
Left side of figure: ACE normally converts angiotension I to angiotension II, and ACE inhibitors
(ACEIs) inhibit this reaction.
Right side of figure: In the presence of ACEIs, bradykinin is not degraded and binds to bradykinin B 2
receptors.
ACE: angiotensin-converting enzyme; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II

receptor blocker.
1955
An overview of angioedema: Clinical features, diagnosis, and management

INTRODUCTION
Angioedema is self-limited, localized subcutaneous (or submucosal) swelling, which results from extravasation of fluid into interstitial
tissues. Angioedema may occur in isolation, accompanied by urticaria, or as a component of anaphylaxis.
The clinical features, diagnosis, differential diagnosis, and management of angioedema will be reviewed here. The pathogenesis and
causes of angioedema are discussed separately. (See "An overview of angioedema: Pathogenesis and causes".)
CLINICAL FEATURES
Angioedema typically affects areas with loose connective tissue, such as the face, lips, mouth, and throat, larynx, uvula, extremities,
and genitalia. Bowel wall angioedema presents as colicky abdominal pain.
Angioedema can be distinguished clinically from other forms of edema by the following characteristics:
● Onset in minutes to hours and spontaneous resolution in hours to a few days

● Asymmetric distribution
● Tendency not to involve gravitationally-dependent areas
● Involvement of face, lips, larynx, and bowels
● Association of some forms of angioedema with other signs and symptoms of allergic reactions or anaphylaxis
Types of angioedema — Two types of angioedema can be distinguished: mast cell-mediated, also called histaminergic angioedema,
and bradykinin-mediated angioedema. However, for many of the known triggers of angioedema, the mechanism is unclear. (See "An
overview of angioedema: Pathogenesis and causes".)
● In mast cell-mediated angioedema, such as allergic reactions to foods or insect stings, there are often (not always) other signs
and symptoms of mast cell-mediator release. Histamine is a prominent mediator, and this type of angioedema is also called
histaminergic. Signs and symptoms of mast cell-mediated reactions include urticaria, flushing, generalized pruritus,
bronchospasm, throat tightness, and/or hypotension. Patients with additional symptoms affecting organ systems other than the
skin may be experiencing anaphylaxis and should be treated immediately with epinephrine (figure 1 and table 1). Mast cell-
mediated angioedema usually begins within minutes of exposure to the allergen, builds over a few hours, and resolves in 24 to 48
hours. (See "An overview of angioedema: Pathogenesis and causes", section on 'Mast cell-mediated etiologies'.)
Angioedema may also be histamine-mediated (histaminergic) without clear evidence of mast cell degranulation. This is typically
seen for idiopathic (also known as spontaneous) angioedema. In these cases, angioedema typically occurs alone or with urticaria,
but is not accompanied by respiratory or circulatory symptoms. (See 'Recurrent, idiopathic angioedema' below.)
● Bradykinin-induced angioedema is not associated with urticaria, bronchospasm, or other symptoms of allergic reactions. It has a
somewhat more prolonged time course, usually developing over 24 to 36 hours and resolving within two to four days [1-7]. In this
type of angioedema, the relationship between the trigger and the onset of symptoms is often not apparent. As an example, in
angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, swelling may appear within a week of starting or increasing
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the medications or after years of use. (See "An overview of angioedema: Pathogenesis and causes", section on 'Bradykinin-
mediated etiologies'.)
Anatomic sites
Larynx — Laryngeal edema can develop rapidly (over minutes) or more slowly over several hours. Early symptoms include hoarse
voice, throat tightness, and difficulty swallowing. Assessment and treatment are discussed below. (See 'Angioedema in or near the
airway' below.)
Lips, tongue, and uvula — The lips, tongue, and uvula are other structures that can be affected by angioedema and result in airway
compromise. ACE inhibitor-induced angioedema most commonly presents with swelling of the lips, tongue, or face, although other
causes of angioedema affect these structures as well [8]. In contrast, swelling of the floor of the mouth is more likely to be caused by
tumors, infections, or lithiasis [9].
Skin and mucous membranes — Angioedema affects the subcutaneous and submucosal tissues (picture 1 and picture 2 and
picture 3). Pruritus is absent, unless the angioedema is associated with urticarial lesions, which are intensely pruritic (picture 4). The
skin is either normal in color or mildly erythematous. Mild pain and warmth may be present, but are much less prominent than the pain
and warmth of cellulitis. Some patients describe the discomfort of angioedema as burning in nature. Angioedema resolves without
leaving residual markings on the skin, unless there has been trauma induced by rubbing or scratching.
Bowel wall — Angioedema affecting the bowel wall presents as colicky abdominal pain, sometimes accompanied by nausea,
vomiting, and/or diarrhea. Bowel wall edema can often be visualized by abdominal computed tomography (CT) or ultrasound. Bowel
wall angioedema is occasionally seen in patients on ACE inhibitors and frequently in those with hereditary or acquired C1 inhibitor
deficiency:
● ACE inhibitors should be suspected in an older adult taking these medications and should be stopped [10-14]. (See 'Imaging for
suspected bowel wall edema' below.)
● Acquired C1 inhibitor deficiency also typically presents in older patients. Many patients are found to have an underlying
lymphoproliferative disorder. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and
diagnosis".)
● Hereditary angioedema (HAE) should be considered in an adolescent or adult, particularly if there is a family history of episodic
swelling or recurrent abdominal pain. A more detailed discussion of the evaluation of abdominal pain in patients with HAE is
found separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis",
section on 'Gastrointestinal attacks'.)
Life-threatening situations — Angioedema is usually a benign and transient condition, although it can be life-threatening when severe
angioedema of the larynx, upper airway, or tongue results in airway obstruction. This characteristically happens in anaphylaxis and in
bradykinin-mediated forms of angioedema (ie, ACE inhibitor-induced angioedema or hereditary or acquired C1 inhibitor deficiency).
(See "Anaphylaxis: Emergency treatment", section on 'Airway management'.)
EVALUATION
In patients presenting with angioedema affecting the airway, airway protection must be given priority over a comprehensive diagnostic
evaluation. (See 'Angioedema in or near the airway' below.)
Clinical history — The history should be directed at identifying possible causes, as well as determining if the patient has had previous
episodes of angioedema. Causes are reviewed elsewhere (table 2). (See "An overview of angioedema: Pathogenesis and causes".)
● The patient should be questioned about any unusual exposures (eg, insect stings), activities (eg, exercise), foods, or other
ingestions in the 24 hours before the onset of symptoms.
● A review of the patient's medications is important, with particular attention to the following:
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• Nonsteroidal anti-inflammatory drugs. (See "An overview of angioedema: Pathogenesis and causes", section on 'Aspirin and
NSAIDs'.)
• Angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). The literature concerning
angioedema related to each of these medications is reviewed in detail separately. (See "ACE inhibitor-induced angioedema".)
• Estrogens, as these can increase the frequency of attacks in patients with hereditary angioedema (HAE), although estrogens
are not a cause of angioedema in patients without this disorder. (See "Hereditary angioedema: Epidemiology, clinical
manifestations, exacerbating factors, and prognosis", section on 'Medications'.)
• Any new medications or significant increases in doses of medications [1].
• Patients with previous episodes of angioedema (cutaneous swelling or abdominal pain) should be asked about activities and
exposures surrounding those episodes to see if any pattern is apparent. Individuals with ACE inhibitor-induced angioedema
may have several episodes of swelling before the drug is recognized as the culprit and discontinued [15]. Patients with
recurrent orofacial angioedema after dental work or episodes of unexplained abdominal pain may have hereditary or acquired
C1 inhibitor deficiency.
• Patients should be asked about family members with similar episodes of cutaneous or laryngeal angioedema or with
recurrent abdominal pain to identify families with HAE. However, about 25 percent of patients with HAE have a new mutation
and so do not have a positive family history. (See "Hereditary angioedema: Epidemiology, clinical manifestations,
exacerbating factors, and prognosis".)
Physical examination — Angioedema is localized swelling of the skin or of the mucous membranes of the upper respiratory or
gastrointestinal tracts. It is not gravitationally dependent, and it is usually asymmetrical and nonpitting. The margins of the affected
areas are often diffuse and the skin may be normal colored or slightly erythematous.
The presence of other signs and symptoms of an allergic reaction (or more precisely, of mast cell activation) is helpful in narrowing
the list of possible causes to those that are mast cell-mediated. These signs and symptoms include urticaria, flushing, generalized
pruritus, bronchospasm, throat tightness, and/or hypotension. If one or more of these other signs or symptoms is present, the history
should be directed toward mast cell-mediated etiologies, such as allergic reactions to foods, drugs, and stinging insects (table 3) [16].
(See "An overview of angioedema: Pathogenesis and causes", section on 'Mast cell-mediated etiologies'.)
If signs and symptoms of mast cell activation are absent and if the angioedema is unaccompanied by urticaria and nonresponsive to
antihistamines, then bradykinin-mediated angioedema, such as that caused by ACE inhibitors and the rare disorder hereditary or
acquired C1 inhibitor deficiency, should be considered. (See "An overview of angioedema: Pathogenesis and causes", section on
'Bradykinin-mediated etiologies'.)
Laboratory tests — The laboratory tests that are indicated in a patient presenting with angioedema are influenced by the presence of
other signs and symptoms and by the suspected cause, as described below.
Isolated angioedema — We suggest that the following laboratories be performed in all patients with isolated angioedema: complete
blood count with differential, basic chemistry panel with liver function tests, C-reactive protein (CRP) or erythrocyte sedimentation rate
(ESR), and levels of the complement protein C4.
● Depressed C4 levels should prompt further evaluation for hereditary or acquired C1 inhibitor deficiency. In cases in which the
history suggests a possible diagnosis of HAE or acquired C1 inhibitor deficiency (ie, lack of response to antihistamines or positive
family history), C1 inhibitor antigen and functional levels should also be measured.
● CRP and ESR may be markedly elevated during infections (particularly bacterial) and in the setting of malignancies, and elevated
to a lesser degree in a variety of inflammatory diseases. These disorders are occasionally associated with angioedema.
Elevations in these tests indicate the need for further evaluation based upon the clinical history. CRP may also be elevated in ACE
inhibitor-induced angioedema [17]. (See "Acute phase reactants".)
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Angioedema with prominent urticaria — Guidelines for the evaluation of urticaria (with or without angioedema) suggest that testing
is generally of low yield if a specific cause or underlying condition is not apparent from the history or physical examination. This
evaluation is reviewed separately. A specific cause can sometimes be identified in patients with new-onset urticaria/angioedema. (See
"New-onset urticaria".)
Urticaria/angioedema is considered chronic when it has been present on most days of the week for a period of six weeks or more. The
evaluation of chronic urticaria/angioedema differs from that of new-onset symptoms, since a specific external trigger or allergy is not
found in most patients and laboratory studies are most often normal. (See "Chronic spontaneous urticaria: Clinical manifestations,
diagnosis, pathogenesis, and natural history".)
Angioedema with anaphylaxis — A serum total tryptase level drawn shortly after the onset of anaphylaxis may be useful in
confirming that the episode was a mast cell-mediated event. Serum tryptase is a mast cell-specific protease that is released upon
mast cell activation. Any elevation in serum tryptase suggests an anaphylactic event. However, a normal level does not exclude
anaphylaxis because tryptase elevations are variable and transient. Tryptase elevations are most consistently found in patients with
hypotension during anaphylaxis. Instructions for proper sample collection are provided in the table (table 4). (See "Laboratory tests to
support the clinical diagnosis of anaphylaxis".)
Angioedema due to a suspect allergen — In cases in which an allergic reaction to an identifiable substance is suspected, there may
be commercially-available tests for immunoglobulin E (IgE) antibodies to the substance in question. Allergen-specific IgE
immunoassays are available for a variety of foods, insect venoms, inhaled allergens, and latex. These tests vary in sensitivity and
specificity, but a positive result can be helpful. IgE immunoassays are not altered by recent allergic reactions, so they can be obtained
at any time. Allergy skin testing provides similar information and is more sensitive in many cases, but it requires referral to an allergy
specialist and should be deferred until the patient has fully recovered from the angioedema event (one month is generally sufficient).
(See "Overview of in vitro allergy tests", section on 'Immunoassays' and "Overview of skin testing for allergic disease".)
Imaging for suspected bowel wall edema — Bowel wall edema may be imaged by ultrasound or abdominal computed tomography
(CT). Multidetector CT (MDCT) has been suggested as particularly helpful for diagnosis of ACE inhibitor-induced angioedema. Most
reported cases of ACE inhibitor-induced intestinal angioedema involved the small bowel, with abdominal CT demonstrating
circumferential thickening of the small bowel wall with ascites or incomplete obstruction [11,13,18]. The thickened area of bowel wall
may have a stratified appearance, and mesenteric lymphadenopathy has not been reported [18]. Recognition of this complication of
ACE inhibitor therapy can spare the patient unnecessary surgical intervention.
DIAGNOSIS
The diagnosis of angioedema is made clinically based on a suggestive history and physical findings. It presents as localized,
subcutaneous (or submucosal), nondependent swelling that typically affects the face, lips, throat, larynx, extremities, genitalia, or the
bowel wall. It develops within minutes to hours and resolves in hours to days. Laboratories may be helpful in confirming an underlying
allergy or a complement disorder. However, routine laboratories are normal in many cases of angioedema.
An algorithmic approach to the evaluation and management of angioedema in an emergency setting is presented (algorithm 1).
The utility of extensive empiric testing — Extensive testing beyond the laboratory tests already mentioned is of relatively low yield.
(See 'Laboratory tests' above.)
The utility of extensive testing was evaluated in a large series of 776 patients with recurrent angioedema, without major urticaria, who
presented to a referral center over a 10-year period [19]. In the majority of these patients, neither the patient nor the referring clinician
could detect an association between the episodes of angioedema and an obvious trigger. All patients underwent a careful history and
physical examination, sinus and dental radiographs, complete blood count, serum protein electrophoresis, complement studies,
erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hepatic enzymes, renal function, thyroid function and anti-tissue
antibodies, stool examination for ova and parasites, urinalysis, pharyngeal cultures, and urine cultures. Further studies, including
allergy testing or medication withdrawal and challenge, were performed only if allergy was suggested by the clinical history. A
condition or trigger was considered causative only if the angioedema improved after treatment/discontinuation.
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The following potentially causative conditions were identified (figure 2):
● Hereditary or acquired angioedema due to C1 inhibitor deficiency was identified in 23 and 2 percent, respectively.
● Angiotensin-converting enzyme (ACE) inhibitors were implicated in 11 percent, with a median duration of treatment of one year
before symptoms began.
● A specific causative factor (a food, drug, insect bite, environmental allergen, or physical stimulus) was identified in 16 percent.
● Other disorders, most commonly chronic infection or autoimmune disease, were identified in 7 percent. Within this group, chronic
infections were identified in 27 patients, 19 of whom had resolution of the angioedema following treatment of the infection.
● Three percent did not have angioedema, but rather other types of peripheral or generalized edema. (See 'Differential diagnosis'
below.)
No trigger could be identified in 38 percent, and these patients were deemed to have idiopathic angioedema. Thus, if the initial
approach suggested above (ie, obtaining complete blood count with differential, basic chemistry panel with liver function tests, CRP,
ESR, and C4 levels, and stopping any ACE inhibitors) were applied to this referral group, patients with hereditary or acquired
angioedema and those with ACE inhibitor-related angioedema would have been reliably detected. A detailed clinical history and review
of systems would likely have identified many of the remaining patients (those with a specific causative factor or an underlying
infection or autoimmune disease) as requiring further evaluation.
Idiopathic angioedema — Idiopathic angioedema is the term applied to recurrent episodes of angioedema without urticaria for which
no explanation can be found after a thorough evaluation (as previously described) to exclude allergic disorders, drug reactions, and
defects in complement pathways [19].
There are several conditions that may be mistaken for angioedema [20,21].
Disorders resembling cutaneous edema — Cutaneous edema mimicking angioedema can result from contact dermatitis, cellulitis,
autoimmune diseases, superior vena cava syndrome, and other disorders.
● Contact dermatitis – Contact dermatitis is a common mimic of facial angioedema and can cause dramatic swelling of the facial
and periorbital skin when it develops in response to cosmetics or topical pharmaceuticals (picture 5 and picture 6).
Microvesiculation and/or deep erythema of the skin can help distinguish contact dermatitis from complement-mediated
angioedema. Poison ivy can cause severe facial swelling, although linear patterns of vesiculations are often present.
Patients with contact dermatitis often report prominent pain, pruritus, and burning of the skin. Resolution of contact dermatitis
may be followed by peeling, which does not occur in angioedema. (See "Clinical features and diagnosis of allergic contact
dermatitis" and "Contact dermatitis in children".)
● Cellulitis and erysipelas – Cellulitis and erysipelas are infections of various layers of the dermis, which present as areas of skin
erythema, edema, and warmth in the absence of an underlying suppurative focus. Cellulitis involves the deeper dermis and
subcutaneous fat and has relatively smooth, flat borders. In contrast, erysipelas involves the upper dermis and superficial
lymphatics and is characteristically raised above the level of surrounding skin, with a clear line of demarcation between involved
and uninvolved tissue (picture 7 and picture 8).
Compared with angioedema, cellulitis and erysipelas are deeply erythematous, painful, and may be accompanied by fever. The
involved areas of skin are more clearly demarcated than angioedematous skin. Resolution may be followed by peeling, whereas
angioedema resolves without peeling.
● Facial lymphedema – Facial lymphedema can be associated with rosacea, although there are other characteristic skin changes in
rosacea. Patients may also experience prominent flushing and warmth of the face, and the combination of flushing, heat, and
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swelling is interpreted by some patients as a possible allergic reaction. However, lymphedema does not develop or resolve rapidly,
in contrast to angioedema. (See "Rosacea: Pathogenesis, clinical features, and diagnosis".)
● Autoimmune conditions – Edema of the face, periorbital areas, and sometimes the hands can be seen in systemic lupus,
polymyositis, dermatomyositis, and Sjögren's syndrome. Early stages of both scleredema and systemic sclerosis can present as
swelling. Scleredema often involves the posterior neck, and systemic sclerosis often affects the hands and is accompanied by
Raynaud phenomenon [22]. These disorders can be distinguished from angioedema by their persistence and by the presence of
associated systemic rheumatologic findings. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in
adults".)
● Eyelid edema – Blepharochalasis is an uncommon disorder in which recurrent and episodic eyelid edema leads to atrophic eyelid
skin with fine wrinkling and bronze discoloration (picture 9) [23-26]. This is seen predominantly in children and young adults. The
etiology is unknown, although immunoglobulin A (IgA) deposits have been described in the periorbital tissues, suggesting an
immunologic pathogenesis [27].
● Parasitic infections – In areas of the world where parasitic infections are prevalent, certain infections can cause periorbital
edema that is persistent rather than episodic. Specific infections that can present with this finding include trichinosis and
American trypanosomiasis (ie, Romana's sign) [28]. (See "Trichinellosis" and "Chagas disease: Acute and congenital
Trypanosoma cruzi infection".)
● Hypothyroidism – Severe hypothyroidism can cause a puffiness of the face and lips that can be mistaken for angioedema, but is
not transient. Nonpitting edema (myxedema) may be generalized. Myxedema results from infiltration of the skin by
glycosaminoglycans with associated water retention. (See "Clinical manifestations of hypothyroidism".)
● Superior vena cava syndrome and tumors – Occasionally, edema of the face, neck, or upper extremities, accompanied by venous
engorgement, is observed with superior vena cava syndrome [28] (see "Malignancy-related superior vena cava syndrome").
Tumors of the head and neck, lymphoma, and superior (pulmonary) sulcus (Pancoast) tumors can also cause localized edema.
With these entities, protracted or progressive swelling would be expected, in contrast to the transient swelling of angioedema.
● Cheilitis granulomatosa (Miescher's cheilitis) and Melkersson-Rosenthal syndrome – These are rare disorders of recurrent
angioedema involving the lips and face that lead to eventual permanent enlargement of the affected areas (picture 10 and picture
11) [29,30].
● Idiopathic edema – Idiopathic edema (as opposed to idiopathic angioedema) is a syndrome of persistent and recurrent fluid
retention, typically occurring in young, menstruating women in the absence of cardiac, hepatic, or renal disease. (See "Idiopathic
edema".)
Disorders resembling laryngeal edema — The differential diagnosis of laryngeal edema includes tonsillitis, peritonsillar abscess, and
pharyngeal foreign body [20]. Historical information should differentiate these entities from angioedema, as infectious causes should
have accompanying fever and other signs of illness. The diagnosis of a pharyngeal foreign body can be difficult, however, particularly
in the preverbal infant. (See "Emergency evaluation of acute upper airway obstruction in children".)
Other causes of bowel wall edema — Thickening of the wall of the small bowel can be seen in multiple disorders, including mesenteric
infarction, vasculitis, intramural hemorrhage, inflammatory bowel disease, acute ileitis (Yersinia, Campylobacter infections), peritoneal
carcinomatosis, inflammatory conditions adjacent to the bowel wall, and other disorders [18,31-33].
TREATMENT
The treatment of angioedema depends upon the acuity, severity, and proposed mechanism (algorithm 1).
Angioedema in or near the airway — The patient with angioedema near or involving the tongue, uvula, soft palate, or larynx must be
immediately assessed for signs of airway compromise. If intubation is necessary, the airway should be managed by the most
experienced person available, because intubation in the presence of laryngeal angioedema can be difficult due to distortion of the
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normal anatomy. Angioedema of the lips or mouth sometimes spreads to involve the throat, and frequent monitoring of airway
patency is critical throughout treatment. (See "Approach to the anatomically difficult airway in adults outside the operating room" and
"The difficult pediatric airway".)
If no airway compromise is detected, then the patient should be treated (depending upon the presumed cause, as described below)
and observed until there are clear signs of improvement to ensure that the angioedema is not the beginning of a more generalized
allergic reaction that is still in evolution. When eventually discharged, the patient should have clear instructions on what to do if
symptoms recur.
Angioedema with anaphylaxis — Anaphylaxis should be treated with intramuscular epinephrine, intravenous fluids, and oxygen. Rapid
overview tables are provided for treatment of anaphylaxis in adults (table 5) and children (table 6). The treatment of anaphylaxis is
reviewed in greater detail elsewhere. (See "Anaphylaxis: Emergency treatment".)
All patients who have experienced anaphylaxis should be equipped with an anaphylaxis emergency action plan, one or more
epinephrine autoinjectors, a plan for arranging further evaluation, and printed information about anaphylaxis and its treatment. These
materials can be found separately. (See "Anaphylaxis: Emergency treatment", section on 'Discharge care'.)
Acute-allergic angioedema (less severe than anaphylaxis) — Antihistamines and glucocorticoids are the main therapies for isolated
angioedema that appears to be allergic (ie, mast cell-mediated) but is NOT part of a larger anaphylactic reaction. In contrast,
anaphylaxis should be treated with intramuscular epinephrine because antihistamines are not sufficient. Angioedema that is
accelerating and could affect the airway would also be appropriately treated with intramuscular epinephrine, although this is unlikely
to help if the angioedema is bradykinin-mediated (as in hereditary angioedema [HAE]).
Suggested treatment for allergic angioedema includes the following:
● H1 antihistamines (eg, cetirizine up to 20 mg twice daily)
● Glucocorticoids (the dosing in acute angioedema has not been specifically studied):
• Methylprednisolone, 60 to 80 mg intravenously initially, replaced with oral preparations and tapered over five to seven days, in
adults requiring hospitalization for severe angioedema
• Prednisone (20 to 40 mg orally daily) in adults or prednisolone (0.5 to 1 mg/kg/day) in children, tapered over five to seven
days in patients discharged to home
The use of antihistamines for angioedema is extrapolated from the treatment of acute urticaria/angioedema, as the data on isolated
allergic angioedema are scant [20]. (See "New-onset urticaria", section on 'Treatment'.)
ACE inhibitor-induced angioedema — Treatment of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema primarily
involves discontinuation of the drug and monitoring for resolution. The airway must be protected if swelling involves the mouth or
throat, as several deaths have been attributed to asphyxiation from massive tongue swelling [34].
The utility of other medications for severe or refractory symptoms is reviewed elsewhere. (See "ACE inhibitor-induced angioedema",
section on 'Management'.)
Future use of related medications, particularly angiotensin-receptor blockers (ARBs) is discussed separately. (See "ACE inhibitor-
induced angioedema", section on 'Future use of related drugs'.)
C1 inhibitor deficiency (hereditary angioedema) — The treatment of acute attacks of hereditary and acquired C1 inhibitor disorders is
outlined here and discussed in detail separately.
The treatment of laryngeal attacks, which are the leading cause of mortality in patients with HAE, must always begin with immediate
and meticulous attention to airway patency, regardless of the therapies available (see 'Angioedema in or near the airway' above).
Those with respiratory distress or stridor may require intubation, because even the first-line therapies take approximately 30 minutes
or more to begin working.
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Briefly, treatment options include:
● Purified C1 inhibitor concentrate (Cinryze, Berinert, or Ruconest).

● Ecallantide (Kalbitor) (a kallikrein inhibitor available in the United States).
● Icatibant (Firazyr), a bradykinin-B2-receptor antagonist.
● FFP or solvent-detergent treated plasma, which should only be used if other therapies are not available. Note that FFP has the
occasional paradoxical effect of making the angioedema acutely worse and the clinician must be prepared to intubate the patient
if this happens.
The dosing and administration of each of these therapies is reviewed separately. (See "Hereditary angioedema: Acute treatment of
angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions' and "Acquired C1 inhibitor deficiency:
Recurrent, idiopathic angioedema — A trial of nonsedating antihistamines administered twice daily is suggested as an initial
intervention to prevent additional angioedema episodes in patients with idiopathic recurrent angioedema without urticaria. Such
patients should be referred to an allergy specialist for further evaluation.
● In the largest series available, 294 patients with idiopathic recurrent angioedema without urticaria were treated with nonsedating
antihistamines initially (ie, either cetirizine 10 mg twice daily or desloratadine 5 mg twice daily) for at least one month [19]. With
this intervention, 86 percent experienced significant improvement or resolution of the angioedema. In those that did not improve
significantly, the addition of hydroxyzine (25 mg three times daily) did not result in additional symptom control. Responsiveness to
antihistamines suggests that mast cell- or basophil-mediated processes were underlying the symptoms of these patients, despite
the lack of identifiable triggers.
● One consensus report suggests increasing the dose of nonsedating antihistamine up to fourfold (eg, cetirizine 20 mg twice daily)
before concluding that the patient's angioedema is not responsive to antihistamine therapy [35].
● Other experts describe less success in preventing recurrence with antihistamines, with no response in up to 30 percent of
patients, even with high doses (ie, up to 200 mg of hydroxyzine or diphenhydramine) [20,36].
The addition of montelukast, a leukotriene receptor antagonist, at the standard dose of 10 mg before bed, may help some patients for
whom antihistamines alone were not adequate [37].
In severe and refractory cases, successful treatment with dapsone, icatibant (bradykinin-B2-receptor antagonist), and rituximab (B cell-
depleting anti-CD20 monoclonal antibody) has been reported [38-40].
Treatment of acute episodes — For adult patients with idiopathic angioedema who have infrequent attacks (ie, a few attacks per
year) and do not wish to take regular medications for prevention, or for those with less frequent breakthrough episodes despite daily
antihistamines, we (the authors and editors of UpToDate) have found the following to be helpful. We instruct patients to take 40 mg of
prednisone and 25 to 50 mg of diphenhydramine, all at once, at the first sign of swelling, with no further doses. Some patients have
identifiable sensations in the skin just before the onset of angioedema, and the medications should be taken when these sensations
appear. This approach has not been formally studied.
DISPOSITION AND REFERRAL
In patients who do not require admission to the hospital for ongoing management, we suggest observation until there are unequivocal
signs of improvement, to ensure that the angioedema is not the beginning of a more generalized allergic reaction that is still evolving.
Episodes of isolated angioedema characteristically peak and then gradually resolve over the course of either hours (if mild) or three to
five days (if severe). It is unusual for angioedema to follow a fluctuating course within a single episode. Therefore, when an episode of
angioedema is clearly resolving, the patient can generally be discharged with clear instructions on how to proceed if another episode
occurs and preferably with an epinephrine autoinjector if the etiology is known or suspected to be histaminergic. In contrast to
idiopathic or bradykinin-mediated angioedema, patients with severe acute allergic angioedema, including anaphylaxis, may experience
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a late-phase reaction and may need longer observation. The prevalence of biphasic and protracted anaphylaxis is reviewed separately.
(See "Anaphylaxis: Acute diagnosis", section on 'Biphasic anaphylaxis'.)
Patients with severe or recurrent angioedema or angioedema/urticaria, for which no cause is readily apparent, should be referred to a
specialist for further evaluation. An allergy specialist is most appropriate in most situations. Dermatology specialists also manage
mast cell-mediated urticaria/angioedema.
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients.
(You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Angioedema (The Basics)")
● Angioedema typically affects the skin and mucosal tissues of the face, lips, mouth, and throat, larynx, extremities, and genitalia,
often in an asymmetric pattern (picture 1). Angioedema can also affect the bowel wall and present as colicky abdominal pain.
(See 'Clinical features' above.)
● Two types of angioedema can be distinguished: mast cell-mediated angioedema (eg, allergic reactions) and bradykinin-mediated
angioedema (eg, angiotensin-converting enzyme [ACE] inhibitor-induced angioedema, hereditary angioedema [HAE]). However,
there are other causes of angioedema for which the mechanism unknown. (See "An overview of angioedema: Pathogenesis and
causes".)
● Angioedema may be life-threatening if it causes airway obstruction or when it represents a component of anaphylaxis. (See 'Life-
threatening situations' above.)
● If the clinical history or physical examination reveals a possible external cause or concomitant condition, then these findings
should guide further testing (algorithm 1). If there is no information to suggest an external cause and the patient has isolated
angioedema (without pruritus or urticaria), then a C4 and a C1 inhibitor antigenic level should be obtained. (See 'Evaluation'
above.)
● Immediate assessment and ongoing protection of the airway is critical in any patient with angioedema near or affecting the
larynx, mouth, soft palate, or tongue. (See 'Angioedema in or near the airway' above.)
● The treatment of angioedema depends upon the acuity, severity, and the mechanism believed responsible (mast cell or
bradykinin-mediated). Mast cell-mediated angioedema responds to epinephrine (if severe), glucocorticoids, and antihistamines. In
contrast, bradykinin-mediated angioedema responds to C1 inhibitor concentrate, fresh frozen plasma (FFP), and other agents that
interfere with the production or action of bradykinin (algorithm 1). (See 'Treatment' above.)
1964
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge Clifton O Bingham, III, MD, who contributed to an earlier version of this topic
review.
1965
GRAPHICS
Clinical criteria for diagnosis of anaphylaxis
Clinical criteria for the diagnosis of anaphylaxis:

The clinical criteria pictured are based upon Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on
the definition and management of anaphylaxis: Summary report: Second National Institute of Allergy and Infectious
Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol 2006; 117:391.
Anaphylaxis with involvement of only one body organ system and anaphylaxis in infants and young children are
described in Simons FER, Ardusso LRF, Bilo MB, et al. World Allergy Organization guidelines for the assessment and
management of anaphylaxis. J Allergy Clin Immunol 2011; 127:587.
BP: blood pressure.

* For example, immunologic but immunoglobulin E-independent or nonimmunologic (direct mast cell activation).
¶ For example, after an insect sting, reduced BP might be the only manifestation of anaphylaxis or after allergen immunotherapy,
generalized hives might be the only initial manifestation of anaphylaxis.
Δ Low systolic BP for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 × age]) from 1 to 10
years, and less than 90 mmHg from 11 to 17 years. Normal heart rate ranges from 80 to 140 beats/minute at age 1 to 2 years, from 80
to 120 beats/minute at age 3 years, and from 70 to 115 beats/minute after age 3 years. In infants and children, respiratory compromise
is more likely than hypotension or shock, and shock is more likely to be manifested initially by tachycardia than by hypotension.
Reproduced with permission from: Simons FER, Ardusso LRF, Beatrice Bilo M, et al. World Allergy Organization guidelines for the assessment
and management of anaphylaxis. WAO Journal 2011; 4:13. Copyright © 2011 Lippincott Williams & Wilkins.
1966
Diagnostic criteria for anaphylaxis
Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)
B. Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence)
2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours):
A. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia)
C. Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence)
D. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP* after exposure to a KNOWN allergen for that patient (minutes to several hours):
A. Infants and children - Low systolic BP (age-specific)* or greater than 30% decrease in systolic BP
B. Adults - Systolic BP of less than 90 mmHg or greater than 30% decrease from that person's baseline
BP: blood pressure.

* Low systolic blood pressure for children is defined as:
Less than 70 mmHg from 1 month to 1 year
Less than (70 mmHg + [2 x age]) from 1 to 10 years
Less than 90 mmHg from 11 to 17 years
Adapted with permission from: Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391. Copyright © 2006 The American Academy of Allergy, Asthma, and Immunology.
1967
Angioedema lip
Angioedema is a diffuse, nonpitting, tense swelling of the dermis and subcutaneous tissue.
It develops over minutes to hours, and resolves over subsequent hours or days.
Angioedema typically does not itch, unless it is associated with urticaria.
Reproduced with permission from: Neville B, et al: Color Atlas of Clinical Oral Pathology, Lea & Febiger,
Philadelphia 1991. Copyright ©1991 Lippincott Williams & Wilkins.
1968
Angioedema of the lips
1969
Unilateral angioedema of the tongue
1970
Angioedema and hives face
Facial angioedema and urticaria (forehead).
Disorders, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2003. Copyright ©2003 Lippincott
Williams & Wilkins.
1971
Causes of angioedema classified by mechanism
Mechanism Known or presumed pathophysiology Examples
Activation of mast cells IgE-mediated mast cell activation (type I hypersensitivity) Allergic reactions to foods, drugs, latex, insect stings, other
Clinical characteristics – Often associated with pruritus and allergens
urticarial. Direct mast cell activation Opioids, radiocontrast agents
May present as part of an allergic reaction or anaphylaxis. Perturbations in arachidonic acid metabolism Aspirin and other NSAIDs
Immunologic and other non-IgE-mediated mast cell Idiopathic histaminergic angioedema, often associated with
activation chronic spontaneous urticaria or inducible urticaria
Generation of bradykinin Inhibition of enzymes involved in degradation of bradykinin ACE inhibitors, DPP-4 inhibitors
Clinical characteristics – Not associated with pruritus or Deficiency or dysfunction of complement C1 inhibitor due to Hereditary angioedema (also known as hereditary C1
urticaria. mutation inhibitor deficiency or dysfunction)
May present with abdominal symptoms due to bowel wall Deficiency or dysfunction of complement C1 inhibitor often Acquired C1 inhibitor deficiency
edema. due to anti-C1 inhibitor antibody or an underlying
malignancy
Defects in several genes have been implicated, including Hereditary angioedema with normal C1 inhibitor
those for coagulation factor XII, plasminogen, and
angiopoietin-1.
Other cases are idiopathic.
Unknown pathophysiology Idiopathic nonhistaminergic angioedema

Clinical characteristics – Variable. Infections (especially in children)
Sometimes associated with urticaria. Drugs – Calcium channel blockers, fibrinolytic agents,
herbal medicines, other hypereosinophilic syndrome
Gleich syndrome
IgE: immunoglobulin E; NSAIDs: nonsteroidal anti-inflammatory drugs; ACE inhibitors: angiotensin-converting enzyme inhibitors.
1972
Major causes of mast cell-mediated angioedema
IgE-dependent allergic reactions

Foods
Drugs (antibiotics, local anesthetics, hormones)
Stinging insects
Latex
Contact (fresh fruits and vegetables, animal saliva)
Direct mast cell-mediator release

Opiates
Muscle relaxants (succinylcholine, curare)
Perturbations in arachidonic acid metabolism within mast cells

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
1973
Instructions for optimal collection and handling of blood samples for measurement of tryptase following suspected anaphylaxis
Tryptase (serum or plasma)

When to collect the sample:
Blood should be collected between 15 minutes and 3 hours after symptom-onset whenever possible. Samples collected <15 minutes or >3 hours after symptom-onset are less likely to
be informative due to diminished sensitivity.
How to collect the sample:
Blood can be drawn using standard technique. Collect blood for serum (red top tube) or plasma (tube with heparin, citrate, or EDTA). A minimum of 1 mL is recommended.
For postmortem samples, collect blood from the femoral artery or vein, not the heart.
How to process the sample:
Serum or plasma should be placed on ice and frozen as soon as possible. Samples should be shipped frozen by overnight courier if the assay cannot be performed on site.
EDTA: ethylenediaminetetraacetic acid.
1974
Algorithm for evaluation and management of angioedema in the urgent care setting
ENT: ear, nose, and throat or otolaryngology; ACE: angiotensin-converting enzyme; C4: complement component 4.
Modified from: Jaiganesh T, Wiese M, Hollingsworth J, et al. Acute angioedema: Recognition and management in the emergency department. Eur J Emerg Med 2013; 20:10.
1975
Etiologies of angioedema in referral populations
ACE inhibitor: angiotensin-converting enzyme inhibitor.
Data from: Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: a large clinical survey. CMAJ
2006; 175:1065.
1976
Contact dermatitis of the periorbital skin
Intense erythema and edema with vesiculation in this patient with allergic contact
dermatitis of the eyelids.
1977
Contact dermatitis involving the facial and periorbital skin
1978
Erysipelas involving the groin and thigh
1979
Erysipelas involving the buttock
1980
Blepharochalasis
The patient had recurrent bouts of upper lid swelling. Chronic changes of distended and
thinned "cigarette-paper" skin remain.
Reproduced with permission from: Tasman W, Jaeger E. The Wills Eye Hospital Atlas of Clinical
Ophthalmology, 2nd ed, Lippincott Williams & Wilkins, Philadelphia 2001. Copyright © 2001 Lippincott
Williams & Wilkins.
1981
Granulomatous cheilitis
Granulomatous cheilitis is a rare disorder in which recurrent swelling of the lips leads to
permanent areas of enlargement.
1982
Granulomatous cheilitis
Granulomatous cheilitis is a rare disorder in which recurrent swelling of the lips leads to
permanent areas of enlargement.
1983
Rapid overview: Emergency management of anaphylaxis in adults
Diagnosis is made clinically:

The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin findings.
Danger signs: Rapid progression of symptoms, respiratory distress (eg, stridor, wheezing, dyspnea, increased work of breathing, persistent cough, cyanosis), vomiting, abdominal pain,
hypotension, dysrhythmia, chest pain, collapse.
Acute management:
The first and most important treatment in anaphylaxis is epinephrine. There are NO absolute contraindications to epinephrine in the setting of anaphylaxis.
Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may lead to complete obstruction. Intubation can be difficult and should be performed
by the most experienced clinician available. Cricothyrotomy may be necessary.
Promptly and simultaneously, give:
IM epinephrine (1 mg/mL preparation): Give epinephrine 0.3 to 0.5 mg intramuscularly, preferably in the mid-outer thigh. Can repeat every 5 to 15 minutes (or more frequently), as
needed. If epinephrine is injected promptly IM, most patients respond to one, two, or at most, three doses. If symptoms are not responding to epinephrine injections, prepare IV
epinephrine for infusion.
Place patient in recumbent position, if tolerated, and elevate lower extremities.
Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.
Normal saline rapid bolus: Treat hypotension with rapid infusion of 1 to 2 liters IV. Repeat, as needed. Massive fluid shifts with severe loss of intravascular volume can occur.
Albuterol (salbutamol): For bronchospasm resistant to IM epinephrine, give 2.5 to 5 mg in 3 mL saline via nebulizer, or 2 to 3 puffs by metered dose inhaler. Repeat, as needed.
Adjunctive therapies:
H1 antihistamine*: Consider giving cetirizine 10 mg IV (given over 2 minutes) or diphenhydramine 25 to 50 mg IV (given over 5 minutes) - for relief of urticaria and itching only.
H2 antihistamine*: Consider giving famotidine 20 mg IV (given over 2 minutes).
Glucocorticoid*: Consider giving methylprednisolone 125 mg IV.
Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed. Urine output should be monitored in patients receiving IV fluid
resuscitation for severe hypotension or shock.
Treatment of refractory symptoms:

Epinephrine infusion ¶: For patients with inadequate response to IM epinephrine and IV saline, give epinephrine continuous infusion, beginning at 0.1 mcg/kg/minute by infusion
pump Δ. Titrate the dose continuously according to blood pressure, cardiac rate and function, and oxygenation.
Vasopressors ¶: Some patients may require a second vasopressor (in addition to epinephrine). All vasopressors should be given by infusion pump, with the doses titrated continuously
according to blood pressure and cardiac rate/function and oxygenation monitored by pulse oximetry.
Glucagon: Patients on beta-blockers may not respond to epinephrine and can be given glucagon 1 to 5 mg IV over 5 minutes, followed by infusion of 5 to 15 mcg/minute. Rapid
administration of glucagon can cause vomiting.
Instructions on how to prepare and administer epinephrine for IV continuous infusions are available as separate tables in UpToDate.
IM: intramuscular; IV: intravenous.

* These medications should not be used as initial or sole treatment.
¶ All patients receiving an infusion of epinephrine and another vasopressor require continuous noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation.
Δ For example, the initial infusion rate for a 70 kg patient would be 7 mcg/minute. This is consistent with the recommended range for non-weight-based dosing for adults, which is 2 to 10
mcg/minute. Non-weight-based dosing can be used if the patient's weight is not known and cannot be estimated.
Adapted from: Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161.
1984
Rapid overview: Emergency management of anaphylaxis in infants and children*
Diagnosis is made clinically:

The most common signs and symptoms are cutaneous (eg, sudden onset of generalized urticaria, angioedema, flushing, pruritus). However, 10 to 20% of patients have no skin
findings.
Danger signs: Rapid progression of symptoms, evidence of respiratory distress (eg, stridor, wheezing, dyspnea, increased work of breathing, retractions, persistent cough, cyanosis),
signs of poor perfusion, abdominal pain, vomiting, dysrhythmia, hypotension, collapse.
Acute management:
The first and most important therapy in anaphylaxis is epinephrine. There are NO absolute contraindications to epinephrine in the setting of anaphylaxis.
Airway: Immediate intubation if evidence of impending airway obstruction from angioedema. Delay may lead to complete obstruction. Intubation can be difficult and should be
performed by the most experienced clinician available. Cricothyrotomy may be necessary.
IM epinephrine (1 mg/mL preparation): Epinephrine 0.01 mg/kg should be injected intramuscularly in the mid-outer thigh. For large children (>50 kg), the maximum is 0.5 mg per dose.
If there is no response or the response is inadequate, the injection can be repeated in 5 to 15 minutes (or more frequently). If epinephrine is injected promptly IM, patients respond to
one, two, or at most, three injections. If signs of poor perfusion are present or symptoms are not responding to epinephrine injections, prepare IV epinephrine for infusion (see below).
Place patient in recumbent position, if tolerated, and elevate lower extremities.
Oxygen: Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.
Normal saline rapid bolus: Treat poor perfusion with rapid infusion of 20 mL/kg. Re-evaluate and repeat fluid boluses (20 mL/kg), as needed. Massive fluid shifts with severe loss of
intravascular volume can occur. Monitor urine output.
Albuterol: For bronchospasm resistant to IM epinephrine, give albuterol 0.15 mg/kg (minimum dose: 2.5 mg) in 3 mL saline inhaled via nebulizer. Repeat, as needed.
H1 antihistamine: Consider giving diphenhydramine 1 mg/kg (max 40 mg IV, over 5 minutes) or cetirizine (children aged 6 months to 5 years can receive 2.5 mg IV, those 6 to 11 years
of age can receive 5 or 10 mg IV, over 2 minutes).
H2 antihistamine: Consider giving famotidine 0.25 mg/kg (max 20 mg) IV, over at least 2 minutes.
Glucocorticoid: Consider giving methylprednisolone 1 mg/kg (max 125 mg) IV.
Monitoring: Continuous noninvasive hemodynamic monitoring and pulse oximetry monitoring should be performed. Urine output should be monitored in patients receiving IV fluid
resuscitation for severe hypotension or shock.
Treatment of refractory symptoms:

Epinephrine infusion ¶: In patients with inadequate response to IM epinephrine and IV saline, give epinephrine continuous infusion at 0.1 to 1 mcg/kg/minute, titrated to effect.
Vasopressors ¶: Patients may require large amounts of IV crystalloid to maintain blood pressure. Some patients may require a second vasopressor (in addition to epinephrine). All
vasopressors should be given by infusion pump, with the doses titrated continuously according to blood pressure and cardiac rate/function monitored continuously and oxygenation
monitored by pulse oximetry.
IM: intramuscular; IV: intravenous.

* A child is defined as a prepubertal patient weighing less than 40 kg.
¶ All patients receiving an infusion of epinephrine and/or another vasopressor require continuous noninvasive monitoring of blood pressure, heart rate and function, and oxygen saturation. We
suggest that pediatric centers provide instructions for preparation of standard concentrations and also provide charts for established infusion rate for epinephrine and other vasopressors in
infants and children.
1985
Hereditary angioedema: Pathogenesis and diagnosis

INTRODUCTION
Hereditary angioedema (HAE) is a disease characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the
skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although the swelling is self-limited and resolves in two to five days without
treatment, laryngeal involvement may cause fatal asphyxiation.
The pathogenesis and diagnosis of hereditary forms of angioedema will be reviewed here. The clinical features, precipitating factors, and treatment of
this disorder are discussed elsewhere. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and
"Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-
term prophylaxis".)
PATHOGENESIS
The swelling (ie, angioedema, sometimes called "giant" swelling) that occurs in HAE results from excessive production of bradykinin, a potent
vasodilatory mediator. Bradykinin also has important vascular permeability-enhancing effects. During episodes of angioedema in patients with HAE,
plasma bradykinin levels have been shown to be sevenfold higher than normal [1]. In bradykinin-mediated angioedema, histamine and other mast cell
mediators are not directly involved, which explains the lack of response to antihistamines and distinguishes this form of angioedema from the histamine-
mediated angioedema that is seen in allergic reactions and urticaria.
The best characterized forms of HAE arise from deficiency or dysfunction of C1 inhibitor (C1INH). However, there are other forms of HAE in which C1INH
is normal. A small but growing number of suspected pathogenic variants in genes for other proteins have been identified to explain the disease in some
families, while the pathogenesis in other families remains unclear.
Functions of C1 inhibitor — C1 inhibitor (C1INH) is an acute-phase reactant and a member of the "serpin" superfamily of serine protease inhibitors.
C1INH inhibits steps in the classical and lectin complement pathways, as well as of the intrinsic coagulation (contact system), fibrinolytic [2], and kinin-
generating pathways. Within these different pathways, C1INH inhibits several plasma proteases: C1r and C1s, mannose-binding lectin-associated serine
proteases (MASP1 and MASP2), coagulation factor XII (Hageman factor), coagulation factor XI, plasma kallikrein, and plasmin [3-6]. The function of
C1INH in the kinin-generating pathway is most directly related to the pathogenesis of HAE (figure 1) [7-9].
Molecular events leading to angioedema — The initial molecular events in the genesis of an attack are not entirely understood. Local activation of the
contact system proteases factor XII and plasma prekallikrein on endothelial cell surfaces is important in initiation. The activation of factor XII, possibly
by phospholipids released from damaged cells, is believed to be a leading mechanism [10]. Heat shock protein 90 generated during cell stress may
enhance contact system activation. Activated factor XII (factor XIIa) and kallikrein catalyze the cleavage of high molecular weight kininogen (HMWK) by
kallikrein, with release of bradykinin. C1INH normally plays a role in limiting bradykinin production by inhibiting both kallikrein and active factor XII, so
when C1INH is deficient or dysfunctional, bradykinin production is relatively unchecked (figure 1) [9,11,12]. Plasma prekallikrein has been reported to be
capable of slowly catalyzing the cleavage of HMWK independently of factor XII. However, the clinical relevance of this is unclear [13,14].
The pathologic mechanisms of this disease have proven difficult to study. An animal model of HAE was produced in knockout mice [15]. However,
despite profound deficiency of C1INH due to homozygous gene defects, the mice do not develop spontaneous episodes of angioedema. Instead, minor
localized swellings can be induced experimentally by the local application of mustard oil (an irritant) to the animal's skin. In response to this, the animals
develop abnormal increases in vascular permeability, which can be reversed either by administration of C1INH, blocking kallikrein, or blocking the
bradykinin B2 receptor.
C1INH deficiency or dysfunction results in low levels of complement component 4 (C4) because the C1 complex normally cleaves C4 as part of the
classical complement pathway, and this is exaggerated if C1INH is deficient (figure 2). C1INH is an extremely potent inhibitor of C1r and C1s (table 1),
relative to the other proteases it inhibits, so the result of C1INH deficiency can be detected in this pathway easily as a low C4 level. Thus, low C4 is not
believed to be directly related to the pathogenesis of HAE but rather just a sensitive screening test for deficiency of C1INH.
1986
Subtypes and genetics — There are several types of HAE [16]. Two forms of the disorder arise from deficiency or dysfunction of C1INH (types I and II,
respectively) and can be detected by abnormal complement protein levels [5,17,18]. The other types of familial angioedema are characterized by normal
C1INH and normal complement studies. Patients with HAE with normal C1INH are likely a heterogeneous group (figure 3). Some patients have
identifiable variants in factor XII. In 2017, two additional variants were implicated as potential causes of HAE with normal C1INH: one in the gene for
angiopoietin-1 (ANGPT1) [19] and another in the gene for plasminogen [20]. The etiology of angioedema in the remaining patients is unknown. The
pathogenesis of HAE with normal C1INH is discussed in more detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)
Patients with hereditary forms of angioedema have these defects from birth and generally present with recurrent angioedema as children or young
adults. There is also an acquired form of C1INH deficiency that presents in older patients (ie, age >40 years) without a family history of angioedema and
is associated with underlying disorders or autoantibodies in most cases. Acquired C1INH deficiency is reviewed in more detail separately. (See "Acquired
C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Acquired C1 inhibitor deficiency: Management and
prognosis".)
HAE with C1 inhibitor deficiency/dysfunction — HAE type I is due to C1 inhibitor (C1INH) deficiency, and type II is caused by C1INH dysfunction.
Together, these two disorders are called HAE with C1INH deficiency (C1INH-HAE) (MIM #106100).
● Type I HAE accounts for 85 percent of C1INH-HAE kindreds and is characterized by reduced secretion of the C1INH protein. Upon testing, plasma
protein (antigenic) and functional C1INH levels are both low and range from undetectable to less than 30 percent of normal in most patients,
although levels can occasionally be between 30 and 50 percent of normal. For example, if the lower limit of a normal protein level is 18 mg/dL, then
a patient with type I HAE would typically have a level <6 mg/dL. These decrements are greater than would be predicted with one intact normal allele,
even though the disorder is almost always heterozygous. Possible explanations for this include increased baseline catabolism or decreased
expression of the normal allele product [21,22].
● Type II HAE results from the presence of a dysfunctional C1INH protein, which is present in normal or elevated amounts. This type of HAE is found
in about 15 percent of affected families. Upon testing, C1INH function is low, but protein levels are normal or elevated. Protein levels may be
elevated because the defective C1INH is unable to form complexes with proteases, resulting in an increased plasma half-life [22].
Inheritance patterns — The inheritance of types I and II HAE is autosomal dominant, so the majority of affected patients have affected family
members. However, approximately 25 percent of cases result from de novo mutations, so a positive family history is not required for diagnosis [21,23].
Nearly all affected patients are heterozygotes with one abnormal allele, although a few patients with homozygous deficiency have been reported [24,25].
Having an abnormal C1INH allele does not result in symptoms of angioedema in all individuals [26]. A Spanish study describing the establishment of an
HAE disease registry illustrated this phenomenon [27]. Patients with HAE were identified throughout the country, and screening was performed to detect
affected family members. Up to 10 percent of individuals carrying the defective gene were asymptomatic, although this figure includes young subjects
who may become symptomatic later in life. Less than 5 percent of C1INH-HAE patients above 20 years of age are asymptomatic [26].
The gene for C1INH is located on the long arm of chromosome 11 [23,28-30]. Nearly 300 pathogenic variants have been reported in unrelated patients
with types I and II HAE [28,31-33]. An electronic database of variants is available [34]. The most common defect is single base-pair mutation, which can
occur throughout the gene. Larger gene rearrangements, including partial gene deletions and duplications, account for another 20 percent of gene
defects.
HAE with normal C1 inhibitor — Other forms of HAE exist in which complement studies are normal, including C4, C1 inhibitor (C1INH) protein level,
and C1INH function. The evaluation described below also applies to these disorders, with the additional consideration of genetic testing to identify one of
the variants in other proteins that has been identified in this subset of patients. HAE with normal C1INH is reviewed in more detail separately. (See
"Hereditary angioedema with normal C1 inhibitor".)
EVALUATION
When to suspect HAE — HAE should be considered in patients who demonstrate one or more of the following:
● Recurrent episodes of angioedema without urticaria or pruritus, lasting two to five days (without treatment).
● Unexplained recurrent episodes of self-limited, colicky, abdominal pain (typically lasting one to three days), especially in patients who also have had
cutaneous angioedema.
● Unexplained laryngeal edema (even a single episode).
● Angioedema episodes in the absence of angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), or history
to suggest an allergic cause.
● A family history of angioedema.
1987
● A low complement component 4 (C4) level in a patient with angioedema. Other causes of a low C4 are discussed below. (See 'Low C4 levels' below.)
The signs and symptoms of HAE are reviewed in greater detail separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations,
exacerbating factors, and prognosis".)
Trial of high-dose antihistamines — Patients with HAE do not respond to antihistamine therapy. Most patients with HAE have been given antihistamines
and glucocorticoids multiple times in the past without benefit. However, if a therapeutic trial of high-dose antihistamines has not been given, this should
be done if C4 is normal and there is no family history, before extensive additional complement tests are ordered (particularly if the resources to perform
accurate complement studies are limited). Nonsedating H1 antihistamines (eg, cetirizine, levocetirizine, loratadine, desloratadine, or fexofenadine)
should be given for at least one month or for a sufficient time period to appreciate a change, depending upon the patient's frequency of angioedema
episodes. We start with twice the usual dose (eg, cetirizine 10 mg twice daily). If there is no improvement, we increase to four times the usual dose or
add a second agent at twice the usual dose. If this does not prevent episodes of angioedema, then the evaluation for HAE can continue [35]. If high-dose
antihistamine therapy does prevent further episodes of angioedema, then the patient has histaminergic acquired angioedema, which is far more
common than HAE (figure 3). If no cause can be found, the diagnosis is idiopathic histaminergic acquired angioedema (IH-AAE, also called idiopathic
angioedema). (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Recurrent, idiopathic angioedema'.)
Complement testing — C4 (the natural substrate for C1 esterase), C1INH protein (or "antigenic") levels, and C1INH function are the critical diagnostic
tests for patients with possible HAE with C1 inhibitor deficiency (C1INH-HAE). Confirmation of C1INH-HAE requires low C4 plus decreased C1INH protein
or function. Two sets of complement tests should be obtained, ideally at least one month apart. Complement studies are normal in HAE associated with
variants in factor XII (FXII-HAE), angiopoietin-1 (ANGPT1), and plasminogen, as well as HAE of unknown origin (U-HAE). The table summarizes
complement results in different angioedema disorders (table 2).
Complement tests are susceptible to laboratory error and should be performed by accredited laboratories that have demonstrated competence in these
assays. In addition, clinicians should be vigilant for other sources of error:
● Complement studies should be done with fresh or freshly frozen serum that has not been standing for more than four hours.
● C4 and C1INH protein levels are relatively reliable. In contrast, tests of C1INH function are particularly prone to error and can be falsely low
(chromogenic assay) or falsely normal (enzyme-linked immunosorbent assay [ELISA]). If C4 is normal and C1INH function is low, the most likely
explanation is laboratory error, and testing should be repeated [36].
● The normal range for C4 is extremely wide (from 10 to 40 mg/dL) and may be reported as a concentration, absolute level, or percentage of normal. A
level below 50 percent of normal is strongly suggestive of C1INH deficiency. If the C4 level is presented in mg without a percent, 25 mg would be
considered a normal level (100 percent), and levels <10 mg are strongly suggestive of C1INH deficiency (pathologic). Levels between 10 and 15 mg
are possibly pathologic, and levels >15 mg are not pathologic.
● Complement studies for diagnosis must be performed when the patient is not receiving C1INH concentrate, because it will alter results. If it has
been initiated, it should be discontinued for one week before diagnostic complement studies are obtained. Patients receiving androgens will often
still have low C4 and C1INH levels, but if complement results are normal, androgens should be withheld for one week and testing repeated.
Therapies for HAE are discussed in detail elsewhere. (See "Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary
angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
Algorithmic approach to evaluation — Our approach to evaluation and testing depends upon whether the clinical suspicion is low or high because this
determines how extensive complement testing should be. When clinical suspicion is high, the evaluation is further influenced by the presence or
absence of a family history of angioedema.
Low clinical suspicion — Clinical suspicion can be considered to be low when the episodes of angioedema are not characteristic of HAE (eg, the
attacks last 24 hours or less, angioedema is sometimes accompanied by hives, or the frequency of angioedema is reduced by antihistamines) or there is
a potential medication or allergy that could be causing the angioedema. In such patients, C4 alone is an adequate screening test [37].
● If C4 is normal, HAE due to C1INH deficiency is unlikely, and other causes of angioedema should be considered. (See 'Differential diagnosis' below.)
● If C4 is low, then C1INH protein level and C1INH function should be measured because the patient may have HAE. The algorithm for patients with a
negative family history (algorithm 1) should be followed. Less dramatic reductions in C4 are seen in autoimmune diseases (eg, lupus and others)
and inherited C4 deficiency. C3 is often also low in autoimmune disease and should be normal in HAE. These disorders are discussed separately.
(See "Acquired deficiencies of the complement system", section on 'Increased consumption by immune complexes' and "Inherited disorders of the
complement system", section on 'C4 deficiency'.)
High clinical suspicion — Clinical suspicion can be considered high when all of the following are true:
● The patient develops recurrent episodes of angioedema without urticaria lasting two to five days (without treatment).
● A trial of high-dose antihistamines, if appropriate, did not prevent symptoms.
1988
● The patient is not taking ACE inhibitors or NSAIDs.
● History does not suggest food, latex, or other allergic cause.
• An algorithm for patients with high clinical suspicion and a positive family history is provided (algorithm 2). C4, C1INH protein level, and C1INH
function should be obtained. At some centers, C4 and C1INH protein levels are measured first because these are adequate to make the
diagnosis in some cases, and C1INH function is measured only if the C1INH protein level is normal or elevated. Other centers order all three
tests together.
• An algorithm for patients with high clinical suspicion and a negative family history (or family history is unknown) is provided (algorithm 1).
Interpretation of complement tests
In patients in whom clinical suspicion is high and there is a positive family history, complement studies are interpreted as follows (algorithm 2):
● If C4 and C1INH protein levels are low, the patient has type I C1INH-HAE. C4 levels are usually less that 50 percent of normal. Levels of C1INH
protein in untreated type I HAE often range from undetectable to less than 30 percent of normal (eg, if the lower limit of normal is 18 mg/dL, then a
typical value would be <6 mg/dL). C1INH function is typically less than 30 percent of normal, although this is not needed for the diagnosis of type I
HAE.
● If C4 is low, C1INH protein levels are normal or high, and if C1INH function is low, the patient has type II C1INH-HAE. C1INH function is usually below
30 percent of normal.
● If C4, C1INH protein levels, and C1INH function are all normal, the patient may have HAE with normal C1INH. If an FXII or another specific variant is
identified, then the diagnosis is HAE associated with a variant in that specific protein. The diagnosis of U-HAE is one of exclusion and requires
failure of an adequate trial of high-dose nonsedating antihistamines. (See 'Trial of high-dose antihistamines' above.)
In 90 percent or more of patients with C1INH-HAE, plasma levels of C4 are always low, even during asymptomatic periods [38,39]. However, because this
is not the case in all patients [40,41], a normal C4 level in an asymptomatic patient does not absolutely exclude disease. If clinical suspicion is high and
C4 is normal when the patient is asymptomatic, C4 should be repeated during an angioedema episode.
In patients in whom clinical suspicion is high and there is no family history (or family history is unknown), complement studies are interpreted as follows
(algorithm 1):
● If C4 is low and C1INH protein level is normal, C1INH function should be measured. If function is also low, the patient has C1INH-HAE. Family history
should be revisited and if truly negative, the patient has a new pathogenic variant. If C1INH function is normal, other causes of C4 consumption
should be considered. (See 'Low C4 levels' below.)
● If C4 and C1INH protein levels are normal, the next step in evaluation is a trial of daily high-dose antihistamines, if not already performed. In patients
with idiopathic histaminergic acquired angioedema (IH-AAE), these interventions result in a dramatic decrease or complete cessation of
angioedema episodes. (See 'Trial of high-dose antihistamines' above.)
If angioedema episodes continue, the patient likely has either HAE associated with a specific variant or idiopathic nonhistaminergic angioedema,
depending upon whether an FXII, angiopoietin-1 (ANGPT1), or plasminogen variant is identified. FXII-HAE is primarily seen in women in whom
symptoms are mainly estrogen-related. (See "Hereditary angioedema with normal C1 inhibitor".)
● If both C4 and C1INH protein level are low, then C1q should be measured. A low C1q level suggests acquired C1INH deficiency, which usually
presents in patients >40 years of age with underlying hematologic or lymphoproliferative disorders. Any patient with low C4, low C1INH protein level,
and low C1q should be evaluated for an underlying hematologic or lymphoproliferative disorder. (See "Acquired C1 inhibitor deficiency: Management
and prognosis", section on 'Associated disorders'.)
If C1q is normal, then further evaluation depends upon the age at which symptoms began. If symptoms began before age 30, the most likely
explanation is a new mutation causing C1INH-HAE. If symptoms began after age 40, acquired C1INH deficiency is the most likely explanation (C1q is
normal in 30 percent of cases), and the patient should be evaluated for an underlying hematologic or lymphoproliferative disorder. Patients between
30 and 40 years of age could have either disorder, and genotyping of the C1INH gene (SERPING1) should be considered for definitive diagnosis.
DIAGNOSIS
The diagnosis of types I and II HAE is based upon a suggestive clinical history and physical findings during episodes, combined with consistent results
from at least two sets of complement studies. Ideally, these should be separated in time by one month or more. A family history of angioedema strongly
supports the diagnosis, but it is not required, since approximately one-quarter of patients have de novo mutations. Genetic testing is not required to
confirm the diagnosis of HAE with C1 inhibitor deficiency (C1INH-HAE) in adults.
1989
The diagnosis of HAE associated with variants in factor XII (FXII-HAE), angiopoietin-1, or plasminogen is based upon suggestive clinical history and
physical findings during episodes, normal complement studies, and a positive family history. Genetic studies confirm the diagnosis and is the only way
to make a definitive diagnosis if the family history is negative.
The diagnosis of HAE of unknown origin (U-HAE) requires a suggestive clinical history and physical findings during episodes, normal complement
studies, a positive family history, and demonstrated lack of effectiveness of a prolonged trial of high-dose nonsedating antihistamines.
TESTING FAMILY MEMBERS
Once a diagnosis of HAE has been made, testing of the patient's children, parents, and siblings (if parents carry the mutation) should be strongly
encouraged. The recommended studies are the same as those used for screening: complement component 4 (C4), C1 inhibitor (C1INH) antigenic levels,
and C1INH functional levels.
In C1INH-HAE, approximately 25 percent of cases result from de novo mutations, so affected descendants are usually but not always identified. C1INH-
HAE does not skip generations, although it can occasionally appear to do so if affected individuals are asymptomatic.
Accuracy of testing in infants — Both C1INH levels and function are difficult to interpret in children younger than one year of age because C1INH levels
are normally 30 to 50 percent lower than adult levels, even in the absence of disease. Both false-positives and false-negatives may occur in infants
screened in the manner suggested for adults [42]. C4 levels are also variable in this age group. Genetic testing is occasionally performed in infants under
the age of one year if a definitive diagnosis is required and the disease-causing mutation in the family is known. In most cases, testing is simply
postponed until the infant is older, and the diagnosis can be made using complement studies [5,43].
A number of disorders share clinical or laboratory features of HAE [44].
Cutaneous and/or laryngeal swelling — Cutaneous and/or laryngeal swelling without urticaria can also result from non-bradykinin-mediated processes.
These include the following:
● Allergic reactions and anaphylaxis – Allergic reactions and anaphylaxis can involve cutaneous and laryngeal swelling. There are often associated
symptoms affecting multiple organ systems simultaneously, such as urticaria, wheezing, vomiting, diarrhea, and hypotension. The onset of allergic
reactions is rapidly progressive or even explosive, and the patient can often identify a precipitating event, such as a meal, an insect sting, or
administration of a new medication. Thus, compared with attacks of HAE, allergic reactions are generally more rapid in onset, involve multiple organ
systems, and can include urticaria and wheezing (which are never seen in attacks of HAE).
If laryngeal edema is present, airway assessment and management must always take precedence over any other treatments. If anaphylaxis is a
diagnostic possibility, the patient should be given epinephrine without delay. Complement studies and/or serum tryptase levels should be obtained
after the patient is stabilized. Any elevation in serum tryptase is consistent with anaphylaxis, although a normal level does not exclude it. (See
"Anaphylaxis: Emergency treatment".)
● Idiopathic angioedema – By definition, idiopathic angioedema is a diagnosis of exclusion. Complement studies are normal in this condition. (See "An
overview of angioedema: Clinical features, diagnosis, and management", section on 'Recurrent, idiopathic angioedema'.)
● Drug-induced angioedema – Medications, particularly angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs
(NSAIDs), may be associated with angioedema. ACE inhibitors create a predisposition to angioedema, and patients have occasional episodes. In
contrast, NSAIDs trigger angioedema with nearly every administration in patients who are susceptible to angioedema with these drugs.
The mouth and throat are commonly affected in drug-induced angioedema. Complement studies and C1 inhibitor (C1INH) levels are normal. Drug-
induced angioedema is reviewed in greater detail elsewhere. (See "An overview of angioedema: Pathogenesis and causes", section on 'Causes' and
"ACE inhibitor-induced angioedema".)
● Allergic contact dermatitis – Allergic contact dermatitis can be confused with facial angioedema. Contact dermatitis can cause dramatic swelling of
the facial and periorbital skin when it develops in response to cosmetic or topical pharmaceuticals. Microvesiculation and/or deep erythema of the
skin can help distinguish this from complement-mediated angioedema. Patients with contact dermatitis may complain of pain and burning of the
skin. Poison ivy can cause a similar clinical picture, but linear patterns of vesiculations are often detectable, and pruritus is prominent. Contact
dermatitis responds to oral glucocorticoids and does not involve complement abnormalities. (See "Clinical features and diagnosis of allergic contact
dermatitis".)
● Autoimmune conditions – Facial, periorbital, and sometimes hand edema can be seen in systemic lupus, polymyositis, dermatomyositis, and
Sjögren syndrome. Early stages of both scleredema and systemic sclerosis can present as swelling. However, the swelling of these conditions is
1990
persistent. Scleredema often involves the posterior neck, and systemic sclerosis often affects the hands and may be accompanied by Raynaud
phenomenon [44]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
● Thyroid disorders – Both hypothyroidism and hyperthyroidism can cause skin changes that could be mistaken for angioedema but develop over a
period of weeks to months and are not episodic. (See "Clinical manifestations of hypothyroidism" and "Pretibial myxedema (thyroid dermopathy) in
autoimmune thyroid disease".)
● Superior vena cava syndrome and tumors – Occasionally, edema of the face, neck, or upper extremities is observed with rapidly developing superior
vena cava syndrome (see "Malignancy-related superior vena cava syndrome"). Tumors of the head and neck and lymphoma can also cause
localized edema. Unlike the C1INH disorders, protracted or progressive swelling would be expected with these entities.
● Cheilitis granulomatosa (Miescher's cheilitis) and Melkersson-Rosenthal syndrome – These are rare disorders of persistent lip angioedema that
lead to eventual permanent enlargement of the lips. The Melkersson-Rosenthal syndrome is also characterized by facial paralysis, facial swelling,
and a fissured tongue, typically beginning in adolescence [45]. Complement studies are normal.
● Trichinosis – Infection with Trichinella spiralis can cause periorbital edema and abdominal symptoms, including abdominal pain, vomiting, and
diarrhea. Eosinophilia is usually present. (See "Trichinellosis".)
Low C4 levels — The differential diagnosis of a consistently low complement component 4 (C4) level in the setting of normal C1INH level and function is
reviewed elsewhere. (See "Overview and clinical assessment of the complement system", section on 'Classical pathway activation' and "Inherited
disorders of the complement system", section on 'C4 deficiency'.)
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society
guideline links: Hereditary angioedema and other forms of nonhistaminergic angioedema".)
● Hereditary angioedema (HAE) is a rare condition characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often
affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. It is predominantly mediated by bradykinin, a potent
vasodilatory peptide, although other mediators may be involved. (See 'Pathogenesis' above.)
● There are several types of HAE:
• Types I and II result from deficiency or dysfunction of C1 inhibitor (C1INH), respectively, and are collectively called HAE with C1INH deficiency
(C1INH-HAE). C1INH plays a role in regulating bradykinin production. However, the precise mechanisms by which these defects predispose to
episodic angioedema are not understood. Complement studies are abnormal in C1INH-HAE. In at least 90 percent of patients with C1INH-HAE,
plasma levels of complement component 4 (C4) are always low, even during asymptomatic periods, and thus, C4 is a good screening test. The
inheritance pattern of C1INH-HAE is autosomal dominant, although 25 percent of cases result from de novo mutations, and occasional affected
individuals may be asymptomatic. (See 'HAE with C1 inhibitor deficiency/dysfunction' above.)
• The other types of HAE are characterized by normal complement studies. At least four disorders have been defined: HAE associated with
variants in the genes for factor XII (FXII-HAE), angiopoietin-1 (ANGPT1), or plasminogen and HAE of unknown etiology (U-HAE). (See 'HAE with
normal C1 inhibitor' above.)
● Indications for screening for HAE include recurrent angioedema without urticaria, unexplained recurrent episodic abdominal pain, a family history of
angioedema, any episode of unexplained laryngeal edema, and a low C4 level. (See 'When to suspect HAE' above.)
● Patients with HAE (of any type) do not respond to antihistamine therapy. Most patients with HAE have been given antihistamines and
glucocorticoids multiple times in the past without benefit. However, if a therapeutic trial of high-dose antihistamines has not been given, this should
be done in cases where there is no evidence of a deficiency or defect in C1INH and no suggestive family history. (See 'Trial of high-dose
antihistamines' above.)
● Our approach to evaluation and testing depends upon whether the clinical suspicion is low or high because this determines how extensive
complement testing should be. When clinical suspicion is high, the evaluation is further influenced by the presence or absence of a family history of
angioedema. (See 'Algorithmic approach to evaluation' above.)
• If clinical suspicion is low, C4 alone is an adequate screening test. (See 'Low clinical suspicion' above.)
• If clinical suspicion is high and there is a family history of angioedema, we suggest one approach (algorithm 2).
1991
• If clinical suspicion is high and there is no family history, we suggest a somewhat different approach (algorithm 1).
● Once a patient has been diagnosed with HAE, screening for the disorder should be offered to family members. (See 'Testing family members' above.)
● The differential diagnosis of HAE includes other causes of angioedema, as well as other conditions that cause similar complement abnormalities.
ACKNOWLEDGMENT
We are saddened by the death of Marco Cicardi, MD, who passed away in August 2019. UpToDate wishes to acknowledge Dr. Cicardi's past work as an
author for this topic.
1992
GRAPHICS
Pathways involved in kinin-mediated angioedema and actions of drugs
C4: complement component 4; C1INH: C1 inhibitor.

* In the disorder hereditary angioedema (HAE) with factor XII mutations, factor XII may be prone to excessive activation.
Data from:
1. Morgan PB. Hereditary angioedema—therapies old and new. N Engl J Med 2010; 363:581.
2. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet 2012; 379:474.
1993
Complement pathways
There are three major independent yet overlapping pathways for complement activation. In the
classical pathway, immune complexes (Ag-Ab complexes) bind C1 via its C1q subcomponent, while its
C1s protease subunit cleaves C4 and C2. The large C4b fragment binds to a target and subsequently
captures the large fragment of C2 (C2a). This bimolecular complex forms an enzyme (the C3
convertase, C4bC2a) that cleaves C3 to C3b and releases the anaphylatoxin, C3a. The binding of
another C3b to the convertase (C4bC2aC3b) generates the C5 convertase.
The lectin pathway is an analogous system, except that the initiating step is the binding by lectins to
repetitive sugars on microbial surfaces. Mannose-associated serine proteases (MASPs) take the place
of the C1 proteases.
The alternative pathway (AP) continuously self-activates at a low level (a process called C3 tickover) to
generate C3b that deposits on pathogens or debris. C3b or C3(H 2 O) engages the alternative pathway
components, factors B (FB) and D (FD), to form a C3 convertase (C3bBb), which in turn cleaves more C3
to C3b. The binding by another C3b to the C3 convertase generates the C5 convertase (C3bBbC3b).
Properdin (P) is a positive regulator that stabilizes both the AP C3 and C5 convertases. The latter
subsequently cleaves C5 to release the potent anaphylatoxin C5a, while C5b engages the terminal
pathway and initiates the formation of the lytic membrane attack complex (MAC). The complement
system is designed to function most efficiently on a biologic membrane.
1994
The contribution of C1INH to protease inhibition in plasma
Protease % of plasma inhibitory capacity provided by C1INH
Complement system
C1r 100
C1s 100
MASP2 *
Contact system
Plasma kallikrein 42 to 84
Coagulation factor XIa 47
Coagulation factor XIIa 90
Fibrinolytic system
Tissue plasminogen activator ¶
Plasmin ¶
C1INH: C1 inhibitor; MASP2: mannose-associated serine protease 2.

* Undetermined; probably the primary inhibitor; alpha 2 -macroglobulin may play some role.
¶ C1INH plays little (if any) role under normal circumstances, but small amounts of complexes with tissue plasminogen activator and plasmin may be observed in some situations (angioedema attacks, endotoxin shock,
and exhaustive exercise).
Reproduced from: Davis AE III. Hereditary angioedema: a current state-of-the art review, III: Mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol 2008; 100 (Suppl 2):S7. Table used with the permission of Elsevier Inc.
1995
Classification of angioedema without wheals
ACE inhibitors: angiotensin-converting enzyme inhibitors; C1INH deficiency: C1 inhibitor deficiency.

* Mutations in the genes encoding factor XII, angiopoietin-1, plasminogen, and kininogen-1 are associated with hereditary angioedema (HAE).
From: Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema
International Working Group. Allergy 2014; 69:602. http://onlinelibrary.wiley.com/doi/10.1111/all.12380/abstract. Copyright © 2014 European Academy of Allergy and
Clinical Immunology. Modified with permission of John Wiley & Sons, Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it
can be downloaded to PowerPoint, printed, shared, or emailed. Please contact Wiley's Permissions Department either via email: permissions@wiley.com or use the
RightsLink service by clicking on the Request Permission link accompanying this article on Wiley Online Library (www.onlinelibrary.wiley.com).
1996
Comparison of complement studies in angioedema disorders
Angioedema disorder C4* C1-INH level C1-INH function C1q Other tests
Hereditary angioedema with C1- Low Low Low Normal Genetic testing
INH deficiency type I (HAE-C1- (usually <50% of normal) (not needed for diagnosis)
INH
type I)
Hereditary angioedema with Low Normal or elevated Low Normal Genetic testing
C1INH deficiency type II (HAE- (usually <50% of normal) (not needed for diagnosis)
C1-INH type II)
Hereditary angioedema with Normal Normal Normal Normal Mutations in gene for factor XII
factor XII gene mutations
(HAE-FXII)
Hereditary angioedema with Normal Normal Normal Normal Mutations in gene for
angiopoietin-1 gene mutations angiopoietin-1
(HAE-ANGPT1)
plasminogen gene mutations plasminogen
(HAE-PLG)
Hereditary angioedema with Normal Normal Normal Normal Mutations in gene for kininogen-
kininogen-1 gene mutations 1
(HAE-KNG1)
Hereditary angioedema of Normal Normal Normal Normal

unknown origin (HAE-U)
Acquired angioedema with Low Normal or low Low Normal or low ¶ Anti-C1INH antibodies
C1INH deficiency (AAE-C1-INH) (usually <50% of normal) (not needed for diagnosis)
Idiopathic acquired angioedema Normal Normal Normal Normal

(histaminergic or
nonhistaminergic)
(AAE-IH or AAE-InH)
ACE inhibitor-associated Normal Normal Normal Normal

angioedema (AAE-ACEI)
Terminology for angioedema disorders is evolving, and the abbreviations HAE-C1-INH and C1INH-HAE are both used for hereditary angioedema in the literature.
C1-INH: C1 inhibitor; HAE: hereditary angioedema; AAE: acquired angioedema; ACEI: angiotensin-converting enzyme inhibitor.
* In HAE-C1-INH types I and II, C4 is always low during an attack (with one published exception) and are chronically low in the majority of patients.
¶ There are rare forms of acquired angioedema in which C1q levels are normal. Refer to the UpToDate topics on acquired C1 inhibitor deficiency for details.
1997
Evaluation of a patient with symptoms suggestive of hereditary angioedema but NEGATIVE family history (or family history not known)
ACE: angiotensin-converting enzyme; NSAIDs: nonsteroidal anti-inflammatory drugs; C1INH: C1 inhibitor; SERPING1: the gene for C1 inhibitor.
* C4: In patients with C1INH-HAE, C4 is usually <50% of normal. If results are not reported as a percentage of normal, then 25 mg is a normal value in adults, C4 <10 mg is definitely pathologic, C4 of 10 to 15 mg is possibly
pathologic, and C4 >15 is not pathologic.
¶ In the presence of normal C4, low C1INH protein levels are usually due to laboratory error.
Δ Identified variants include those in the genes for factor XII, angiopoietin-1, and plasminogen.
1998
Evaluation of a patient with symptoms and family history suggestive of hereditary angioedema
ACE: angiotensin-converting enzyme; NSAIDs: nonsteroidal anti-inflammatory drugs; C1INH: C1 inhibitor.

* C4: In patients with C1INH-HAE, C4 is <50% of normal. If results are not reported as a percentage of normal, then 25 mg is a normal value in adults, C4 <10 mg is
definitely pathologic, C4 of 10 to 15 mg is possibly pathologic, and C4 >15 is not pathologic.
¶ In the presence of normal C4, low C1INH protein levels are usually due to laboratory error.
Δ Identified variants include those in the genes for factor XII, angiopoietin-1, and plasminogen.
1999
Hereditary angioedema: Epidemiology, clinical manifestations,

exacerbating factors, and prognosis
INTRODUCTION
Hereditary angioedema (HAE) is a disease characterized by recurrent episodes of angioedema,

without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper
respiratory and gastrointestinal tracts. Although the swelling is self-limited, laryngeal involvement
may cause fatal asphyxiation. Prior to the availability of effective therapy, this disorder was
associated with a mortality rate of approximately 30 percent due to asphyxiation from laryngeal
swelling.
The epidemiology, clinical manifestations, triggering and exacerbating factors, and prognosis of HAE
are discussed in this topic review. The laboratory evaluation, establishing definitive diagnosis, and
acute and prophylactic therapies of this disorder are discussed separately:
● (See "Hereditary angioedema: Pathogenesis and diagnosis".)

● (See "Hereditary angioedema: Acute treatment of angioedema attacks".)
● (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term
prophylaxis".)
HAE types I and II are the focus of this topic review. These disorders are caused by deficiency or
dysfunction of the C1 inhibitor protein. (See "Hereditary angioedema: Pathogenesis and diagnosis",
section on 'Pathogenesis'.)
HAE with normal C1 inhibitor (also called type III HAE) is a clinically similar disorder, seen mostly in
women, in which C1 inhibitor is normal. Some patients have factor XII defects. This disorder is
2000
discussed separately. (See "Hereditary angioedema with normal C1 inhibitor".)
EPIDEMIOLOGY
The prevalence of hereditary angioedema (HAE) is estimated at 1 individual per 50,000, with reported
ranges from 1:10,000 to 1:150,000 [1-3]. Males and females are affected equally, and there are no
known differences in prevalence among ethnic groups [2,4,5].
Age of onset — The age at which attacks begin is variable, with rare reports of initial episodes of
angioedema in the perinatal period [6]. Approximately 40 percent of patients experience their first
attack before age 5, and 75 percent, by age 15, although repeated attacks in preadolescent children
are uncommon [6-9]. Thus, for the majority of patients, the disease first presents in childhood or
adolescence. Attack frequency usually increases after puberty. In most cases, the diagnosis is
eventually made in the second or third decade of life and can be further delayed if there is no family
history.
Laboratory findings — Patients with hereditary angioedema (HAE) demonstrate characteristic

abnormalities in the complement system, upon which the diagnosis is based. These are discussed in
detail separately. (See "Hereditary angioedema: Pathogenesis and diagnosis".)
Other than abnormal complement studies, patients with HAE are usually healthy and most
commonly have normal routine laboratory values, although hypergammaglobulinemia has been
noted in some patients [10,11].
Characteristic features of angioedema attacks — Attacks most often affect three anatomical
locations:
● The skin (cutaneous attacks)

● The gastrointestinal tract (gastrointestinal attacks)
● The upper airway (laryngeal/pharyngeal attacks)
Many attacks involve only one site at a time, although combination attacks, such as cutaneous
attacks that spread to involve the larynx, are not uncommon. Attacks are always self-limited, lasting
two to four days, and range in severity from inconvenient cutaneous swelling to life-threatening
laryngeal edema [12,13]. Approximately 50 percent of patients experience all three manifestations
during the course of their lives [7]. Other general observations about HAE include the following:
2001
● Attack frequency varies from weekly to one or two episodes per year [13]. Untreated, patients
with frequent attacks may miss up to 100 to 150 work days per year [7]. A few subjects remain
asymptomatic and are identified as having hereditary C1 inhibitor deficiency only as a result of
family screening [1,6].
● Disease severity differs markedly among affected members within families, despite the
presence of the same mutation [6]. Disease severity may also vary significantly in the same
patient over time. The factors determining disease severity are unknown. A study found that
severity correlated with the presence of elevated levels of immunoglobulin M (IgM)
autoantibodies to the C1 inhibitor protein [11]. This was noted in patients who had never
received C1 inhibitor concentrate for treatment, as well as in patients who had, so that it did not
appear to be related to exposure to this agent. Nor was it proposed to have a direct role in
determining disease severity. Rather, it was hypothesized that antibody formation may be a
secondary phenomenon resulting from frequent activation of inflammatory pathways during
attacks. (See "Hereditary angioedema: Pathogenesis and diagnosis", section on 'Pathogenesis'.)
Prodromal symptoms and skin changes — Prodromal symptoms include fatigue, nausea or other
gastrointestinal symptoms, and myalgias and flu-like symptoms [14,15]. Some patients develop skin
changes that are usually described as a serpentine, mottled, and/or "chicken-wire" pattern of
erythematous discoloration (picture 1) [16-19]. These findings can be mistaken for urticaria, but more
closely resemble erythema marginatum. Skin changes were noted consistently in 26 percent of
patients in one series [20]. Prodromal symptoms usually occur within 24 hours before the onset of
angioedema, although not all prodromal symptoms are followed by an angioedema episode.
Cutaneous attacks — Cutaneous attacks are common and temporarily disfiguring, although not
generally dangerous. Skin swelling was present in 97 percent of 131,110 edema episodes in a
retrospective series of 221 patients [6]. The extremities, face, and genitals are most commonly
affected, although any site can be involved (picture 2). Swelling occurs in nondependent areas and is
nonpitting. Cutaneous attacks are often associated with pain and dysfunction in addition to swelling
[21]. An episode typically begins in the skin with a peculiar tingling or sensation of fullness and
irritation, followed by swelling and a sense of tightness in the next two to three hours. The
angioedema builds over the first 24 hours, then gradually subsides over 48 to 72 hours [22]. Swelling
may last up to five days in some patients. Attacks can also last longer if the swelling spreads from
one site to another.
Laryngeal attacks — Laryngeal swelling can occur in isolation, or in association with swelling of
the lips, tongue, uvula, and soft palate [6]. Laryngeal edema occurs in approximately one-half of all
patients over their lifetimes; however, only a few percent experience recurrent episodes, and in the
large retrospective series mentioned above, laryngeal attacks accounted for less than 1 percent of all
2002
angioedema episodes [6]. Laryngeal attacks are less common in patients over the age of 45 [22].
Tooth extraction and oral surgery are common triggers. (See 'Triggers and exacerbating factors'
below.)
Laryngeal swelling usually develops over hours, with a reported mean of seven hours [23]. However,
there are disturbing reports of fulminant laryngeal attacks, including a nine-year-old boy with a family
history of HAE, but no previous attacks who died of asphyxiation 20 minutes after the apparent onset
of symptoms [23-25]. Although each laryngeal attack has the potential to become life threatening,
the majority resolves before complete airway obstruction, and one large series documented only two
intubations and four cricothyrotomies among 342 laryngeal attacks [22].
In a study of 70 fatal laryngeal attacks, researchers proposed that three phases of an attack can be
distinguished [25]:
● The predyspnea phase, which starts with the first noticeable symptom and ends when dyspnea
develops (average length, 3.7 hours, range 0 to 11 hours). During this phase, patients typically
reported the sensation of a lump or feeling of tightness in the throat or swallowing difficulties,
but not frank dyspnea. Six patients did not appear to have a predyspnea phase at all, as their
initial symptom was dyspnea.
● The dyspnea phase, from onset of dyspnea to loss of consciousness (average length 41
minutes, range 2 minutes to 4 hours).
● The loss of consciousness phase, which starts with loss of consciousness and ends with death
(average length 9 minutes, range 2 to 20 minutes).
Thus, there is a window of opportunity in the predyspnea phase in which patients can seek and
receive help, followed by a much shorter period in the dyspnea phase. In this study, 63 patients had
not been diagnosed with HAE at the time of death, and 7 had. Possible triggers were apparent in a
minority of patients (eight had preceding upper respiratory tract infections and six had tooth
extractions). The mean age of death by asphyxiation in undiagnosed patients was 40.6 years.
Gastrointestinal attacks — Gastrointestinal attacks present as varying degrees of gastrointestinal

colic, nausea, vomiting, and/or diarrhea [26]. These symptoms result from bowel wall edema.
Gastrointestinal attacks are experienced by a majority of patients with HAE, and can be the principal
presentation in one-quarter of patients [6,13]. A few families have been reported in which bowel
attacks were the only manifestation.
In a large, mostly retrospective, observational study of over 33,000 gastrointestinal attacks in 153
patients with HAE, symptoms and patterns of symptom development were analyzed [27]. The
patients included in this series had received treatment with analgesics or spasmolytics only. All
2003
attacks were painful, with a mean pain score of 8.4 on a subjective scale of 1 (minimal) to 10
(maximal). Three-quarters included nausea, vomiting, and abdominal distension, and 41 percent
involved diarrhea. Four percent of patients experienced circulatory collapse. At least one prodromal
symptom occurred at the onset of 70 percent of the attacks, and symptoms included fatigue,
irritability, sensitivity to noise, hunger, and erythema marginatum. Attacks lasted four days on
average, from the onset of prodromal symptoms to complete resolution, and peaked on the second
day.
Gastrointestinal attacks can be challenging to diagnose and the clinician must determine if the
abdominal symptoms are due to angioedema or to an unrelated process. Patients who have had
previous gastrointestinal attacks should be questioned carefully to ascertain if their current
symptoms are similar to past episodes. Because of the clinical similarities between bowel attacks of
angioedema and true surgical emergencies, as many as one-third of patients with undiagnosed HAE
may undergo unwarranted abdominal surgery [7,28].
Objective findings
● Most abdominal attacks are NOT associated with fever, peritoneal signs, or an elevated white
blood cell count. However, during severe abdominal attacks, elevations of neutrophils (without
increased bands), hypovolemia from fluid losses, or hemoconcentration from plasma
extravasation and/or vasodilation have been reported [29-31]. Neutrophils have been reported to
be elevated, but without a left shift (ie, without an increase in bands) [31].
● Imaging is not routinely needed during an abdominal attack in a patient with known HAE who is
reporting characteristic symptoms. However, if the cause of the patient's presentation is unclear,
a computed tomography (CT) scan of the abdomen and pelvis or ultrasonography is useful in
confirming the findings of gastrointestinal angioedema. The most common early finding is
bowel wall edema, although this may resolve rapidly [31-33]. Ascites may be the only finding
during later stages of the attack [34].
Unusual manifestations of hereditary angioedema — Unusual forms of attacks include episodic

swelling of the bladder and urethra, circumscribed induration of muscles, chest tightness or pain,
renal colic, joint swelling, and pleural or pericardial fluid accumulations [6,35]. There is sometimes
accompanying or preceding cutaneous swelling.
Associated conditions — Most patients with HAE are otherwise healthy.
● Those with severe or frequent attacks have impaired quality of life and may suffer from
depression [36].
2004
● Pancreatitis has been reported in patients with HAE, although it is not clear if the two disorders
are pathologically related [10,37-44].
● There may be an association with autoimmune diseases and enhanced autoantibody

production. Autoimmune conditions were reported in 19 of 157 patients (12 percent) in one
series of patients with HAE [10]. Associated disorders include thyroiditis, systemic lupus
erythematosus (SLE), Sjögren's syndrome, inflammatory bowel disease, glomerulonephritis, and
a nonrheumatoid erosive arthritis of the wrists and hips [45-47]. It has been proposed that the
depressed levels of C4 seen in patients with HAE may contribute to the development of
autoimmune disease, since C4 is important in the solubilization and clearance of immune
complexes [48,49]. Chronic overactivation of B cells (as determined by heightened expression of
toll-like receptor 9), has also been demonstrated [50]. High rates of positivity for antinuclear
antibodies were found in two series (16 and 28 percent, compared with 5 percent in the general
population) [50,51].
TRIGGERS AND EXACERBATING FACTORS
Patients report a variety of triggers for episodes of angioedema. Stress (either mental or physical)
and dental procedures are the most common.
Physical triggers — Mild trauma, including dental work, is a common trigger and will precipitate
episodes of angioedema in many patients. Intubation is another important trigger. Prophylaxis for
prevention of attacks associated with dental work or surgery is discussed elsewhere. (See
"Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
Tongue-piercing and snoring-induced local trauma of the soft palate have been implicated in isolated
case reports [52,53]. Genital swelling in women can be precipitated by sexual intercourse, as well as
bicycle or horse riding [54]. The reason one type of insult precipitates attacks, while another does
not, is poorly understood.
Other triggers that have been reported (although not all necessarily validated) include excitement,
sleep deprivation, cold exposure, prolonged sitting or standing, ingestion of certain foods, bacteriuria,
and menstruation [48,55,56].
Helicobacter pylori infections can trigger gastrointestinal attacks and eradication of this infection
can lead to significant reduction in the frequency of gastrointestinal attacks [57,58].
Medications — The following medications can exacerbate the frequency and/or severity of hereditary
angioedema (HAE) attacks:
2005
● Estrogen-containing medications, such as hormone replacement therapy and contraceptives
[59]. (See 'Hormonal changes in women' below.)
● Tamoxifen, a selective estrogen-receptor modulator (SERM) that has mixed agonist/antagonist

actions on the estrogen receptor. In one reported case, a patient with HAE who developed
increased episodes on tamoxifen was successfully treated with the aromatase inhibitor letrozole
[60].
● Angiotensin-converting enzyme (ACE) inhibitors [55]. In contrast, the experience of one author
(MC) is that angiotensin II receptor blockers (ARBs) are well-tolerated.
Hormonal changes in women — The impact of hormonal fluctuations, including pregnancy, on

women with HAE is variable [20,61-64]. The largest study was a retrospective questionnaire-based
survey of 150 postpubertal women with HAE (both on and off therapy) from eight European
countries, which reported the following observations [62]:
● Disease worsened with puberty in 62 percent and did not change for the others.
● Attacks were associated with the perimenstrual or menstrual period in 35 percent.
● Use of oral contraceptives containing both estrogen and progesterone worsened disease
severity in 80 percent of respondents. In contrast, progesterone-only contraceptives improved
disease in 64 percent. Intrauterine devices were well-tolerated by 83 percent.
● Pregnancy was associated with more attacks in 38 percent, fewer in 30 percent, and no change
in 32 percent [62]. Most women reported that the effects during an initial pregnancy were similar
in subsequent pregnancies. Women who had attacks in association with menses were more
likely to have worsening of disease during pregnancy, indicating that a subset of women is
particularly sensitive to hormonal triggers.
● Delivery did not precipitate attacks in most women, as noted in other studies [20,63]. The
majority (89 percent) were not given prophylactic treatment in preparation for delivery, and yet
attacks during or within two days of delivery occurred in only 6 percent.
● Of the 29 percent of participants who had experienced menopause, 55 percent noticed no

change in disease activity. A worsening of attacks was reported by 32 percent.
● There were no detectable differences in the rates of gynecologic disease, infertility, or

spontaneous abortion in women with HAE compared with those in the general population.
Another study followed 22 women with HAE through 35 pregnancies and found an increase in attack
rates during pregnancy or in the postpartum period in 83 percent [64]. All women received
2006
replacement C1 inhibitor therapy during pregnancy and just prior to delivery, and none experienced
attacks during labor or delivery. These patients were followed at a referral center, and so the severity
of their disease may have been greater than that of patients with HAE treated elsewhere.
Recommendations for the gynecologic and obstetric care of women with HAE are reviewed
elsewhere. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term
prophylaxis", section on 'Gynecologic and obstetric care'.)
PROGNOSIS
The prognosis for patients with hereditary angioedema (HAE) is variable. Once attacks have begun,
they generally continue throughout the patient's life, although the frequency of attacks can be
dramatically reduced by therapy.
Prior to the introduction of effective therapies for HAE, up to one-third of patients died of
asphyxiation [20]. However, despite effective therapies, deaths secondary to laryngeal attacks still
occur with some regularity, although data are limited. A series of Austrian, Swiss, and German
patients published in 2004 cited a mortality rate as high as 13 percent [48].
the world are provided separately. (See "Society guideline links: Hereditary angioedema and other
forms of nonhistaminergic angioedema".)
SUMMARY
Hereditary angioedema (HAE) is a rare disorder caused by deficiency or dysfunction of the C1

inhibitor. HAE is characterized clinically by recurrent episodes of angioedema, without
accompanying hives or pruritus, which most commonly affect the skin, bowel, or upper airway. (See
● HAE affects men and women equally. There are no known racial predilections. Although
symptoms often begin in childhood, the disease is commonly diagnosed during puberty or early
adulthood, when attacks become more frequent. (See 'Epidemiology' above.)
● An attack of HAE usually involves one site at a time (skin, viscera, or larynx). A prodrome of
fatigue or erythematous rash is noticed by some patients. Attacks build in severity for 24 hours
2007
and then subside over the next 24 to 72 hours. (See 'Clinical manifestations' above.)
● The most life-threatening type of attack involves the upper airway, and any swelling in this area
should be regarded as an emergency. Laryngeal attacks usually develop over hours, but there
are reports of precipitous airway closure. Laryngeal edema occurs in approximately one-half of
all patients over their lifetimes, although only a few percent experience recurrent episodes. (See
'Laryngeal attacks' above.)
● Gastrointestinal attacks are experienced by a majority of patients with HAE and present as
varying degrees of gastrointestinal colic, nausea, vomiting, and/or diarrhea, which result from
bowel wall edema. (See 'Gastrointestinal attacks' above.)
● Cutaneous attacks are common and temporarily disfiguring, although not generally dangerous.
The extremities, face, and genitals are most commonly affected, although any site can be
involved (picture 2). Swelling occurs in nondependent areas and is nonpitting. (See 'Cutaneous
attacks' above.)
● Mild trauma, including dental work, is the most common trigger for cutaneous and laryngeal
attacks. Other triggers that have been reported include estrogens, angiotensin-converting
enzyme (ACE) inhibitors, stress, H. pylori infection, and menstruation. (See 'Triggers and
exacerbating factors' above.)
● Once attacks have begun, they generally continue throughout the patient's life, although the
frequency of attacks can be dramatically reduced by therapy. The mortality rate for patients with
HAE, despite effective therapies, has been estimated to be as high as 13 percent. (See
'Prognosis' above.)
ACKNOWLEDGMENTS
The editorial staff at UpToDate would like to acknowledge John P Atkinson, MD, who contributed to
earlier versions of this topic review.
We are saddened by the death of Marco Cicardi, MD, who passed away in August 2019. UpToDate
wishes to acknowledge Dr. Cicardi's past work as an author for this topic.
2008
GRAPHICS
Hereditary angioedema prodromal rash
Annular erythematous lesions mimicking chicken-wire appearance.
Reproduced with permission from: Yucelten D, Kus S. Chicken-wire erythema, but not urticaria, as the
presenting sign of hereditary angioedema. Eur J Dermatol 2006; 16:197. Copyright © 2006 John Libbey
Eurotext.
2009
Hereditary angioedema
Top) Severe angioedema of the face during a cutaneous attack of hereditary angioedema.
Bottom) The same patient's normal appearance.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al. (Eds). Color Atlas and
Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York, 1997. Copyright © 1997 McGraw Hill.
2010
Hereditary angioedema (due to C1 inhibitor deficiency): General

care and long-term prophylaxis
Authors: Bruce Zuraw, MD, Henriette Farkas, MD, PhD, DSc
INTRODUCTION
Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare genetic disorder in which
mutations in the SERPING1 gene result in deficiency (type I) or dysfunction (type II) of C1 inhibitor
(C1-INH) protein [1,2]. Terminology is evolving, and the abbreviations HAE-C1-INH and C1INH-HAE
are both used for this disorder in the literature [2,3]. HAE is characterized by recurrent episodes of
angioedema without pruritus or urticaria, which most often affect the skin or mucosal tissues of the
upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to five
days in the absence of treatment, angioedema is often temporarily debilitating, and laryngeal
angioedema may cause fatal asphyxiation.
In patients with sufficiently frequent or severe episodes of angioedema, regularly administered

prophylaxis is required to maintain an acceptable quality of life. This is referred to as long-term
prophylaxis, in contrast to short-term prophylaxis, which is premedication given briefly before a
specific medical or dental procedure. Short-term prophylaxis is discussed separately. (See
"Hereditary angioedema: Temporary prophylaxis before procedures or stress to prevent angioedema
episodes".)
The general management of adults and children with HAE-C1-INH and the various long-term
prophylactic therapies that are used to prevent attacks will be reviewed here. The management of
HAE attacks as well as the clinical manifestations, pathogenesis, and diagnosis of this condition are
discussed separately:
2011
● (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and
prognosis".)
There is another form of HAE in which patients have normal complement studies called HAE with
normal C1-INH. This disorder affects mainly women, while men are often asymptomatic carriers.
Mutations in at least four genes (coding for coagulation factor XII, plasminogen, angiopoietin 1, and
kininogen 1) have been associated with some patients with HAE with normal C1-INH. This disorder is
also characterized by the tendency of estrogens in exacerbating the swelling. HAE with normal C1-
INH is reviewed separately. (See "Hereditary angioedema with normal C1 inhibitor".)
GENERAL CARE
General care measures for HAE include education, testing of family members, identification and
avoidance of possible triggers, and planning for HAE attacks. An international committee formulated
a consensus report for the management of patients with HAE-C1-INH in 2010, which was updated in
2012 and is based upon the available literature and practices worldwide [1,4]. Recommendations
have also been published by an expert American group [5]. The recommendations made in this
review are consistent with these publications.
Education — The most important intervention for a patient who has been newly diagnosed with HAE
is education about the disease. Both the affected individual and his/her family members should be
involved. Patients can access detailed, patient-oriented information through the United States
Hereditary Angioedema Association and the International Patient Organization for C1 Inhibitor
Deficiencies. Patients should be taught about attack triggers, potential risks, and the benefits of early
treatment of HAE attacks. The genetics of HAE and the implications regarding family members
should be discussed. Finally, the entire range of treatment options should be explained.
Testing of family members — First-degree relatives of the patient should be offered diagnostic
testing for HAE. The disease is transmitted in an autosomal dominant fashion with variable but
typically high penetrance. However, the patient may be the first affected member in the family, since
approximately 25 percent of cases result from new mutations.
The importance of testing first-degree family members is illustrated by a cohort study that
demonstrated that the risk of death from asphyxiation was greater in patients with undiagnosed HAE
compared with those who had been formally diagnosed and educated about the condition [6]. It
should be explained to patients that one-half of the children of a person with HAE can be expected to
have the abnormal gene, although not everyone with the abnormal gene has symptoms. Some
2012
people with the abnormal gene have minimal or no symptoms, while others have symptoms of
variable severity, and there is no way to predict how severely an individual will be affected. Another
advantage of testing is that it may help avoid diagnostic confusion and inappropriate treatment if
and when the person does develop symptoms.
Complement studies (C4, C1-INH level, and C1-INH function) are the recommended tests for
screening family members. Additional issues surrounding testing are discussed separately. (See
"Hereditary angioedema: Pathogenesis and diagnosis", section on 'Testing family members'.)
Trigger avoidance — Triggers vary among patients, although the following measures are important
for most:
● Avoidance of trauma, particularly to the face and upper respiratory tract

● Recognition and prompt treatment of oral and dental infections
● Avoidance of medications that can worsen the severity or frequency of angioedema episodes
(estrogens, angiotensin-converting enzyme inhibitors, others)
Triggers are reviewed in more detail separately. (See "Hereditary angioedema: Epidemiology, clinical
manifestations, exacerbating factors, and prognosis", section on 'Triggers and exacerbating factors'.)
Planning for acute treatment — All patients should be equipped with the following:
● A medical information bracelet or necklace identifying the condition.
● A written plan for treatment of HAE attacks for use in emergency department care. This
document (also available in a wallet card) should briefly explain the patient's diagnosis, outline
the indicated treatment for HAE attacks, and provide contact information for the supervising
clinician (form 1 and form 2). (See "Hereditary angioedema: Acute treatment of angioedema
attacks".)
● Whenever possible, the ability to self-administer an effective drug outside of a medical facility.
Patients should have a sufficient amount of medicine available and be trained in self-
administration.
Baseline laboratory studies — Baseline studies are recommended to assess hepatic and other organ
function (due to the potential need for chronic medications) and to screen for blood-borne illnesses
(due to the possible need for blood products). The following tests are suggested: liver function tests
(including alanine aminotransferase, total bilirubin); albumin; creatine kinase; blood urea nitrogen;
creatinine; complete blood count and differential; pregnancy testing (if applicable); urinalysis; and
screening tests for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C [4]. A
cholesterol panel should be obtained if the patient may be treated with androgens.
2013
Vaccinations — Patients should be vaccinated against hepatitis B in case they require blood-derived
products in the future [4].
Gynecologic and obstetric care — An international expert panel produced guidelines on the
gynecologic and obstetric care of women with HAE [7].
● Well-tolerated options for contraception include progesterone-based methods, such as

progesterone-only oral contraceptives, other progesterone delivering methods, and intrauterine
devices [8].
● The effect of pregnancy on a given patient's frequency and pattern of HAE attacks is difficult to
predict, although abdominal attacks usually become more frequent [9]. Disease activity during
one pregnancy does not necessarily predict disease activity during subsequent pregnancies
[10]. C1-INH is the preferred agent for prophylaxis and acute treatment of HAE attacks during
pregnancy.
● Labor and delivery generally do not precipitate HAE attacks, and the rate of cesarean deliveries
is not elevated compared with the overall population. However, C1-INH concentrate should be
available during delivery in case acute symptoms develop and for at least 48 hours afterward.
● Lactation can cause an increase in HAE attacks in some women. C1-INH concentrate is
preferred during lactation because the effects of tranexamic acid and androgens on infants are
not known.
● The impact of menopause on HAE severity is variable.
● Other issues, such as the management of polycystic ovary syndrome, infertility, and breast,
uterine, and cervical cancers, are also discussed in the guidelines [7].
ACCESS TO "ON-DEMAND" THERAPIES
All patients should have access to therapies to treat acute episodes of angioedema. Optimized on-
demand treatment is highly effective in reducing the number of symptomatic days and thus, the
overall burden of the disease. Options include plasma-derived C1-INH concentrate (human),
recombinant C1-INH concentrate (human), icatibant, ecallantide, and fresh frozen plasma. On-
demand treatment is reviewed in detail separately. (See "Hereditary angioedema: Acute treatment of
angioedema attacks", section on 'Overview'.)
APPROACH TO LONG-TERM PROPHYLAXIS
2014
The consensus guidelines provide several options for long-term prophylaxis to prevent attacks of
HAE-C1-INH, with which the authors agree, although practice differs somewhat around the world
[1,4].
Overview of available therapies — The therapies used for long-term prophylaxis in patients with HAE-
C1-INH are various preparations of C1-INH concentrate, lanadelumab, antifibrinolytics, and
attenuated androgens. Each has advantages and disadvantages, as summarized in the table (table
1). C1-INH concentrate and lanadelumab are first-line therapies where available. Antifibrinolytics and
attenuated androgens are alternatives that are less costly and are given orally, but these either have
significant side effects (androgens) or are less effective (antifibrinolytics) than the first-line
therapies.
● C1-INH concentrate – Regular injections of plasma-derived C1 inhibitor (pdC1-INH) are effective

and well-tolerated by nearly all patients. pdC1-INH prophylaxis can be administered by
intravenous or subcutaneous injection. When administered intravenously, repeated injections
can lead to problems with venous access, and the placement of indwelling ports is discouraged
because of risk of infection and thrombosis [11]. (See 'Intravenous plasma-derived C1 inhibitor'
below.)
A subcutaneous preparation of pdC1-INH was approved for long-term prophylaxis in the United
States in 2017 (Haegarda [brand name]). Subcutaneous administration provides more
consistent plasma levels compared with intravenous (IV) administration. It is also helpful for
patients with difficult venous access. It is anticipated to become available in other countries
soon. (See 'Subcutaneous C1 inhibitor' below.)
Recombinant human C1 inhibitor (rhC1-INH) is not approved for long-term prophylaxis, although
in a clinical trial, prophylaxis with rhC1-INH provided clinically relevant reductions in frequency
of hereditary angioedema attacks and was well-tolerated [12]. If shortages of pdC1INH arise,
rhC1INH could be used instead. The suggested dose is 50 international units (IU) per kilogram
twice weekly initially, rounding up to use the whole vial and avoid wasting drug and
subsequently adjusted up or down to achieve control of symptoms. Use of rhC1-INH for acute
treatment of HAE attacks is reviewed separately. (See "Hereditary angioedema: Acute treatment
of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
● Lanadelumab – Lanadelumab is a fully human monoclonal antibody to kallikrein, which became

available in the United States in 2018. It is injected at a dose of 300 mg subcutaneously every
two weeks, and was shown to be safe and effective. In patients who experience no attacks after
six months of treatment with lanadelumab, the dose may be reduced to 300 mg every four
weeks. (See 'Lanadelumab' below.)
2015
● Attenuated androgens – Long-term androgen therapy is usually effective but can have
significant adverse effects. It is least problematic in postpubertal males, particularly when used
at a low dose. It may be tolerated by women too, if the doses required to control symptoms are
sufficiently low. It should not be used in growing children or pregnant or lactating women, unless
there are extenuating circumstances. (See 'Attenuated androgens' below.)
● Antifibrinolytics – Antifibrinolytic agents include tranexamic acid (TA) and epsilon aminocaproic
acid (also called aminocaproic acid). These are less predictably effective for preventing HAE
episodes compared with pdC1-INH concentrate, lanadelumab, or androgens, and some patients
have problems tolerating them. However, antifibrinolytics can be useful for long-term
prophylaxis in growing children and possibly in women who are pregnant or planning to become
pregnant in the near future in whom androgens should not be used and pdC1-INH is not
available. Once a woman is pregnant or lactating, pdC1-INH concentrate is preferred for
prophylaxis. Consensus guidelines do not emphasize the use of antifibrinolytics, but they remain
an option [5]. (See 'Antifibrinolytics' below.)
Indications for long-term prophylaxis — Long-term prophylaxis is given to decrease the number,
severity, and length of HAE attacks. Not all patients require it, and as effective on-demand therapies
have become widely available in many countries, the percentage of patients who require long-term
prophylaxis has decreased substantially. Data are limited, but the authors estimate that from 20 (HF)
to 70 percent (BZ) of their patient panels are on long-term prophylactic therapies. In contrast, in
countries where on-demand therapies are less available, long-term prophylaxis is required by most
symptomatic patients.
The decision to administer long-term prophylaxis to a specific patient should take into account the
frequency and severity of attacks, access to emergency treatment, comorbid conditions, patient
preference and experience, and failure to attain adequate control with appropriate on-demand
therapies [13,14]. Before long-term prophylaxis is considered, the clinician should assure the
following [10]:
● Trigger avoidance should be optimized in all patients. (See 'Trigger avoidance' above.)
● All patients should have access to on-demand therapy in countries where these medications are
available. When on-demand treatment is readily available to patients, it is highly effective in
reducing the time a patient remains symptomatic and can efficiently prevent the burden of the
disease, which is directly related to symptoms. (See 'Access to "on-demand" therapies' above.)
Provided these aspects of care are in place, patients who do not experience sufficient benefit can be
considered for long-term prophylaxis. The decision about when it is appropriate to initiate long-term
prophylaxis is approached somewhat differently around the world:
2016
● United States guidelines suggest that the decision to initiate long-term prophylaxis be
individualized based upon multiple parameters, including attack frequency, comorbidities,
patient preferences, and access to emergency care [5].
● In some countries, regulatory authorities have stipulated that patients are eligible for long-term
prophylaxis with twice weekly injections of pdC1-INH if they are requiring four or more on-
demand treatments per month, an approach that was adapted from hemophilia, where
prophylactic injections of factor VIII are initiated when the number of on-demand approaches
the number of prophylactic injections [15].
Goal of long-term prophylaxis — Long-term prophylaxis is deemed successful when symptoms are
controlled to a level that is acceptable to that patient.
CHOICE OF AGENT IN SPECIFIC GROUPS
The options for long-term prophylaxis are intravenous (IV) or subcutaneous (SC) plasma-derived C1-
INH (pdC1-INH) concentrate, lanadelumab (the monoclonal antibody to plasma kallikrein), attenuated
androgens, and antifibrinolytics. Head-to-head trials are lacking. Within this group of therapies, pdC1-
INH and lanadelumab, both of which are costly, have either better efficacy or fewer adverse effects,
and are thus considered preferable to androgens and antifibrinolytics. The choice of which long-term
prophylactic agent to use is influenced both by patient characteristics (age, gender,
pregnancy/lactation), as well as regulatory requirements in different countries (table 2).
Prepubescent children — Prepubertal children can usually be managed with on-demand therapies
alone because HAE symptoms are generally less severe prior to puberty. The expanded availability of
these therapies for HAE attacks has greatly reduced the number of children who require long-term
prophylaxis. However, for those who do require preventative therapy, SC or IV pdC1-INH or oral
tranexamic acid (TA) are commonly used. We suggest avoiding androgens in children who require
long-term prophylaxis despite on-demand therapy. TA is easier to administer, while pdC1-INH is more
effective. However, data reflecting the impact of modern therapies on the management of children
are still limited.
Long-term prophylaxis with IV pdC1-INH is approved down to the age of six, while SC pdC1-INH is
approved for adolescents and adults. In many countries, access to long-term prophylaxis with pdC1-
INH is limited.
One approach in this circumstance, based on clinical experience, is a trial of TA initially. If this does
not control symptoms sufficiently, then it should be discontinued and regular injections of pdC1-INH
2017
given instead. These suggestions are based on clinical experience and may change as more
information about the newer therapies becomes available. (See 'Dosing and efficacy' below.)
Before the newer therapies became available, management options in children consisted of TA and
androgens, while C1-INH was usually reserved for life-threatening HAE attacks. The experience with
these therapies remains relevant in resource-limited settings. One group published outcomes of a
cohort of 48 children (23 boys and 25 girls) followed from diagnosis until age 18 in which TA was the
initial agent given for long-term prophylaxis [16]. Overall, a relatively low percentage of children (19
percent) required long-term prophylaxis initially, compared with adult populations. However, by the
age of 18 years, 43 percent required prophylaxis, with most needing to start long-term prophylaxis
around the time of puberty. Some patients were adequately controlled with intermittent use of long-
term prophylaxis during times when more attacks were anticipated (eg, during school exams, flu
season, winter months, family crises, or puberty). If symptoms were not controlled by TA, it was
stopped and replaced with low-dose danazol (starting at 100 mg every other day). Only 2 of 48
patients required significant use of pdC1-INH concentrate. Using this approach, serious side effects
of danazol were avoided in children of both sexes. Androgen therapy should be administered in
consultation with an endocrinology specialist.
Postpubescent and adult men — If on-demand therapy does not sufficiently reduce disease burden in
an adult male, long-term prophylaxis should be considered. The options that are most successful in
adult men are regular injections of pdC1-INH, lanadelumab, androgens, or TA.
The approach of the American author (BZ) is to present all four treatment options, review the
advantages and disadvantages of each, and make a joint decision about which therapy should be
tried initially (table 1).
In more resource-limited settings, TA and androgens are commonly used and pdC1-INH is reserved
for men with contraindications to or inadequate response to these therapies. If TA is chosen as an
initial prophylactic agent, a trial of full-dose therapy is undertaken for a few weeks. If TA does not
result in sufficient improvement, it should be stopped and androgen therapy initiated. Once attacks
have subsided on androgens, most patients do not require high doses to keep the disease under
control. Prophylaxis can also be given intermittently during times of anticipated stress, to reduce
overall exposure.
Women not considering pregnancy in the near future — The agents that are preferred in women who
are not considering pregnancy in the near future, and who require preventative therapy, are pdC1-INH,
lanadelumab, and TA. Attenuated androgens can also be used, provided symptoms can be controlled
with lower doses. (See 'Gynecologic and obstetric care' above.)
2018
The approach of the American author (BZ) is to present all treatment options, review the advantages
and disadvantages of each, and make a joint decision about which therapy should be tried initially.
Androgens are generally avoided.
Pregnant and lactating women — If long-term prophylaxis is required in a pregnant or lactating

woman, the best-studied approach is regular injections of pdC1-INH concentrate [7]. If pdC1-INH
injections are not tolerated (rare) or not available, TA or fresh frozen plasma on-demand may be used
instead [10]. Lanadelumab has not been studied in pregnancy. (See 'Adverse effects and safety'
below.)
SPECIFIC AGENTS
The agents that can be used for long-term prophylaxis are reviewed here, with mechanisms of action,
availability, efficacy, adverse effects, contraindications, and monitoring [17]. Monitoring C4 or C1-INH
antigenic levels for the purpose of assessing disease control is not indicated or useful, except
possibly in the case of subcutaneous (SC) plasma-derived C1-INH (pdC1-INH). (See 'Subcutaneous
C1 inhibitor' below.)
Prophylactic treatments may be divided into targeted therapies (eg, various forms of C1-INH
replacement therapy and lanadelumab), which were specifically developed for use in HAE-C1-INH or
related disorders and are generally more effective, and non-targeted therapies (eg, androgens and
antifibrinolytics) that were originally developed for other disorders and have proven useful in the
clinical management of HAE.
Intravenous plasma-derived C1 inhibitor — pdC1-INH concentrate can be injected intravenously (IV)

at regular intervals (continuous replacement therapy) to prevent attacks of angioedema. Two human
pdC1-INH are available in the United States: Cinryze (brand name) and Berinert (brand name). pdC1-
INH concentrate is available throughout Europe, the United Kingdom, Canada, and Argentina [4,18].
Indications — Continuous replacement therapy with IV pdC1-INH is a first-line option for patients
requiring long-term prophylaxis [19,20]. In the United States, pdC1-INH is a first-line long-term
prophylactic agent for HAE-C1-INH without the need to have failed or experienced side effects from
other medications such as androgens or antifibrinolytics. In some other countries, pdC1-INH may be
restricted to patients who have had adverse effects to androgens or antifibrinolytics, were not
adequately controlled on these agents, or who do not wish to take these agents. pdC1-INH
concentrate is the treatment of choice for long-term prophylaxis during pregnancy [7]. (See 'Choice
of agent in specific groups' above.)
2019
Dosing and efficacy — Dosing of pdC1-INH Cinryze (brand name) for prophylaxis is 1000 units IV
every three to four days. This dose may be adjusted over time to determine the lowest effective dose
for each patient.
Small randomized trials and other studies have demonstrated that pdC1-INH concentrate is highly
effective for long-term prophylaxis when given either on-demand or on a regular schedule [19-23].
Earlier estimates of efficacy may be understated, since the patients enrolled in these studies were
refractory to other treatments and represented the severe end of the disease spectrum. The efficacy
of treatment is highly dependent on the severity of the patient's underlying disease.
The first randomized controlled trial of pdC1-INH for long-term prophylaxis studied six severely
affected HAE-C1-INH patients who demonstrated significant decreases in attack frequency when
receiving pdC1-INH 25 units per kilogram every third day for 17 days compared to placebo in a
crossover design [19]. The phase 3 trial included 24 patients randomized to pdC1-INH (1000 units
every three to four days) or placebo injections for 12 weeks, after which the groups crossed over for
another 12 weeks [20]. Subjects receiving pdC1-INH experienced approximately one-half as many
attacks as those in the placebo group, and attacks were significantly shorter and less severe.
An open-label extension study of pdC1-INH (1000 units every three to four days) in 146 HAE patients
for up to 2.6 years found an overall 93.7 percent reduction in the number of angioedema attacks
compared with historical controls [23]. Just over one-third of patients experienced no attacks on
prophylactic pdC1-INH. Another 7.5 percent of patients continued to experience frequent attacks,
despite using the pdC1-INH, and no predictive marker for nonresponsiveness was found. No
evidence for loss of effectiveness of the pdC1-INH over time was observed.
Adverse effects — Adverse effects of IV pdC1-INH are rare and include headache, fever, and
anaphylaxis [24]. Other concerns are rare thrombotic events and the possibility of disease
transmission.
● Rare thrombotic events have been reported in association with long-term prophylaxis with pdC1-
INH, particularly in patients with indwelling injection ports or those receiving higher than usual
doses. A retrospective analysis of the US Food and Drug Administration (FDA) event reporting
system database identified an association between thrombotic events and use of Cinryze (brand
name), especially in patients with ports, although no conclusions about causality or frequency
could be made from the data [25]. In a registry of patients receiving Berinert (brand name), there
was one thrombotic event considered related to pdC1-INH, although this patient also had an
indwelling port [26]. However, there are no data to suggest that pdC1-INH at registered doses is
associated with an increased risk of thromboembolism in patients without indwelling ports [27].
A retrospective study of patients treated for many years with pdC1-INH found no evidence for an
2020
increased risk of thromboembolism during treatment with pdC1-INH, even in patients with
multiple predisposing factors [28]. In addition, animal studies suggest that high-dose C1-INH
therapy is antithrombotic, rather than prothrombotic [29]. However, because of the uncertainty
surrounding this issue, pdC1-INH product inserts include a warning that patients with risk
factors for thromboembolic events (eg, ports, previous thrombosis, underlying atherosclerosis,
oral contraceptives, androgens, morbid obesity, or immobility) should be monitored for
thrombotic events. In addition, the use of ports should be avoided in patients with HAE.
● Treatment with any plasma-derived product, including pdC1-INH, confers some risk of disease
transmission. Before the introduction of virucidal methods (from 1980 to 1985), a high
percentage of HAE patients were infected with hepatitis C virus through a lyophilized
preparation manufactured by Immuno Vienna (later Baxter). Production of the Baxter pdC1-INH
product was subsequently discontinued in 2004. In response to this, pdC1-INH was
subsequently vapor-heated to inactivate viruses, and the source of plasma was changed to
carefully screened donors and continually monitored for pathogens [30]. Since vapor-heated
pdC1-INH became standard, only hepatitis G transmission has been reported, and the
pathogenic significance of hepatitis G infection is unclear [31]. (See "GB virus C (hepatitis G)
infection".)
The preparations in use in most of the world are Berinert (brand name) and Cinryze (brand
name), which are virus-inactivated by pasteurization and nanofiltered. Postmarketing
surveillance for Berinert (brand name) since 1985 has revealed no case of viral transmission,
despite the administration of hundreds of millions of units. Processing methods also remove
prions [32]. Still, patients must be informed that there is a theoretical risk of transmission of
unidentified pathogens.
Monitoring — The efficacy of pdC1-INH therapy should be assessed clinically by sufficient

reduction of HAE attacks. Usefulness for monitoring C4 or C1-INH antigenic levels has not been
tested. For patients receiving C1-INH concentrate, studies have not been undertaken to correlate
successful therapy with specific C1-INH levels, and attacks may subside at levels of C1-INH that are
still significantly below normal.
Periodic testing for hepatitis C and human immunodeficiency virus (HIV) is recommended for
patients regularly receiving pdC1-INH.
Subcutaneous C1 inhibitor — The administration of a concentrated formulation of pdC1-INH

subcutaneously (SC) is easier for most patients and also appears to be more effective for preventing
attacks compared to IV administration. The SC formulation contains 1500 international units (IU) in 3
mL of water, compared with the IV formulation, which contains 500 IU in 10 mL. In addition, SC
2021
administration results in more consistent plasma levels between doses, compared to IV [33]. SC
pdC1-INH is available for prophylaxis in the United States [Haegarda (brand name)] and in Europe [Sc
Berinert 2000/3000 (brand name)] [34,35].
A SC formulation of Cinryze (brand name) is in development [36]. Although not yet available, this
product would further expand options for SC therapy.
Dosing and efficacy — The dose of SC pdC1-INH for prophylaxis of HAE attacks in adolescents
and adults is 60 IU per kilogram body weight twice weekly (every three or four days). It is injected SC
into the abdominal area. Pending additional information about the use of higher doses, patients who
do not achieve the desired level of control with the recommended dose should use the shortest
interval between doses (ie, three days) to maximize efficacy.
Efficacy was demonstrated in a randomized, multicenter trial of 90 patients (12 years of age and
older), in which participants self-administered one of two doses of SC pdC1-INH (40 IU or 60 IU per
kilogram body weight) twice weekly or placebo for 16 weeks each in a crossover design [37]. The
primary endpoint was number of episodes of angioedema, which was reduced 89 and 95 percent
with the lower and higher dose, respectively, relative to placebo. For patients taking the higher dose,
there were 3.51 fewer attacks per month compared with placebo (95% CI -4.21 to -2.81). The
predominant adverse effect was mild injection site reactions that did not lead to discontinuation.
Earlier studies of twice weekly injections of pdC1-INH demonstrated that SC injection resulted in
higher and more sustained plasma levels relative to twice weekly IV administration [33,37]. Higher
levels of plasma C1-INH function correlated with a lower risk of attacks, with a functional level of
approximately 40 percent being an inflection point for the relative risk of attacks. The study also
showed that postinjection functional C1-INH plasma levels varied among patients, such that
individualized dose adjustment may be needed for optimal disease control. In the open-label
extension trial, the mean C1-INH functional trough level was 66 percent, and 83 percent of the 23
subjects receiving pdC1-INH for 30 months were attack-free in the last 6 months [34]. Longer
duration studies are needed to assess long-term safety.
Compared to IV — Although studies direction comparing SC to IV pdC1-INH are not available,

SC administration provides the advantage of more consistent plasma levels, and preliminary
evidence suggests it provides better symptom control. An analysis of a subset of patients from a
larger study examined attack rates in individuals who changed from IV to a SC preparation of pdC1-
INH [38]. Although the design was not optimized for this assessment, the majority of patients
changing from various doses of IV to 40 IU/kg or 60 IU/kg of the SC preparation experienced
clinically meaningful reductions in HAE attacks.
2022
Adverse effects — Adverse effects occurring in more than 4 percent of subjects treated with SC
C1-INH in initial trials were injection site reactions, hypersensitivity, nasopharyngitis, and dizziness.
SC C1-INH carries a similar theoretical risk for disease transmission as IV pdC1-INH concentrate.
Thromboembolic events have not been reported.
Monitoring — Higher levels of functional C1-INH correlated with lower attack risk in patients
receiving SC C1-INH, in contrast to IV C1-INH, which does not result in a sustained increase in
plasma levels of C1-INH function at clinically effective doses. As with other C1-INH formulations,
periodic testing for HIV and hepatitis C should be done. (See 'Monitoring' above.)
Lanadelumab — A fully human monoclonal antibody to plasma kallikrein, lanadelumab (brand name
Takhzyro), was approved by the United States FDA and European Medicines Agency (EMA) in 2018
for prophylaxis in patients 12 years of age and older [39,40]. This agent limits the production of
excess bradykinin by reducing plasma kallikrein activity (figure 1). It is intended for subcutaneous
use, and its long duration of action, which is significantly longer than other prophylactic therapies,
allows dosing once or twice a month.
Dosing and efficacy — The recommended initial dose of lanadelumab is 300 mg injected SC every
two weeks.
In the study on which approval was based, patients discontinued other prophylactic therapies
completely before starting lanadelumab, but in clinical practice, this may be less than ideal, as it
takes over two months to reach a steady state of lanadelumab. A conservative empiric approach is
to continue the patient's current therapy for at least two weeks and possibly longer for those with
frequent or severe attacks and to gradually reduce the dose of the previous prophylactic agent over
an additional two weeks for a total of one month of overlap.
● The dose should not be increased, because higher doses have not been studied.
● If a patient is free of attacks for a period of more than six months, the dosing interval can be
lengthened to 300 mg every four weeks.
In a phase 1b study, two doses of lanadelumab given 14 days apart reduced attack rates by between
88 and 100 percent [41]. A phase 3 randomized trial involving 125 HAE patients showed a reduction
in attacks ranging from 73 to 87 percent, depending on the dose and timing. Monthly attack rates
were 1.64, 0.42, and 0.21 in subjects receiving placebo, 300 mg every four weeks, and 300 mg every
two weeks, respectively [42].
Adverse effects and safety — Injection site reactions were the most common adverse effect with
lanadelumab, occurring in 45 to 56 percent of subjects receiving active drug, compared with 34
percent of those receiving placebo. Increased aspartate and alanine transaminase levels occurred in
2023
2 percent of active drug recipients versus 0 in the placebo group. These were asymptomatic and
transient and did not require drug discontinuation. Lanadelumab can increase activated partial
thromboplastin time but has not been associated with abnormal bleeding.
There are no known contraindications to use of lanadelumab. However, lanadelumab has not been
studied in pregnant or lactating women, and although animal studies in pregnancy are reassuring, we
would avoid use in pregnant or lactating women until more information is available [43].
Attenuated androgens — Synthetic 17-alpha-alkylated androgens ("attenuated" or anabolic

androgens) include danazol, stanozolol, oxandrolone, oxymetholone, tibolone, and
methyltestosterone. The precise mechanism of action of attenuated androgens is unknown [44-46].
The choice of androgen is based largely upon availability, since differences among drugs have not
been well-characterized. Danazol is widely available throughout the world. Stanozolol is not
produced commercially in the United States, although it is available by prescription and can be
compounded by individual pharmacies. Tibolone and oxandrolone may be less virilizing than other
agents [47-49]. Methyltestosterone is another alternative [50].
Efficacy — In a double-blind, placebo-controlled study of nine patients, high doses of androgen

therapy (danazol, 600 mg daily) dramatically reduced the risk of at least one acute episode during a
one-month treatment period from 94 to 2 percent and reduced attack rates from monthly to 1 every
10 months [51]. Other small, controlled studies and multiple observational studies also concluded
that androgens were effective at preventing attacks [49,52-58]. A retrospective survey of 650 HAE
patients revealed substantial variability in the efficacy of androgens [59].
Dosing — Most patients with HAE are controlled with doses ranging from 50 to 200 mg of danazol,
either daily or every other day (or an equivalent dose of another androgen, eg, stanozolol 1 to 2 mg
daily or every other day). We suggest either of the following two ways of administering androgens for
long-term prophylaxis: starting with a high dose and then tapering or starting with a low dose and
gradually increasing (table 1) [4].
● Initial high dose – This protocol is based on the strategy of initiating androgen therapy with high
doses that are subsequently tapered as tolerated. This approach is favored for rapid control of
attacks. Using danazol as an example, therapy is begun with 400 to 600 mg daily until new
attacks have ceased (usually a few weeks). The dose can then be tapered over several weeks to
200 mg daily, although the guidelines suggest tapering more slowly (eg, by 100 mg daily per
month or by one-third of the dose per month if there are no breakthroughs). When 200 mg daily
is attained, therapy is tapered by 50 mg every two months and by every three months when
below 100 mg per day. The minimum dose is 50 mg daily for five days every week for most
2024
patients. For those in whom a breakthrough attack occurs, remission can be reinduced by
resuming the last effective dose and then using a higher maintenance dose.
The equivalent dosing for stanozolol is 4 to 6 mg daily for the first month and then gradual
tapering to the minimal effective dose, which is generally in the range of 0.5 to 2 mg daily.
● Initial low dose – This regimen involves the initiation of therapy with low doses, with increases
in the dose as necessary. This approach minimizes medication side effects. Using danazol as
an example, therapy is initiated at a dose of 100 mg daily for men and 50 mg daily for women. If
there is no response after two weeks, the dose is increased to 200 mg daily (men)/100 mg daily
(women) for two to four weeks.
General observations regarding the use of attenuated androgens for long-term prophylaxis include
the following:
● In postpubertal females, androgenic effects may be troublesome, and regulation of periods and
use of other hormones can become issues. We suggest that treatment decisions be made with
the cooperation of the patient's obstetrician/gynecologist.
● Some patients have reported that increasing the dose of androgen in response to prodromal
symptoms or at the first sign of swelling seems to help prevent progression to more severe
symptoms. As an example, a patient taking 200 mg of danazol daily for prophylaxis could
increase the dose to 400 mg three times daily and maintain the higher dose until there is some
indication of clinical improvement or an attack ensues. Although there are anecdotal reports of
efficacy, this intervention has not been studied, and opponents of the practice counter that
androgens do not act quickly enough to be effective when used in this manner [4,60].
Adverse effects and contraindications — At the doses typically required (ie, 200 mg danazol daily
or less), androgen therapy is usually tolerated by postpubertal males and by some female patients as
well. However, most patients do experience some adverse effects, and there are important
contraindications [59].
Adverse effects with long-term androgen administration may include weight gain, lipid abnormalities,
arterial hypertension, virilization, abnormalities in serum transaminases, menstrual irregularities,
postmenopausal bleeding, diminished libido, vasomotor symptoms, and depression [4,52,56,58-62].
These adverse effects can be controlled or minimized by using the lowest effective dose. Elevations
of transaminases are most often seen with prolonged administration of higher doses (eg, danazol,
400 mg or more daily). There are also rare reports of hepatocellular adenomas and carcinoma with
years of use [63,64]. Because of these concerns, daily doses greater than 200 mg per day are not
recommended for long-term use [10]. Although androgen-related adverse effects are more common
2025
with higher doses, they are not always dose-dependent, and some patients experience side effects at
low doses [65]. A yearly measurement of alpha-fetoprotein and liver ultrasound was also suggested
by the 2010 consensus guidelines as a possible means of detecting liver neoplasms, although not all
experts agree that this is helpful.
Contraindications to long-term androgen use include childhood, pregnancy and lactation, liver
disease, nephrotic syndrome, hypercholesterolemia, hypertension, mood disorders, and breast or
prostate cancer, although rare exceptions are made.
Androgens should not be used in children prior to Tanner stage 5 (table 3). The main concern about
androgen use in prepubertal children is the potential of these agents to cause premature epiphyseal
closure and decreased growth [66]. However, findings of the only retrospective study conducted
among pediatric patients suggest that treatment with the lowest effective doses of danazol does not
influence growth [67].
Monitoring — The efficacy of androgen therapy should be assessed clinically by sufficient

reduction of attacks. Monitoring C4 or C1-INH antigenic levels is not necessary or useful.
● Laboratory values – The 2010 consensus guidelines recommend obtaining a complete blood
count, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lipid profile,
and urinalysis (to detect hematuria that can result from androgen use) every six months in
patients taking long-term androgen therapy [4]. A yearly measurement of alpha-fetoprotein was
also suggested by the 2010 consensus guidelines as a possible means of detecting liver
neoplasms, although not all experts agree that this is helpful.
● Ultrasonography – The risk of hepatic neoplasms may be increased with the long-term use of
androgen therapy, both for patients with HAE and other diseases [64,68,69]. This risk appears to
be small, although there are insufficient data to quantitate magnitude. In addition, it is not clear
how best to detect focal neoplastic lesions, which may not necessarily result in elevations in
serum transaminases [70]. As a result, not all of the authors of this review agree with the below
suggestions.
In the absence of consensus, the 2010 guidelines suggest that ultrasonography of the liver be
performed every six months for adult patients receiving more than 200 mg/day of danazol (or
the equivalent of another androgen) and for all prepubertal patients receiving maintenance
androgens [4]. Yearly screening may be sufficient for adults receiving 200 mg or less of danazol
daily.
Antifibrinolytics — Antifibrinolytics interfere with the functions of plasminogen and plasmin, leading
to decreased production of bradykinin, although the mechanism of action in angioedema remains
2026
poorly defined (figure 1) [71]. The only antifibrinolytic medication in widespread use for HAE is
tranexamic acid (TA). Another agent, epsilon aminocaproic acid (EACA), was shown to reduce the
frequency of HAE attacks in a randomized trial in the 1970s [72]. However, EACA is less potent and
has more gastrointestinal side effects compared to TA, although some patients do well with it [73].
Antifibrinolytics effectively prevent attacks in a smaller proportion of patients, compared to pdC1-
INH.
In settings in which C1-INH replacement therapy is not available or access is limited, antifibrinolytics
are generally preferable to androgens for long-term prophylaxis in pregnant women, children, and
patients who do not tolerate androgens. Androgens should be avoided in patients with increased risk
for thrombosis. Because pregnancy itself is a relative risk factor for thrombosis, C1-INH replacement
therapy is a better choice for prophylaxis in pregnancy. However, one of the authors (HF) has some
experience with using TA successfully in pregnant women, particularly if the patient has taken the
drug successfully before pregnancy, and it could be considered if C1-INH replacement therapy is not
feasible. Of note, Cinryze (brand name) has been associated with a small number of cases of
thrombosis as well. (See 'Adverse effects' above.)
Experience with TA is greatest in Europe and Asia, where it has been available for decades [16,74,75].
In the United States, EACA has been available for many years, and an oral preparation of TA became
available in 2009 when it was approved by the FDA for the treatment of menorrhagia. Antifibrinolytics
are not FDA-approved for HAE, although this does not preclude their use.
Dosing and efficacy — In both children and adults, TA is administered for long-term prophylaxis at
a dose of 1 to 3 grams per day or at a total daily amount of 25 mg/kg, divided into two to three doses
per day. It is available in a 500 mg dose in much of the world, and in a 650 mg dose in the United
States.
● In children, we usually start with 250 mg twice daily for a few weeks, and gradually increase if
tolerated to 500 mg twice or three times daily.
● In adolescent and adults, we start with 500 mg (or 650 mg of the United States preparation), two
to three times daily for a few weeks, and gradually increase if tolerated to 1 gram three times
daily. Only about one-third of patients will achieve adequate control with doses below 3 grams
per day. However, the dose of TA must be reduced for patients with renal impairment.
In observational studies of TA, attack frequency and severity are reduced somewhat in approximately
70 percent of patients, although efficacy seems higher in some case series [73,76,77]. Overall, there
is a general agreement that a sufficient response is seen in less than 30 percent. Still, TA has been
used successfully for long-term prophylaxis in some pediatric patients [78]. (See 'Prepubescent
children' above.)
2027
The usual prophylactic dose of EACA in adults is 1 to 2 grams per dose, given three times per day (ie,
3 to 6 grams daily). For children, the suggested dose is 0.05 g/kg per dose, given two times per day.
Adverse effects and contraindications — Antifibrinolytics carry the potential risk of intravascular
thrombosis, although the true prothrombotic effects of these medications have not been quantified
[79,80]. These agents should not be used in patients with increased thrombotic risk or history of
ischemic events.
Additional side effects associated with these agents include the following:
● TA uncommonly causes gastrointestinal distress (eg, nausea, vomiting, diarrhea), headache,

hypotension, and anal pruritus, which can occur early in therapy [16,73]. There are also reports
of retinal damage with prolonged use of higher doses of TA [81].
● EACA is associated with several adverse effects at higher doses than are indicated for HAE
[72,76]. However, at the doses typically used in HAE patients, gastrointestinal distress is typically
the main adverse effect, and some patients tolerate it quite well.
Monitoring — The therapeutic success of TA is determined clinically, and each patient should be
maintained on the lowest dose that adequately prevents attacks.
● Laboratory values – Doses are adjusted for decreased renal function, so blood urea nitrogen
and serum creatinine should be measured yearly. The 2010 consensus algorithm suggests that
creatinine kinase, tests of liver and renal function, and urinalysis be performed every six months,
although some experts believe yearly evaluation is sufficient.
● Ophthalmologic exam – Annual assessment of ocular pressure has been suggested for patients
on long-term therapy, based on the theoretical concern that retinal thrombosis could block
outflow of aqueous humor. Periodic ophthalmologic exams for patients on long-term therapy are
suggested by some drug information databases because of early reports of ophthalmologic
tumors in animals treated with high doses of TA, although this has never been reported in
humans. The authors have not performed ophthalmologic exams as part of monitoring therapy.
INVESTIGATIONAL THERAPIES
A prophylactic agent that can be administered orally is in development. BCX7353 is an inhibitor of

plasma kallikrein (figure 1) [82,83]. In the multicenter Angioedema Prophylaxis 1 (APeX-1) trial, 77
patients with a history of at least two attacks per month were randomized to placebo or four different
doses of active drug once daily for 28 days [84]. The primary endpoint was the number of confirmed
angioedema attacks, expressed as the least-squares mean number of attacks per week. Subjects
2028
receiving a dose of 125 mg once daily or higher showed a significant reduction in attacks compared
with placebo. The 125 mg dose had the lowest rate of adverse events and greatest benefit: a 73.8
percent difference compared with placebo, and 43 percent of patients were attack-free. Adverse
effects were mostly gastrointestinal and mild, and three subjects receiving active drug had
elevations in liver function tests.
Patients can access detailed, patient-oriented information through the United States Hereditary
Angioedema Association and the International Patient Organization for C1 Inhibitor Deficiencies.
● General care measures for hereditary angioedema (HAE) include education, testing of family
members, identification and avoidance of possible triggers, and planning for HAE attacks.
Common triggers include dental and medical procedures, periods of stress, menstruation,
pregnancy, infections, and certain medications, such as estrogens and angiotensin-converting
enzyme inhibitors. (See 'General care' above.)
● Immediately upon diagnosis, clinicians should help construct a plan for emergency care,
including how and where the patient will access treatment and education about the need to seek
care in a medical facility for laryngeal attacks. Patients should be offered a medical
identification bracelet and a written plan for treatment of HAE attacks for use in emergency
department care (form 1 and form 2). (See 'Planning for acute treatment' above and 'Access to
"on-demand" therapies' above.)
● In countries where on-demand therapies (ie, C1 inhibitor [C1-INH] concentrate, icatibant, or

ecallantide) are available, most clinicians advocate the optimization of trigger avoidance and on-
demand therapies first, with long-term prophylaxis added for the subset of patients whose
disease is still not adequately controlled. Approaches differ somewhat around the world. (See
'Approach to long-term prophylaxis' above.)
2029
● The options for long-term prophylaxis are regularly injected (intravenously or subcutaneously)
plasma-derived C1-INH (pdC1-INH), lanadelumab (a monoclonal antibody to plasma kallikrein),
attenuated androgens, and antifibrinolytics. Each agent has advantages and disadvantages
(table 1). (See 'Overview of available therapies' above.)
● The choice of which long-term prophylactic agent to use is influenced both by patient
characteristics (age, gender, pregnancy/lactation) as well as regulatory requirements in different
countries (table 2). There are few studies directly comparing the different therapies to each
other. (See 'Choice of agent in specific groups' above.)
● For patients requiring prophylaxis for severe disease (ie, laryngeal attacks or frequent attacks of
other types) we recommend pdC1-INH or lanadelumab over other agents (Grade 1B). (See
'Specific agents' above.)
• For patients receiving pdC1-INH, we suggest subcutaneous in preference to intravenous

administration (Grade 2C). (See 'Compared to IV' above.)
• For pregnant and lactating women, we suggest pdC1-INH in preference to other agents
(Grade 2C). If pdC1-INH is not available, we suggest tranexamic acid (Grade 2C). (See
'Pregnant and lactating women' above.)
● If pdC1-INH or lanadelumab are not available, or for patients who prefer the convenience of an
oral therapy, tranexamic acid or androgens are options. Androgens are more effective but are
contraindicated in children younger than Tanner stage 5 (table 3), pregnant or lactating women,
and patients with certain comorbidities. Tranexamic acid is less effective but has fewer side
effects. (See 'Attenuated androgens' above and 'Antifibrinolytics' above.)
ACKNOWLEDGMENT
2030
GRAPHICS
Instructions for emergency care of hereditary angioedema (HAE)
2031
Hereditary angioedema (HAE) emergency care wallet card
2032
Long-term prophylaxis to prevent angioedema in adults and children with hereditary angioedema (HAE)
Prophylactic therapy Advantages Disadvantages
C1 inhibitor concentrate - Well-tolerated Requires reliable venous access (but indwelling

Intravenous Widely available ports are not recommended)
C1 inhibitor concentrate Convenient: Subcutaneous injection every 3 to 4 Limited availability

- days
Subcutaneous
Lanadelumab Convenient: Subcutaneous injection every 2 to Clinical experience is limited

4 weeks Not approved for use in children younger than 12
years of age
Androgens Oral administration Side effects are prohibitive in some patients

Effective in most patients (hypercholesterolemia, liver enzyme
Inexpensive abnormalities, virilization, hypertension, mood
effects, weight gain, others)
Avoid in prepubertal children (premature closure
of growth plate) and pregnant women (virilization
of female fetus)
Avoid in patients with liver disease or nephrotic
syndrome
Antifibrinolytics: Oral administration Less effective than other therapies

Tranexamic acid Safe in children Avoid in patients with history of thrombosis or
(preferred) or epsilon Well-tolerated by most patients thromboembolic disease or risk factor for
aminocaproic acid thrombosis
Inexpensive
Treatment for breakthrough symptoms (required in combination with any of the options above)
C1 inhibitor As above As above

concentrate
Icatibant Subcutaneous injection

Approved for self-administration at home
Ecallantide Subcutaneous injection Should be given under medical supervision due

to possible hypersensitivity reactions usually
within one hour
Only available in the United States
Plasma: Widely available Efficacy not as well-established as other

Solvent/detergent- Inexpensive therapies
treated or fresh Theoretical risk of transmission of blood-borne
frozen agents
Requires visit to hospital or clinic for
administration
2033
Choice of prophylactic agent for hereditary angioedema (HAE) in specific patient groups
Agents to be
Patient population Preferred agents Alternate agents Other notes
avoided
Pre-pubertal children Plasma-derived C1- Tranexamic acid Androgens ¶ Lanadelumab not

(male and female) INH* (less effective but studied or approved for
may be sufficient for children under 12 years
mild disease) of age
Adult women not Plasma-derived C1- Tranexamic acid Androgens (multiple

considering pregnancy INH* (less effective but side effects and
and post-pubertal girls Lanadelumab may be sufficient for virilization)
mild disease)
Adult men and post- Plasma-derived C1- Tranexamic acid

pubertal boys INH* (less effective but
Lanadelumab may be sufficient for
mild disease)
Androgens (multiple
side effects but
virilization less of an
issue for men)
Pregnant and lactating Plasma-derived C1- Tranexamic acid Androgens Δ Lanadelumab not
women INH* (has most (less effective but recommended because
safety data) history of safe use) it has not been studied
in pregnancy
The choice of which long-term prophylactic agent to use is influenced both by patient characteristics (age, gender,
pregnancy/lactation), as shown in the table, as well as regulatory requirements in different countries.
HAE: hereditary angioedema; C1-INH: C1 inhibitor.

* Plasma-derived C1-INH can be given subcutaneously or intravenously. Subcutaneous is more convenient and appears to be more effective
based on preliminary evidence.
¶ Androgens are contraindicated in pre-pubertal children because they can cause premature closure of the growth plates.
Δ Androgens are avoided in pregnancy because they can result in virilization of female fetuses, although if a woman with HAE is carrying a
male fetus, androgens have been successfully used with supervision by an endocrinologist.
2034

Data from:
2035
Sexual maturity rating (Tanner stages) of secondary sexual characteristics
Boys – Development of external genitalia

Stage 1: Prepubertal
Stage 2: Enlargement of testes and scrotum; scrotal skin reddens and changes in texture
Stage 3: Enlargement of penis (length at first); further growth of testes
Stage 4: Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotal skin darker
Stage 5: Adult genitalia
Girls – Breast development

Stage 1: Prepubertal
Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3: Further enlargement of breast and areola; no separation of their contour
Stage 4: Areola and papilla form a secondary mound above level of breast
Stage 5: Mature stage: Projection of papilla only, related to recession of areola
Boys and girls – Pubic hair

Stage 1: Prepubertal (the pubic area may have vellus hair, similar to that of forearms)
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia
Stage 3: Darker, coarser, and more curled hair, spreading sparsely over junction of pubes
Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs
Stage 5: Adult in type and quantity, with horizontal upper border
2036
Hereditary angioedema with normal C1 inhibitor

Author: Eveline Wu, MD
INTRODUCTION
Hereditary angioedema (HAE) is characterized by recurrent, self-limited episodes of swelling primarily involving the
skin and the mucosa of the gastrointestinal tract and upper airway. There are several subtypes. The clinical
manifestations, pathogenesis, diagnosis, and management of HAE with normal C1 inhibitor (HAE with normal
C1INH, previously called type III HAE) will be reviewed here.
HAE types I and II, which are characterized by abnormalities in the level and/or function of the inhibitor of
complement component 1 (C1 inhibitor or C1INH), are discussed separately:
● (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)
● (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
● (See "Hereditary angioedema: Temporary prophylaxis before procedures or stress to prevent angioedema
episodes".)
EPIDEMIOLOGY
Information about the incidence and prevalence of HAE with normal C1INH is limited. It is a rare disorder, and there
are no accepted test(s) for establishing the diagnosis. HAE with normal C1INH was initially assumed to be specific
to women, but male members of affected families have since been reported [1]. In the largest single series,
approximately 11 percent of patients were male [2].
BACKGROUND AND TERMINOLOGY
Historically, HAE was described as a familial disorder resulting from either deficiency or dysfunction of the inhibitor
of the complement protein C1, termed C1 inhibitor (C1INH). Types I and II are now collectively referred to as C1INH-
HAE. However, in 2000, two different groups published descriptions of another familial form of angioedema, in
which affected individuals had normal C1INH levels and activity [3,4].
2037
● Thirty-six people from 10 families were detailed in the earliest study [3]. All of the affected individuals were
women, and all of those tested had normal C1INH function and plasma concentration.
● In a second report published in the same year, seven women from a single family were described in whom
episodes only occurred during pregnancy or with the use of exogenous estrogens [4].
Subsequently, a number of additional families were described [2,5-7]. The largest series included 265 patients from
88 families [2]. The terms "estrogen-dependent" and "estrogen-associated inherited angioedema" were used to
describe this disorder prior to the identification of male patients [8]. This disorder has also been referred to as
"familial angioedema with normal C1INH" and "type III HAE." In an attempt to standardize nomenclature, a
consensus statement from an international expert panel has recommended the disorder be designated "HAE with
normal C1INH" [9,10].
Two subtypes of HAE with normal C1INH are recognized:
● HAE with normal C1INH and a factor XII mutation (FXII-HAE)
and
● HAE with normal C1INH of unknown cause (U-HAE)
In 2017, other possible mutations were identified that may represent additional subtypes. (See 'Pathogenesis'
below.)
HAE with normal C1INH has signs and symptoms similar to those of HAE associated with C1INH defects, with some
distinguishing features.
Similarities between the three disorders include the occurrence of self-limited episodes of subcutaneous and
submucosal angioedema lasting two to five days in the absence of treatment. All disorders affect the skin and the
mucosa of the gastrointestinal and upper respiratory tract. Cutaneous attacks are the most common type, and
episodes affecting the upper airway are less common but potentially life-threatening in all three disorders [7,11].
Affected skin is nonpruritic and nonpitting, and urticaria is not seen. Some patients report a prodrome of numbness
or tingling at the affected site. There is significant heterogeneity in all three disorders. Members of an affected
family may be asymptomatic or symptomatic to varying degrees [7,12].
The clinical manifestations of HAE are presented in more detail separately. The remainder of the discussion here
will focus on the differences between HAE with normal C1INH and the other forms. (See "Hereditary angioedema:
Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)
Unique characteristics of HAE with normal C1INH — Differences have been noted between HAE with normal C1INH
and C1INH-HAE:
● Age of onset – HAE with normal C1INH usually presents in adulthood (after puberty). In a large series of 138
patients with the disorder, the mean age at disease onset was 26.8 years [7]. In contrast, more than one-half of
patients with C1INH-HAE present during childhood with a mean age at disease onset of 11.7 years [7,9,11].
2038
● More prominent involvement of the tongue, uvula, and face – In HAE with normal C1INH, angioedema of the
tongue, uvula, and facial skin occurs with higher frequency, and tongue swelling may be a diagnostic clue to its
presence [7,13]. In the series of 138 patients mentioned previously, 54 percent experienced tongue swelling,
compared with 12 percent in a series of patients with C1INH-HAE [7]. Tongue swelling may herald laryngeal
edema. Among 35 patients with laryngeal edema, 13 had experienced episodes associated with tongue
swellings [7]. Four of 138 patients in this series died due to asphyxiation.
● Less frequent abdominal attacks – Approximately 50 percent of patients with HAE with normal C1INH
experience abdominal attacks, compared with at least 90 percent in patients with types I and II [7,11,13,14].
● Females are affected more often and more severely – Within families affected by HAE with normal C1INH,
females are more often symptomatic and have more severe symptoms than males [7].
● Less intense and more variable disease activity – Patients with HAE with normal C1INH usually have a
decreased frequency of symptoms and a greater number of disease-free intervals. Many patients with the
disorder experience prolonged periods (ie, one to several years) without symptoms [7]. In addition, attacks more
often involve a single location in HAE with normal C1INH compared with C1INH-HAE [15].
● Different cutaneous findings – Hemorrhages into skin swellings and easy bruising have rarely been reported in
patients with HAE with normal C1INH, although not in patients with types I and II [7]. The prodromal skin
discoloration, erythema marginatum, which is reported by up to one-third of patients with C1INH-HAE, has not
been observed in HAE with normal C1INH (picture 1).
● Lower penetrance – The inheritance pattern of HAE with normal C1INH shows generally low penetrance
compared with C1INH-HAE, and obligate, asymptomatic carriers appear to be relatively common.
PATHOGENESIS
The mediator(s) responsible for swelling in HAE with normal C1INH has not been definitively identified. Excess
generation of bradykinin, a potent vasoactive substance, has convincingly been shown to be the major facilitator of
angioedema in C1INH-HAE [16]. Activation of the kinin system is also thought to be critical in HAE with normal
C1INH, but this has not been conclusively demonstrated.
The underlying molecular defect(s) for most patients with HAE with normal C1INH has not been determined,
although the pattern of affected family members in successive generations supports an autosomal dominant mode
of inheritance [2,4,5,7].
Mutations in factor XII — Given the importance of excess bradykinin formation in C1INH-HAE, it is reasonable to
speculate that mutations of elements in the kinin-generating cascade may be responsible for HAE with normal
C1INH as well. The kinin-generating pathways interface with the coagulation (contact system) and fibrinolytic
pathways (figure 1).
Several mutations in the coagulation factor XII (FXII, Hageman factor) gene have clearly been identified in patients
with HAE with normal C1INH:
2039
● Two missense mutations involving the FXII gene were detected in 6 of 20 index patients from unrelated families
[17]. Both mutations were single heterozygous nucleotide substitutions within exon 9 of the FXII gene. The first
and most common point mutation c.983C>A (alternatively termed c.1032C>A, Thr309Lys) results in substitution
of a threonine residue for lysine (Thr328Lys), and the second c.983C>G (alternatively termed c.1032C>G,
Thr309Arg) results in substitution of the same threonine residue for arginine (Thr328Arg) [17,18]. Neither
mutation was detectable in 145 healthy controls. The same mutations have subsequently been identified in
multiple other affected families and appear to segregate with the disease [2,9,19-27].
● A different FXII gene mutation resulting in deletion of a considerable number of base pairs
(c.971_1018+24del72*) was identified in another family [18]. This large deletion is located in the same gene
region as the previously identified missense mutations and was not detected in control subjects.
● A duplication of 18 base pairs (c.892_909dup) in the FXII gene has also been reported [2,28]. The duplication
occurs in the same region as the three mutations previously described and causes a repeated amino acid
sequence (p.Pro283_Pro303) [28].
The observation that several different mutations involving the same FXII gene region are present in affected patients
and not in controls supports an association between FXII protein modifications and the disorder [29]. In one study,
mutations in the FXII gene were associated with normal plasma concentrations of FXII but an increase in its
enzymatic activity when compared with healthy controls [19]. However, these findings could not be reproduced in a
follow-up study using a more sensitive assay, and functional defects in FXII were not found [30]. Subsequently, a
2015 study proposed that mutations in FXII result in abnormal glycosylation and increased autoactivation of FXII.
This increased FXII autoactivation could lead to excessive activation of the kallikrein-kinin pathway and bradykinin
formation [31]. In 2019, another study showed that FXII variants Thr309Lys and Thr309Arg are cleaved after residue
309 by coagulation proteases like thrombin and FX1a, producing a truncated form of FXII (δFXII) [32]. The truncated
δFXII converts prekallikrein to kallikrein more efficiently than native FXII. In addition, δFXII is a better substrate than
FXII for kallikrein, resulting in greater δFXII production and further prekallikrein activation. This accelerated
FXII/prekallikrein activation overwhelms the regulatory functions of C1INH, and more kallikrein can cleave high
molecular weight kininogen to bradykinin (figure 1) [32].
Not all members of a given family (not even all the females) who carry the FXII mutations are symptomatic,
indicating that penetrance is incomplete, and other factors are necessary for disease development. Among 23
families affected by HAE with normal C1INH, 35 (33.7 percent) of 104 carriers of FXII mutations were asymptomatic
[2]. Results from another study suggest variations in enzymes involved in kinin metabolism may modify disease
expression and severity in HAE with normal C1INH associated with FXII mutations [33]. The study included
symptomatic and asymptomatic carriers of FXII mutations, as well as noncarrier relatives and healthy controls. The
study showed a significant inverse relationship between disease severity and both angiotensin-I-converting enzyme
activity and carboxypeptidase-N activity [33].
FXII mutations do not appear to be equally prevalent in all populations. In the large German series of 265 patients,
69 (26 percent) demonstrated one of the four identified FXII mutations [2]. In other series by the same group, one of
these mutations was present in 17 to 25 percent of the families tested [7,12]. However, neither of these mutations
was found in 40 patients analyzed in the United States, although the study in which this was reported was an
analysis of samples submitted to a specialty commercial laboratory, and the clinical features of the patients were
not available to the researchers [34].
2040
Other mutations — Other variants, including those in the genes for angiopoietin-1 and plasminogen, have been
identified in patients with HAE with normal C1INH and no detectable variants in the FXII gene:
● In one Italian family with HAE with normal C1INH of unknown cause (U-HAE), a variant was identified in the
gene encoding angiopoietin-1 (ANGPT1) [35]. The mutation, which is rare in the general population, was present
in four symptomatic women and absent in seven unaffected relatives. Angiopoietin-1 has been shown to
decrease bradykinin-induced plasma leakage [36]. The family was part of a cohort of 47 patients with U-HAE:
25 patients from 10 unrelated families plus 22 additional individuals, although the angiopoietin-1 mutation was
not found in the other families or the individual patients. The mutation did not alter plasma levels of
angiopoietin-1 but impaired its ability to interact with its receptor (tunica interna endothelial cell kinase 2 [TIE2])
on endothelial cells. Thus, a potential additional cause of HAE has been identified in one family with multiple
affected individuals.
● In four German families, variants in the gene for plasminogen (PLG) was identified in 20 individuals, 18 of whom
were symptomatic, with prominent swellings of the tongue, lips, and face [37]. The same variant was found in
all families, suggesting a common ancestor.
Patients without an identified mechanism — Most patients with HAE with normal C1INH do not have identifiable
mutations in FXII, angiopoietin-1, or plasminogen and these individuals are said to have HAE of unknown etiology
(U-HAE). There could be multiple mechanisms underlying U-HAE, and there could be subtle clinical and laboratory
differences among different forms of HAE with normal C1INH [9]. In a study of 265 patients with HAE with normal
C1INH, those with a U-HAE were less sensitive to estrogens [2].
Other laboratory abnormalities — Other laboratory abnormalities that have been identified in some patients with
HAE with normal C1INH include genetic mutations in other proteins and deficiency of plasminogen activator
inhibitor-2 (PAI-2). The presence of these abnormalities, as well as their role in pathogenesis, remains to be
confirmed.
● Polymorphisms in the genes encoding aminopeptidase P and angiotensin-converting enzyme (ACE), two
enzymes that degrade bradykinin, were reported in three female subjects with HAE with normal C1INH.
However, these patients also possessed the Thr328Lys mutation in the FXII gene [38].
● Deficiency of PAI-2, a molecule that inhibits the activation of plasminogen, was found to be deficient in 23
patients with HAE with normal C1INH, including patients both with and without a FXII mutation [39]. This
abnormality was not present in 23 control patients with C1INH-HAE.
Role of estrogens — The effects of estrogens in HAE with normal C1INH is highly variable. The adverse effect of
estrogens on female patients with this disorder was first highlighted in one of the original descriptions of the
disease [4]. In this study, women only experienced angioedema attacks during pregnancy or while using some form
of exogenous estrogen, including oral contraceptives and hormone replacement therapy. Additional patients with
estrogen-exacerbated angioedema have since been described [6,40,41]. However, other women with HAE with
normal C1INH can tolerate high levels of estrogen without a worsening of angioedema attacks [6,29].
It is not entirely clear how estrogens would induce attacks, although they may influence expression of factors
important in the synthesis and degradation of bradykinin. High levels of estrogens are reported to reduce plasma
C1INH levels, increase transcription of FXII protein, and increase plasma prekallikrein levels, all favoring an increase
2041
in bradykinin production (figure 1). In keeping with some interaction between estrogens and FXII, patients with FXII-
HAE were found to be more sensitive to estrogens than patients with U-HAE in one study [2]. ACE is important in
degradation of bradykinin and its metabolite, and estrogens may reduce expression of ACE and allow bradykinin
accumulation. Estrogens may also increase the expression of bradykinin type 2 receptors [42].
The negative influence of estrogens is not specific to HAE with normal C1INH, since estrogen is a well-established
trigger in some females with C1INH-HAE. (See "Hereditary angioedema: Epidemiology, clinical manifestations,
exacerbating factors, and prognosis", section on 'Triggers and exacerbating factors'.)
DIAGNOSIS
The diagnosis of HAE with normal C1INH is based on characteristic clinical features and normal complement
studies. Since angioedema is associated with multiple causes, a family history of angioedema or presence of factor
XII (FXII) mutations known to be associated with the disease is also required [10]. HAE should be suspected in a
patient with recurrent, self-limited angioedema without urticaria or pruritus, recurrent episodes of abdominal pain,
laryngeal edema, and a family history of angioedema. Clinical features that help differentiate this disorder from
C1INH-HAE were reviewed previously. (See 'Unique characteristics of HAE with normal C1INH' above.)
A diagnostic algorithm has been established for evaluating such patients (algorithm 1). In contrast to those patients
with either C1INH-HAE, patients with this type have normal plasma C1INH levels and activity, as well as normal
plasma C4 levels (table 1). Complement studies should be obtained during symptoms on at least one occasion to
confirm that they are normal even during an episode of angioedema. Because there is no specific confirmatory test
for HAE with normal C1INH, an international expert panel proposed a set of defined diagnostic criteria [9]. It is
generally accepted that in the absence of a reliable blood test to confirm the diagnosis, either the presence of an
identified FXII mutation or a family history of angioedema is required for diagnosis, with the understanding that
sporadic cases probably also exist. Thus, the following elements are necessary to make the diagnosis:
● Episodic angioedema affecting characteristic organs, without urticaria
● A family history of angioedema and failure to respond to chronic, high-dose antihistamine therapy or the
presence of a FXII (or possibly an angiopoietin-1 or plasminogen mutation) associated with the disease (see
'Mutations in factor XII' above)
● Normal C4
● Normal C1INH level and function
● No medications that could cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors or
nonsteroidal anti-inflammatory drugs (NSAIDs)
Exclude idiopathic angioedema — Idiopathic angioedema is a diagnosis of exclusion that describes recurrent
episodes of angioedema without urticaria, for which no explanation can be found after a thorough evaluation to
exclude drug reactions and allergic disorders (if indicated by the clinical history). Complement studies are normal in
idiopathic angioedema. However, unlike HAE with normal C1INH, idiopathic angioedema often improves with
antihistamines, alone or in combination with glucocorticoids. Therefore, a trial of antihistamine therapy is an
important diagnostic step. The evidence supporting the use of H1 antihistamines in idiopathic angioedema is
2042
reviewed separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on
'Recurrent, idiopathic angioedema'.)
The following represents our approach, which has not been formally studied:
● We treat patients with a nonsedating H1 antihistamine for at least one month (or an appropriate amount of time,
depending on the patient's frequency of attacks). Options include cetirizine (10 mg daily), loratadine (10 mg
daily), fexofenadine (180 mg daily), or a similar agent. If this does not prevent episodes of angioedema, we
double or quadruple the dose for another one to three months (cetirizine up to four times daily or an equivalent
for one month or an interval long enough to expect three or more angioedema attacks) [9].
● In addition, we instruct patients to treat with additional medications at the first sign of symptoms. Some
patients have identifiable sensations in the skin or tissue just before the onset of angioedema, and the
medications should be taken when these sensations appear. In this setting, we ask patients to self-administer
40 mg of prednisone and 25 to 50 mg of diphenhydramine all at once at the first sign of swelling, with no further
doses.
If one or both of these measures prevents further episodes of angioedema, then the most appropriate diagnosis is
idiopathic angioedema. A nonresponsive patient is presumed to fall into the category of nonhistaminergic
angioedema, of which HAE with normal C1INH is one subgroup.
Genetic testing — The majority of the patients do not have identifiable FXII or angiopoietin-1 mutations, based on
available data, and identification of a mutation does not impact management. The prevalence of the FXII mutation
appears to be particularly low in the United States [43]. However, FXII mutational testing is available through some
commercial laboratories and establishes the diagnosis if positive [44,45].
Differential diagnosis — The differential diagnoses of hereditary forms of angioedema are discussed in detail
elsewhere. (See "Hereditary angioedema: Pathogenesis and diagnosis", section on 'Differential diagnosis'.)
Idiopathic angioedema — The primary disorder in the differential diagnosis of HAE is idiopathic angioedema.
This disorder must be excluded before the diagnosis of HAE with normal C1INH can be assigned, especially without
a family history or if testing for FXII mutations is not performed or shows no mutations. A limitation to the proposed
diagnostic criteria is the inability to completely distinguish HAE with normal C1INH of unknown cause (U-HAE) from
nonhistaminergic idiopathic angioedema, highlighting the need for a valid confirmatory diagnostic test. (See
'Exclude idiopathic angioedema' above.)
MANAGEMENT
Reported treatment options for HAE with normal C1INH are overall similar to those for C1INH-HAE and may also be
divided into management of acute attacks and prophylactic therapy [46]. However, treatment experience is limited,
because there are no placebo-controlled clinical trials, and most evidence is anecdotal. (See "Hereditary
angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency):
General care and long-term prophylaxis" and "Hereditary angioedema: Temporary prophylaxis before procedures or
stress to prevent angioedema episodes".)
2043
Treatment of acute attacks — Patients with acute symptoms involving the upper airway are at risk for fatal
asphyxiation. Assessment and protection of the upper airway is the first and most important management issue in
the patient with an acute attack involving any part of the airway, because none of the available therapies are
universally effective. In addition, these agents take time to work, and the patient's airway must be protected in the
interim. (See "Hereditary angioedema: Acute treatment of angioedema attacks".)
Intubation should be performed immediately if stridor or signs of respiratory arrest are present. A clinician trained in
difficult airway management should be summoned, if possible, because failed attempts can lead to fatal
obstruction. Emergent cricothyroidotomy may be required in rare cases. (See "Emergency cricothyrotomy
(cricothyroidotomy)".)
Once the patient is assessed and either intubated or deemed stable, additional therapies can be considered.
Transfer to the intensive care unit should be arranged. Frequent and meticulous monitoring of airway status should
continue throughout the course of the attack until complete resolution, and patients should not be discharged until
all airway symptoms have resolved.
Specific agents — Unlike with C1INH-HAE, data on the effectiveness of different therapies for HAE with normal
C1INH are limited to small, uncontrolled trials and case reports.
● Icatibant is a bradykinin type 2 receptor antagonist that has been effective in treating acute symptoms in small
numbers of patients [47-49]. In an open-label, noncomparative prospective study including eight patients with
HAE type III, most symptoms improved rapidly following icatibant self-administration, although some attacks
required a second or third injection of the drug [48]. In addition, 2 of 19 attacks could be classified as failures
with a time of initial improvement ≥4 hours [48]. Dosing and administration are reviewed separately. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Icatibant dose and
administration'.)
● Ecallantide is a plasma-kallikrein inhibitor, which has been used successfully to treat HAE with normal C1NH in
a limited number of reports [50,51]. (See "Hereditary angioedema: Acute treatment of angioedema attacks",
section on 'Kallikrein inhibitor (United States only)'.)
● C1INH concentrate has also been used presumably to raise the set point for activation of kallikrein and
generation of bradykinin. In one retrospective study of 38 attacks in 21 patients, 22 showed symptom
improvement within one hour, and another nine, within 180 minutes [52]. In another study, seven patients were
treated with C1INH concentrate for 63 attacks, and it was subjectively effective for six of these individuals and
ineffective for one [12]. Other cases reported lack of effect [3]. However, since C1INH is one of the plasma
proteins that controls the set point for coagulation and fibrinolysis and C1INH levels are normal in these
patients, there is a danger of thrombosis, particularly in patients with ports for vascular access.(See "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'C1 inhibitor (plasma-derived)' and "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
● Fresh frozen plasma (or solvent detergent-treated plasma) has not been reported for treatment of this disorder,
to our knowledge. Use of plasma in other types of HAE is reviewed separately. (See "Hereditary angioedema:
Acute treatment of angioedema attacks", section on 'Plasma'.)
2044
Patients with HAE with normal C1INH tend not to respond to epinephrine, antihistamines, or glucocorticoids, similar
to those with C1INH-HAE [12,46]. However, if the diagnosis is uncertain, these therapies should certainly not be
withheld. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Ineffective therapies'.)
Avoidance of triggers — Triggers for episodes of angioedema include local trauma or physical pressure to the
affected area, emotional stress, and certain medications [12]. Exogenous estrogens are the most consistently
reported medication to worsen symptoms [4]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II
receptor blockers (ARBs) have been implicated in case reports [11,53]. In some patients, withdrawal of aggravating
medications is sufficient to prevent most attacks, and no other prophylactic therapy is needed [54].
Short-term prophylaxis prior to medical/dental procedures — Dental and medical procedures can trigger episodes
of angioedema. The goal of short-term prophylaxis is to prevent these episodes with premedications. Prophylactic
therapy has not been carefully studied in HAE with normal C1INH, although management is extrapolated from that
used in patients with HAE types I and II, which is discussed separately. (See "Hereditary angioedema: Temporary
prophylaxis before procedures or stress to prevent angioedema episodes".)
Long-term prophylactic treatment — Long-term prophylaxis is given to decrease the overall number of attacks. It
should be considered if attacks persist despite avoidance of aggravating medications for:
● Patients with more than one severe event per month
● Patients who are disabled (ie, unable to perform their usual activities) more than five days per month
● Patients who have experienced a laryngeal attack
The decision to initiate prophylaxis must consider several other factors, including the availability of effective
therapies for acute attacks (ie, icatibant or ecallantide), the patient's proximity to emergency care, the likelihood of
side effects from long-term prophylactic therapies, and the patient's preferences. Each case must be considered
individually. It should be recognized that no controlled studies of prophylaxis of HAE with normal C1INH have been
reported and that the efficacy of prophylaxis is uncertain.
Choice of prophylactic agent — Both androgens and tranexamic acid have been administered to HAE with normal
C1INH patients for prevention of angioedema attacks with reported success, but responses have been variable.
● Danazol has been used with success in some patients with HAE with normal C1INH [3,5,27,55]. Androgens
increase the levels of C1INH in humans and factor XII (FXII) in rats, as well as increase ACE levels in other
animal studies [42]. Dosing and adverse effects are reviewed separately. (See "Hereditary angioedema (due to
C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Attenuated androgens'.)
● Tranexamic acid has also been used with success in some patients with HAE with normal C1INH [3,12,27,56-
59]. Dosing and adverse effects are reviewed separately. (See "Hereditary angioedema (due to C1 inhibitor
deficiency): General care and long-term prophylaxis", section on 'Antifibrinolytics'.)
Therapies of uncertain benefit — Injections of C1INH concentrate and progesterone preparations are of
uncertain utility in preventing symptoms.
● Regular injections of C1INH concentrate have been used successfully during the peripartum period in two
women experiencing attacks during pregnancy [20,24]. However, it is unclear if there are potential adverse
2045
effects of providing more C1INH to a patient with normal levels of functional C1INH. Since C1INH is important
in fibrinolytic, clotting, and kinin pathways, the authors recommend caution, as there may be toxicity related to
supraphysiologic amounts of C1INH.
● Progesterone-only contraceptives have been reported to be helpful for some women with HAE with normal
C1INH [12]. However, it has not been demonstrated conclusively that the improvement in symptoms was
attributable to use of progesterone or avoidance of estrogens.
Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Hereditary angioedema and other forms of nonhistaminergic
angioedema".)
● Hereditary angioedema with normal C1 inhibitor (HAE with normal C1INH) is characterized by recurrent, self-
limited episodes of skin swelling, tongue swelling, and episodes of abdominal pain. It is distinguished from
other forms of HAE (ie, types I and II, together called C1INH-HAE) by the presence of normal complement
studies. The disorder was described in 2000 and was reported initially in females, although male patients have
since been identified. (See 'Introduction' above and 'Background and terminology' above.)
● HAE with normal C1INH is clinically similar to C1INH-HAE, although there are minor differences. Patients with
HAE with normal C1INH have more frequent facial and tongue swellings, less prominent abdominal symptoms,
onset later in life (typically in adulthood), and different cutaneous findings. (See 'Clinical presentation' above.)
● Patients with HAE with normal C1INH have normal function and plasma concentrations of C1INH, in contrast to
those with C1INH-HAE. Some families have mutations in the coagulation factor XII (FXII) gene, though the
functional consequence of these mutations has not been established. Many female patients have more severe
disease when pregnant or taking exogenous estrogens, while others are not influenced by hormonal factors.
(See 'Pathogenesis' above.)
● In the absence of a validated diagnostic test, HAE with normal C1INH is based on characteristic clinical
features, a family history of angioedema or the presence of FXII or angiopoietin-1 mutations associated with
the disease, and normal complement studies (table 1). In patients who lack a family history of angioedema, it is
important to exclude idiopathic angioedema, a disorder in which complement studies are also normal.
Idiopathic angioedema usually responds to therapy with antihistamines (often at supratherapeutic doses),
alone or in combination with glucocorticoids.(See 'Diagnosis' above.)
● For patients with acute symptoms involving the tongue or upper airway, assessment and protection of the
airway is the first and most important management issue, because none of the available therapies can be
considered universally effective. (See 'Treatment of acute attacks' above.)
● The options for acute and prophylactic therapy for HAE with normal C1INH are very similar to those for C1INH-
HAE. However, information about the efficacy of various treatments for acute symptoms is limited, and none of
2046
the therapies appear to be uniformly successful. (See 'Management' above.)
ACKNOWLEDGMENT
We are saddened by the death of Michael M Frank, MD, who passed away in August 2019. UpToDate wishes to
acknowledge Dr. Frank's past work as an author for this topic.
2047
GRAPHICS
Hereditary angioedema prodromal rash
Annular erythematous lesions mimicking chicken-wire appearance.
Reproduced with permission from: Yucelten D, Kus S. Chicken-wire erythema, but not urticaria, as the
presenting sign of hereditary angioedema. Eur J Dermatol 2006; 16:197. Copyright © 2006 John Libbey
Eurotext.
2048

Data from:
2049
C1INH deficiency diagnostic algorithm
FXII: factor XII.
Modified with permission from: Bowen T, Cicardi M, Farkas H, et al. 2010 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.
Allergy, Asthma, and Clinical Immunology 2010; 6:24. Copyright © 2010 BioMed Central Ltd.
2050
Angioedema
C4* C1-INH level C1-INH function C1q Other tests
disorder
Hereditary angioedema Low Low Low Normal Genetic testing

with C1-INH deficiency (usually <50% of (not needed for
type I (HAE-C1-INH normal) diagnosis)
type I)
Hereditary angioedema Low Normal or elevated Low Normal Genetic testing

with C1INH deficiency (usually <50% of (not needed for
type II (HAE-C1-INH normal) diagnosis)
type II)
Hereditary angioedema Normal Normal Normal Normal Mutations in gene for

with factor XII factor XII
gene mutations
(HAE-FXII)

with angiopoietin-1 gene angiopoietin-1
mutations (HAE-
ANGPT1)

with plasminogen gene plasminogen
mutations (HAE-PLG)

with kininogen-1 gene kininogen-1
mutations (HAE-KNG1)
Hereditary angioedema Normal Normal Normal Normal

of unknown origin (HAE-
U)
Acquired angioedema Low Normal or low Low Normal or low ¶ Anti-C1INH antibodies
(AAE-C1-INH) normal) diagnosis)
Idiopathic Normal Normal Normal Normal

acquired angioedema
(histaminergic or
nonhistaminergic)
(AAE-IH or AAE-InH)

Terminology for angioedema disorders is evolving, and the abbreviations HAE-C1-INH and C1INH-HAE are both used for hereditary
angioedema in the literature.
2051
Hereditary angioedema: Acute treatment of angioedema attacks

Authors: Bruce Zuraw, MD, Henriette Farkas, MD, PhD, DSc
INTRODUCTION
Hereditary angioedema (abbreviated HAE throughout this review) is a rare autosomal dominant
disorder characterized by recurrent episodes of well-demarcated angioedema without urticaria,
which most often affects the skin or mucosal tissues of the upper respiratory and gastrointestinal
tracts. Although swelling resolves spontaneously in two to four days in the absence of treatment,
laryngeal edema may cause fatal asphyxiation, and the pain of gastrointestinal attacks may be
incapacitating or lead to unnecessary abdominal surgery. The most common forms of HAE (types I
and II) are caused by deficiency or dysfunction in C1 inhibitor (C1-INH) [1-3]. There are other forms of
the disorder in which C1-INH is normal called HAE with normal C1-INH, which are discussed
separately. (See "Hereditary angioedema with normal C1 inhibitor".)
The evaluation and treatment of HAE attacks in adults and children will be reviewed here. Other
aspects of these conditions are discussed separately:

prognosis".)
prophylaxis".)
OVERVIEW
2052
Attacks of HAE are commonly categorized as upper airway (commonly referred to as "laryngeal"),
gastrointestinal, or cutaneous. Laryngeal attacks are the least common but most dangerous type of
attack because airway obstruction can progress to asphyxiation and death. More than one-half of all
HAE patients experience a laryngeal attack at some point [4]. Therefore, all patients should be
educated about the early signs and symptoms of laryngeal attacks, even if the individual has never
experienced one. There should also be a specific plan for how the individual will access emergency
treatment. (See 'Laryngeal attacks' below.)
Gastrointestinal attacks can range from mild to severe but usually resolve without serious
complications, unless the patient undergoes unnecessary surgical interventions because the
disorder is not recognized as HAE [5]. Cutaneous attacks are not associated with significant risk of
serious complications or death, although they often cause substantial morbidity, as patients' lives
can be significantly disrupted by repeated episodes. In addition, cutaneous attacks of the face may
extend to involve the larynx in 15 to 30 percent of cases [4].
In HAE, deficiency or dysfunction of C1 inhibitor (C1-INH) leads to excessive production of the

vasoactive mediator bradykinin, which leads to episodic increases in vascular permeability and
angioedema. The bradykinin-mediated angioedema of HAE is fundamentally different from the
angioedema that occurs with allergic reactions (which is mediated by histamine and other mast cell
mediators), and it does not respond to epinephrine, antihistamines, or glucocorticoids. Instead, first-
line therapies for HAE act by replacing C1-INH or by blocking the production or function of
bradykinin.
Equipping patients for emergency care — HAE is rare, and clinicians in emergency settings may not
be familiar with the disease or its treatment. Therefore, as soon as a patient has been diagnosed with
HAE, a plan for emergency care should be put in place, with particular focus on how the patient
should seek care in the event of a laryngeal attack. Patients should be educated that any swelling
involving the airway is potentially life-threatening and should be treated as an emergency. All
patients should have a plan for accessing treatment rapidly. An important concept that has arisen
with the availability of effective on-demand therapies is that of a personalized care plan that takes
into account the severity of disease, resources available, and the patient's values and preferences
regarding the different therapies [6,7].
● When possible, clinicians or their representatives should communicate with the hospitals
nearest to the patient's home to ensure that acute therapies are available [6].
● Patients should be equipped with a form that summarizes treatments for acute episodes of
angioedema to assist in communication with emergency providers and ensure appropriate care
(full-sized and wallet forms are provided) (form 1 and form 2).
2053
● In some countries (not the United States), national call centers have been established to provide
24-hour phone access to HAE expert clinicians who can be consulted for help with emergency
treatment [8,9].
First-line therapies — There are several first-line therapies for acute treatment of episodes of
angioedema in HAE with C1-INH deficiency which are summarized in the table and discussed in
more detail below (table 1) (see 'First-line agents: Dosing, efficacy, and adverse reactions' below):
● C1-INH concentrate, derived from human plasma (plasma-derived C1-INH or pdC1-INH) (see 'C1
inhibitor (plasma-derived)' below)
● Recombinant human C1-INH (rhC1-INH, conestat alfa) (see 'Recombinant C1 inhibitor' below)
● Icatibant, a synthetic bradykinin B2-receptor antagonist (see 'Bradykinin B2-receptor antagonist'
below)
● Ecallantide, a recombinant plasma kallikrein inhibitor (see 'Kallikrein inhibitor (United States
only)' below)
A clinical response should be evident within two hours with first-line therapies. No direct, head-to-
head trials comparing these agents have been performed, and attempts to compare therapies
indirectly are likely confounded by the multiple variables specific to each protocol [10]. Each
medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy
data, and adverse effects. (See 'First-line agents: Dosing, efficacy, and adverse reactions' below.)
Initiating acute treatment of HAE attacks at home — Early treatment of HAE attacks has been shown
to result in improved efficacy [11-13]. Initiating treatment at home (or other settings away from a
medical environment) can decrease the delay between the onset of symptoms and time of treatment,
and time to start of improvement and resolution of swelling are both significantly shorter when
therapies can be given at home. All of the first-line therapies for HAE are likely to be effective if given
in the first few hours of the angioedema attack (when the swelling is increasing). Most patients are
willing and able to initiate treatment of acute attacks at home. The medications which can be given
at home by the patient or by a nursing service on demand are:
● C1-INH concentrate (plasma-derived or recombinant), which may be self-administered or given

by a caregiver or nurse through a peripheral intravenous line at the first sign of symptoms [14].
Practices regarding injection by the patient versus injection by a nurse in the home setting differ
by country. (See 'C1 inhibitor (plasma-derived)' below and 'Recombinant C1 inhibitor' below.)
● Icatibant, which may be self-administered as a subcutaneous injection. (See 'Bradykinin B2-

receptor antagonist' below.)
2054
● Ecallantide, which is only available in the United States and is given as three subcutaneous
injections. Although it is not approved by the US Food and Drug Administration for self-
administration, because of a risk of hypersensitivity reactions, it can be given by a trained nurse
in the patient's home. (See 'Kallikrein inhibitor (United States only)' below.)
While home treatment is preferred, the decision to prescribe therapies for acute treatment at home
must be individualized. The clinician must consider each patient's situation, history of attacks,
proximity to care, ability to self-administer medications, and preferences.
Second-line therapies — If none of the first-line therapies are available, other options for laryngeal
and gastrointestinal attacks are solvent/detergent-treated plasma (preferred because of lower risk of
transmission of infectious diseases) or fresh frozen plasma (table 2). (See 'Plasma' below.)
MANAGEMENT ISSUES FOR SPECIFIC TYPES OF HAE ATTACKS
Laryngeal attacks — More than one-half of all HAE patients experience a laryngeal attack at some
point [4]. Airway angioedema can present as a sensation of throat swelling, change in voice quality,
difficulty swallowing secretions, or difficulty breathing. Angioedema usually progresses over hours,
although it can escalate precipitously. Intubation may become very difficult due to distortion of the
anatomy of the upper airway. Features of laryngeal attacks and patterns of progression are reviewed
separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating
factors, and prognosis", section on 'Laryngeal attacks'.)
A first-line therapy (C1 inhibitor, icatibant, or ecallantide) should be administered as early as possible
in the attack (table 1). Patients who have first-line therapies at home and self-administer an initial
dose should still seek medical care promptly, in case further intervention is required.
Airway management — Assessment and protection of the upper airway is the first and most
important management issue in the patient with an attack involving any part of the airway because
none of the available therapies, including first-line agents, can be considered universally effective in
all cases. In addition, these agents take time to work, and the patient's airway must be protected in
the interim.
Intubation should be attempted immediately if stridor and/or signs of respiratory arrest are present.
A clinician trained in difficult airway management and able to perform tracheostomy should be
summoned if possible because failed attempts can lead to fatal obstruction. Emergent
cricothyroidotomy may be required at this stage. (See "Emergency cricothyrotomy
(cricothyroidotomy)".)
2055
Once the patient is assessed and either intubated or deemed stable, additional treatment can be
considered. Transfer to the intensive care unit should be arranged, unless the laryngeal angioedema
responds promptly to treatment in a stable patient. Frequent and meticulous monitoring of airway
status should continue throughout the course of the attack until complete resolution, and patients
should not be discharged until all airway symptoms have resolved.
Gastrointestinal attacks — Gastrointestinal attacks present with varying degrees of gastrointestinal

colic, nausea, vomiting, and/or diarrhea, which result from bowel wall edema. Gastrointestinal
attacks can range from mild to severe but usually resolve without serious complications, unless
patients undergo unnecessary surgical interventions because the disorder is not recognized [5]. The
clinical presentation and evaluation of gastrointestinal attacks is reviewed in more detail separately.
(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and
prognosis", section on 'Gastrointestinal attacks'.)
When a patient with known or suspected HAE presents with gastrointestinal colic, the clinician must
determine if the abdominal symptoms are actually due to angioedema or to an unrelated process.
Patients who have had previous gastrointestinal attacks should be questioned carefully to ascertain
if their current symptoms are similar to past episodes.
The clinical response to one of these first-line therapies can be valuable in distinguishing
gastrointestinal attacks of HAE from other abdominal pathologies. With all of the first-line therapies,
clinical response should be evident within two hours, keeping in mind that improvement is usually
most prompt when the therapy is given in the first several hours of the episode (table 1). If given later
in the attack, a slower, more gradual response may be seen. However, if there is no response at all
two hours after the initial dose, then evaluation for other causes of abdominal symptoms should
proceed.
If first-line therapies are not available, then management of gastrointestinal attacks is largely
supportive (table 2). Alternatively, two units of plasma can be administered after reviewing the risk of
disease transmission with the patient. Dosing is discussed below. (See 'Dosing' below.)
Rehydration and symptomatic therapy — Therapy to abort the attack is most important, but some
patients with gastrointestinal attacks also require treatment for dehydration and pain, particularly if
effective treatment was not given early in the attack. Agents such as butylscopolamine (not available
in the United States), metoclopramide, or prochlorperazine can be helpful for cramping, nausea, and
vomiting.
Cutaneous attacks — Cutaneous attacks may involve any part of the body, including the extremities,
torso, face, and genitalia. Many cutaneous attacks result in significant dysfunction, and patients may
miss several days of school or work [15]. Thus, consideration of treating early rather than waiting
2056
until swelling becomes more severe should be given particularly in facial attacks, which may extend
to involve upper airway mucosa. Acute therapies are less likely to provide relief when given late in an
attack. However, the decision to treat obviously depends upon the availability of acute therapies
(table 2).
Attacks involving multiple locations — HAE attacks can involve more than one location, with
approximately 30 percent of severe attacks affecting multiple sites [16]. These attacks can involve
any combination of laryngeal, gastrointestinal, or cutaneous locations. Symptoms at the individual
locations typically parallel each other, although in some cases, swelling can start at a new site while
resolving at an earlier site. Management of multisite attacks is based on the management principles
for each individual site. The response to effective treatment tends to be similar at the various sites.
FIRST-LINE AGENTS: DOSING, EFFICACY, AND ADVERSE REACTIONS
The medications used for acute treatment of episodes of angioedema in HAE are discussed in this
section, with proposed mechanism of action, dosing, efficacy data, and side effects (table 1). An
approach to using these medications to manage acute angioedema was presented previously. (See
'Overview' above.)
C1 inhibitor (plasma-derived) — C1 esterase inhibitor (C1-INH), concentrate from human plasma, is

referred to in this review as plasma-derived C1-INH or pdC1-INH. It is administered intravenously for
acute treatment of HAE attacks. pdC1-INH is the best-studied first-line therapy for acute episodes of
angioedema in patients with HAE [17,18]. It is also the preferred acute treatment for HAE attacks in
pregnant women with HAE [19-22]. (See 'Pregnant or lactating women' below.)
C1-INH acts at several points in the pathways important in the generation of angioedema (figure 1).
(See "Hereditary angioedema: Pathogenesis and diagnosis", section on 'Pathogenesis'.)
Two pdC1-INH products are available for acute treatment: Cinryze (brand name) and Berinert (brand
name), which are administered by intravenous injection. Other C1-INH products (ie, Haegarda [brand
name] or Berinert 2000/3000 [brand name]) are administered by subcutaneous injection and
approved only for prophylaxis. Prophylaxis is discussed in detail separately. (See "Hereditary
angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on
'Subcutaneous C1 inhibitor'.)
Dosing — The dosing of pdC1-INH (Berinert) for treatment of acute episodes is based upon
weight, and the recommended dose is 20 units/kg [23,24]. Each vial of drug contains 500 units of
pdC1-INH. Thus, doses for patients of different weight ranges are:
● Administer 1000 units if weight is ≤50 kg (110 pounds)

2057
● Administer 1500 units if weight is >50 kg (>110 pounds) and ≤75 kg (165 pounds)
● Administer 2000 units if weight is >75 kg (>165 pounds) and ≤100 kg (220 pounds)
● Administer 2500 units if weight is >100 kg (>220 pounds)
pdC1-INH should be reconstituted, warmed to body temperature before administration, and given
through a peripheral vein by slow infusion (eg, 1000 units over 10 minutes). It can be administered at
home by the patient, a caregiver, or a nurse, or in a medical facility [25,26]. The solution must not be
shaken, as this can cause denaturation of the protein. In an emergency, it can be given without
prewarming. These therapies should be given as early as possible in the course of an attack. One
study showed that patients treated within six hours of symptom-onset had shorter times to relief and
resolution of symptoms compared with those treated later [27].
Stabilization or improvement in symptoms is usually seen within 30 minutes in laryngeal or

gastrointestinal attacks [28]. Fewer than 1 percent of attacks require a second dose [29,30]. However,
if symptoms initially improve but then start to recur or only partially improve, a second dose can be
given after the first, and if symptoms are still worsening after the initial dose of pdC1-INH, a second
dose can be administered, particularly for attacks affecting the airway. Berinert (brand name) might
be used as rescue therapy in patients not responding to icatibant [29].
The US Food and Drug Administration (FDA) has not approved Cinryze (brand name) for acute
treatment of HAE attacks (only for prophylaxis). However, there is no empiric reason to suspect that
Cinryze (brand name) would be less effective than the C1-INH products. The Cinryze (brand name)
dose approved in the European Union for HAE attacks is 1000 units, with the possibility of another
1000 units if not improving. In the absence of trials to determine optimal dosing of Cinryze (brand
name) in HAE attacks, either this dosing or weight-based dosing (described above) is acceptable.
Efficacy — The efficacy of pdC1-INH for acute treatment of HAE attacks has been well-
demonstrated in randomized trials [23,31-36].
● A randomized trial of pdC1-INH (Cinryze [brand name]) for acute treatment of HAE attacks
involved 68 patients assigned to either 1000 units of pdC1-INH (regardless of weight, with the
possibility of another 1000 units after one hour based on clinician and patient assessment of
need) or placebo for nonlaryngeal attacks [36]. The median time to onset of unequivocal relief
(the primary endpoint) was two hours in the pdC1-INH group, compared with over four hours in
the placebo group.
● A subsequent randomized trial of 125 patients with acute gastrointestinal or facial cutaneous
angioedema episodes compared pdC1-INH (Berinert [brand name]) at doses of 10 units/kg or 20
units/kg with placebo [23]. Patients were treated within five hours of the symptoms reaching
moderate intensity. Median time to onset of relief was significantly shorter with the higher dose
2058
of pdC1-INH (0.5 hours), compared with the lower dose of pdC1-INH (1.2 hours) or placebo (1.5
hours).
● A retrospective comparison of data from 881 laryngeal attacks treated with any of the available
first-line therapies found that weight-adjusted pdC1-INH appeared to give the best outcomes,
with time to onset of relief ranging from 15 minutes to two hours and none of the 48 attacks
requiring a second dose [10]. A subsequent nonrandomized trial also confirmed the efficacy of
weight-based pdC1-INH (Berinert [brand name]) (20 units/kg) in patients with laryngeal edema
[37].
Data from a multicenter registry found that the response could be improved when patients were able
to self-administer pdC1-INH at home at the first sign of swelling (pdC1-INH "on demand") and that
this practice was safe [38]. In a small study, 12 patients reported initiation of relief in a mean of
approximately 40 minutes after the onset of symptoms when pdC1-INH was self-administered, as
compared with about 2.5 hours when the patients were dependent on a health care facility for
administration [11].
Adverse effects — In an international registry of 296 patients receiving pdC1-INH (Berinert [brand
name]), the most common adverse event considered possibly related to pdC1-INH was headache
[38]. There were no hypersensitivity reactions reported in the registry, although there were earlier
case reports of generalized itching, urticaria, and edema of the tongue and oral mucosa or
anaphylactic shock shortly after infusion of pdC1-INH [39,40].
Thrombotic events have been associated with pdC1-INH and are discussed in more detail separately.
(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term
prophylaxis", section on 'Adverse effects'.)
Disease transmission is a theoretical risk of pdC1-INH treatment, since it is obtained from pooled
human plasma that has been pasteurized and nanofiltered. However, there have been no reported
cases of viral transmission with the most extensively used preparation (Berinert [brand name]),
despite the administration of over 100 million units [21,38,41-43]. The issue of disease transmission
with C1-INH products is discussed in more detail separately. (See "Hereditary angioedema (due to C1
inhibitor deficiency): General care and long-term prophylaxis", section on 'Adverse effects'.)
There is no indication that "resistance" to pdC1-INH develops with repeated use, at least in most
patients. This was evaluated in a study of 18 patients treated for at least 15 HAE attacks over a mean
duration of 34 months [44]. No decrease in time to relief of symptoms or interval between attacks
was observed.
2059
Recombinant C1 inhibitor — Recombinant human C1-INH (rhC1-INH, conestat alfa) (Ruconest [brand
name] in Europe and the United States, Rhucin [brand name] in other countries) became available in
Europe in 2011 and in the United States in 2014 [45]. It is collected from the milk of transgenic
rabbits [46-48]. Compared with the plasma product, rhC1-INH has a similar protease inhibitory
activity but a shorter half-life. Thus, higher doses are required to achieve adequate plasma levels
over a period of time sufficient to impact acute symptoms, compared with the plasma-derived
product.
Dose — The recommended dose of rhC1-INH for acute treatment of an HAE attack is 50 units/kg,
rounded up to the nearest whole vial, and up to a maximum of 4200 units [49-51]. The medication is a
lyophilized powder that is reconstituted in sterile water, warmed to body temperature before
administration, and given through a peripheral vein over five minutes. The patient should be
observed during administration for signs or symptoms of an allergic reaction.
Patients generally respond within four hours and do not require repeat dosing, although a second
identical dose can be given if there is no improvement for a maximum of 4200 international units per
24 hours. Relapse may occur in 2 to 3 percent of patients [52].
Efficacy — The efficacy of rhC1-INH for acute treatment of HAE attacks has been demonstrated in
several randomized trials [51,53-55].
● In two similar randomized trials, patients received rhC1-INH at doses of 100 units/kg, 50
units/kg, or placebo [51]. The primary endpoint was the time to initial relief of symptoms, which
was a median of 66 minutes (95% CI 61-122) with the higher dose, 122 minutes (95% CI 72-136)
with the lower dose, and 495 minutes (95% CI 245-520) with placebo. At both doses, rhC1-INH
was well-tolerated.
● In another randomized trial, 75 patients were treated with rhC1-INH (50 international units/kg to
a maximum of 4200 international units/treatment) or placebo [53]. Median time to the beginning
of symptom relief was 90 minutes and 152 minutes in patients receiving rhC1-INH and placebo,
respectively. Median time to minimal symptoms was 303 minutes in the rhC1-INH group.
Recombinant and plasma-derived C1-INH have not been compared in head-to-head studies, and
information about their relative risks and benefits is limited. A small series described the use of rhC1-
INH in patients with disease that was not fully responsive to pdC1-INH and other therapies with
mixed results [56].
Adverse effects — Side effects with rhC1-INH were uncommon and included headache, nausea,
and diarrhea [49]. No postexposure antibody responses against the product have been detected [57].
2060
Allergy to rabbits is a contraindication to the use of rhC1-INH because anaphylaxis was reported
during a phase I study in a normal volunteer with pre-existing rabbit allergy [58]. Patients can simply
be asked about this. Formal testing for rabbit allergy is not necessary unless the patient reports
allergy.
Thrombotic events were not seen in the randomized trials of Ruconest (brand name) mentioned
above [49,51,53]. (See 'Adverse effects' above.)
Bradykinin B2-receptor antagonist — Icatibant (Firazyr [brand name]) is a synthetic bradykinin B2-
receptor antagonist, which has been available in the European Union since 2008 and became
available in the United States in 2011, where it was approved for patients 18 years of age and older
[59-61]. In the European Union, icatibant was approved for use in children as young as two years of
age.
Icatibant is a synthetic polypeptide that is structurally analogous to bradykinin and acts by

selectively and competitively antagonizing the bradykinin B2-receptor (figure 1). It is approved for
acute treatment of HAE attacks in patients with hereditary C1-INH deficiency.
Icatibant dose and administration — The dose of icatibant in adults is 30 mg, given by slow
subcutaneous injection because of the relatively large volume (3 mL) involved, preferably in the
abdominal region [62]. It can be self-administered. The pediatric dose is dependent on the patient's
weight as below (table 1):
● Administer 10 mg if weight is 12 to 25 kg
● Administer 30 mg if weight is >65 kg
Most patients require only one dose to treat symptoms adequately [63-66]. If symptoms are
gradually improving after the initial dose, no further doses are needed. However, if symptoms
continue to worsen after the initial dose, a second dose can be given after six hours, and a third dose
can be given, if needed, after an additional six hours. A maximum of three doses within 24 hours is
recommended.
Efficacy studies — The "For Angioedema Subcutaneous Treatment" (FAST-1 and FAST-2) trials
were randomized, multicenter, phase III trials, in which 130 adults with C1-INH deficiency were
treated with icatibant for laryngeal, gastrointestinal, or cutaneous attacks of moderate-to-severe
intensity [67]. FAST-1 compared icatibant with placebo, and FAST-2 compared icatibant with oral
tranexamic acid (TA). The primary endpoint was median time to onset of symptom relief. FAST-1 did
2061
not demonstrate a clear benefit of icatibant over placebo (2 hours versus 4.2 hours), but FAST-2 did
(2 hours with icatibant versus 11 hours with TA). In a pooled analysis of the two trials, significantly
more patients receiving icatibant had symptom relief within four hours compared with placebo or TA
(73 versus 45 and 29 percent, respectively) [68]. In addition, median time to near-complete symptom
relief was significantly shorter with icatibant compared with placebo or TA (15, 21, and 36 hours,
respectively).
In a third trial, FAST-3, 83 patients were randomly assigned to receive icatibant or placebo for
moderate-to-severe attacks at any location [69]. Icatibant significantly reduced median times to ≥50
percent reduction in symptom severity (2 versus 19.8 hours, primary endpoint), onset of primary
symptom relief (1.5 versus 18.5 hours, secondary endpoint), or near-complete symptom relief (8
versus 36 hours) and provided a shorter time to initial symptom relief (0.8 versus 3.5 hours). For
laryngeal attacks, median times to ≥50 percent reduction in symptom severity were 2.5 and 3.2 hours
for icatibant and placebo, respectively. None of the patients receiving icatibant required rescue
therapy before symptom relief occurred.
A phase III study involved 32 children and adolescents with HAE, ranging in age from 2 to 18, who
were treated with 0.4 mg/kg of icatibant [63]. Among 11 children and 11 adolescents treated for
attacks, the median time to symptom relief was one hour. Adverse events occurred in nine subjects,
were mild or moderate, and consisted predominantly of injection site reactions and gastrointestinal
complaints.
Adverse effects and precautions — Mild and transient pain at the injection site is the most
common adverse reaction to icatibant. Other uncommon adverse effects include nausea,
gastrointestinal colic, fever, asthenia, dizziness, increase in transaminases, and headache [70].
Icatibant should be used with caution in patients with acute ischemic heart disease or unstable
angina, since antagonism of the bradykinin B2-receptor can reduce coronary blood flow in animal
models, and patients with these comorbidities were excluded from clinical trials [71]. HAE attacks
may relapse in 10 percent of cases [72].
Kallikrein inhibitor (United States only) — Ecallantide (Kalbitor [brand name]) is a genetically
engineered recombinant plasma kallikrein inhibitor [73]. This drug blocks the production of
bradykinin by inhibiting plasma kallikrein (figure 1) [59,74-78]. Ecallantide was approved by the FDA
in 2009 for the treatment of acute attacks of HAE in patients 12 years of age or older [79]. It is only
available in the United States [80].
Like pdC1-INH, ecallantide is a first-line acute therapy for laryngeal angioedema (following airway
protection) and for gastrointestinal attacks. It is occasionally used for severe cutaneous attacks.
However, clinical experience with ecallantide is more limited.
2062
Ecallantide should be administered by a clinician or a nurse, in a setting equipped to manage
anaphylaxis as well as severe angioedema related to HAE. Anaphylaxis and allergic reactions were
reported in 2 to 3 percent of patients in clinical trials. (See 'Efficacy studies and safety' below.)
Ecallantide dosing and administration — Ecallantide is available in 1 mL vials of 10 mg each, and

the adult dose is 30 mg. Injections should be given as three separate injections of 10 mg in the
abdomen, upper arm, or thigh. The sites of injection should be anatomically distant from the area
affected by the angioedema.
A second dose of 30 mg may be administered if symptoms persist. Based on limited information, the
second dose could be given as early as 1 hour and up to 24 hours after the first dose. Relapse has
been reported in less than 3 percent of patients [81].
Efficacy studies and safety — The efficacy of ecallantide was assessed in two randomized trials:
EDEMA3 [82] and EDEMA4 [80]. In an analysis of the pooled data from these studies, 143 subjects
were treated with either ecallantide or placebo [83]. All types of attacks occurred (gastrointestinal,
laryngeal, and cutaneous), with gastrointestinal attacks being the most common. Change from
baseline mean symptom complex score at four hours after dosing was significantly greater in the
ecallantide group compared with the placebo group (-0.97±0.78 and -0.47±0.71, respectively). The
percentages of ecallantide- and placebo-treated patients with meaningful improvement at four hours
were 70 and 38, respectively.
Allergic reactions and anaphylaxis — The leading safety issue is a risk of allergic reactions and
anaphylaxis, which have been reported in 3 to 4 percent of patients receiving it subcutaneously in the
clinical trials [80,82,84]. For this reason, ecallantide should be administered in a supervised setting
by a medically trained provider. Patients should be monitored carefully following administration
because some symptoms of anaphylaxis overlap with those of HAE (ie, angioedema, throat
discomfort), and recognition of an allergic reaction may be challenging. In the available reports,
anaphylaxis presented within one hour of administration as flushing, urticaria, pruritus, rhinitis, chest
discomfort, pharyngeal or laryngeal edema, wheezing, and/or hypotension. Anaphylaxis has not
been reported with the first dose when the drug is given subcutaneously. All episodes have
responded to epinephrine and other appropriate treatments with no fatalities [84]. Until more
information is available, patients experiencing anaphylaxis or clear symptoms of hypersensitivity
should not be given the drug again until evaluated by an allergy specialist. The mechanism
responsible for these reactions has not been conclusively demonstrated, and the role of skin testing
is not clear [84]. However, some patients with hypersensitivity reactions have tolerated the drug upon
graded challenge [84].
2063
Other adverse effects of ecallantide are generally mild and include headache, nausea, fatigue, and
diarrhea [80]. Injection site reactions are reported in <10 percent of patients.
Cost of first-line therapies — All first-line acute therapies for HAE attacks are costly. In the United
States, the cost of one treatment with pdC1-INH, ecallantide, or icatibant ranged from USD $5000 to
10,000 [85]. In European countries, the cost of one treatment with pdC1-INH, rhC1-INH, or icatibant is
about 1500 to 2000 euros.
PLASMA
Plasma is a second-line therapy in the acute treatment of laryngeal attacks and severe
gastrointestinal attacks and should be used only if the therapies discussed above are not available.
There have been no studies directly comparing plasma with C1 inhibitor (C1-INH), ecallantide, or
icatibant.
Plasma is available as solvent/detergent (S/D)-treated plasma or fresh frozen plasma (FFP), and
both are reported to be helpful. Guidelines recommend S/D plasma over FFP, when both are
available, because S/D-treated plasma theoretically carries a lower risk of viral transmission
compared with FFP. However, most of the case reports of HAE treatment used FFP. This is potentially
relevant because S/D treatment removes some plasma components, and the effect on C1-INH
specifically has not been investigated. (See 'Effectiveness' below.)
Dosing — Two units of plasma are given initially. This dose can be repeated every two to four hours
until there is clinical improvement. Once the attack begins to subside, further plasma is not usually
required. If a patient has comorbid conditions that increase the risk for volume overload, then dosing
of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume status and
cardiopulmonary function [86].
Effectiveness — The efficacy of plasma in treating HAE attacks has been suggested by case reports.
No controlled trials have been performed [87-93]. A review of the literature included 23 case reports
in which FFP was used for acute treatment of HAE attacks and revealed improvement in 22 cases
[94]. The time to first signs of improvement ranged from 30 minutes to 12 hours. No clinical
improvement was noted in one case, and transient worsening of symptoms, followed by
improvement, was reported in two cases. Plasma could theoretically exacerbate angioedema
because it contains not only C1-INH but also substrate proteins (prekallikrein and high molecular
weight kininogen) that could consume the available inhibitor and paradoxically worsen the
angioedema, although this has been reported only rarely [94]. Still, the clinician must monitor
patients with airway angioedema carefully and be prepared to intubate if necessary.
2064
The data on S/D-treated plasma are scant [95], and we know of no reports comparing S/D plasma
and FFP for the acute treatment of angioedema episodes. (See "Clinical use of plasma
components".)
Risks — The primary concern with plasma products is disease transmission, and the risks of this
must be presented to the patient prior to each administration.
● S/D treatment inactivates enveloped viruses (such as HIV, human T lymphotropic virus, and
hepatitis B and C) but not prions or nonenveloped viruses (eg, hepatitis A, parvovirus).
● FFP does not undergo processing to remove infectious agents. However, it is obtained from
single donor units rather than pooled plasma, and each unit undergoes serologic testing for viral
markers. The risk of infection for a unit of FFP is identical to that of whole blood, which is also
obtained from single donors. This risk is summarized in the table and presented in more detail
separately (table 3). (See "Risk of HIV from blood transfusion" and "Epidemiology and
transmission of hepatitis C virus infection".)
SPECIAL POPULATIONS
Pregnant or lactating women — The preferred acute treatment of HAE attacks in pregnant and
lactating women is plasma-derived C1 inhibitor (pdC1-INH), given at 20 units per kilogram, because
there is extensive experience with the pdC1-INH products that have been available in the European
Union [96]. Fewer data are available regarding the use of icatibant [97-99], recombinant C1 inhibitor
(rhC1-INH) in pregnant women [99,100], or ecallantide. These should be used only if pdC1-INH is not
available.
Children and adolescents — pdC1-INH is safe and effective in patients of all ages [101]. The other
first-line therapies have been studied less extensively in children but appear to be safe and effective
(table 1):
● rhC1-INH is effective and well-tolerated for HAE attacks in adolescents [102]. In an open-label,
phase 2 study that included children aged 2 to 13 years with HAE, rhC1-INH was efficacious,
safe, and well-tolerated [103].
● Icatibant has been studied in children and adolescents and was also well-tolerated [63].
Icatibant is approved for use in the European Union for children as young as two years of age.
● Ecallantide is approved in the United States for children 12 years of age and older.
2065
INEFFECTIVE THERAPIES
Therapies that are minimally effective or have no benefit at all in the acute treatment of angioedema
in HAE include androgens, tranexamic acid (TA), and treatments for allergic (histaminergic)
angioedema.
● Androgens and TA are therapies that prevent attacks of angioedema in HAE, but androgens have
never been conclusively shown to be useful in acute treatment, and TA appears to be minimally
effective [104]. If first-line agents are not available, attacks are best managed with plasma
products or supportive care. Preventative therapies for HAE are reviewed in detail separately.
prophylaxis".)
● Epinephrine is effective in histaminergic (allergic) angioedema but is not known to have any
impact on the bradykinin-mediated angioedema of HAE. There are isolated case reports
suggesting benefit from epinephrine in HAE attacks [105,106]. However, controlled studies
would be needed to validate a true effect, since the angioedema of HAE resolves spontaneously
with time.
● Glucocorticoids and antihistamines are not effective for angioedema associated with disorders
of C1 inhibitor (C1-INH) and should not be given once the diagnosis of a C1-INH disorder has
been made.
● A few studies have examined the effects of inhaled or injected heparin or heparin-like
compounds in treating (and preventing) the symptoms of HAE attacks [107-109]. However, more
data are needed before this therapy can be considered.
CARE FOLLOWING ATTACKS
Following any HAE attack, events leading up to the attack should be examined to determine if an
identifiable trigger was present. Common triggers include the following [110]:
● Regularly missing doses of prophylactic medication

● Running out of prophylactic medication
● Initiating interfering medications (such as estrogens or angiotensin-converting enzyme
inhibitors)
● Infections
● Trauma, including iatrogenic interventions (dental work and other procedures)
● Physical exertion or fatigue
2066
● Mental stress (although often not avoidable, some patients increase their prophylactic
medications during stressful periods)
● Menstruation
● Pregnancy
● Narcotic addiction (which can lead to increased complaints of abdominal pain)
Discussing common triggers with the patient directly after an event should help that individual avoid
the same set of circumstances in the future. In addition, the clinician should review how and when
the patient sought medical attention and whether the written plan of action was available and
utilized. It has been the experience of the authors that such review sessions are consistently
illuminating and critical to improving care.
● Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction is a

condition characterized by recurrent episodes of angioedema affecting the upper airway, bowel
wall, or skin, which typically last two to four days. The angioedema of HAE is mediated by
bradykinin and does not respond to epinephrine, antihistamines, or glucocorticoids. Instead,
first-line therapies for HAE act by replacing the C1-INH that is deficient or dysfunctional in this
disease or by inhibiting the production or function of bradykinin. (See 'Overview' above.)
● Because HAE is rare, clinicians in emergency settings may not be familiar with the disease or its
treatment. Once the diagnosis has been established, it is helpful for patients to be equipped with
a personalized form or wallet card containing information about the acute treatment of HAE
attacks, which can assist emergency providers (form 1 and form 2). In addition, call centers
have been established in some countries to provide 24-hour access to HAE experts who can
assist with emergency management. (See 'Equipping patients for emergency care' above.)
● First-line acute therapies for HAE and dosing of each agent are summarized in the table (table
1):
2067
• Human plasma-derived C1-INH concentrate (pdC1-INH) (see 'C1 inhibitor (plasma-derived)'
above)
• Recombinant human C1-INH (rhC1-INH) (see 'Recombinant C1 inhibitor' above)
• Icatibant, a bradykinin B2-receptor antagonist (see 'Bradykinin B2-receptor antagonist'

above)
• Ecallantide, a kallikrein inhibitor (available only in the United States) (see 'Kallikrein inhibitor
(United States only)' above)
(See 'First-line agents: Dosing, efficacy, and adverse reactions' above.)
● More than 50 percent of all HAE patients experience a laryngeal attack at some point. The
airway should be assessed immediately because laryngeal swelling may progress rapidly and
can result in fatal asphyxiation. Those with respiratory distress or stridor may require intubation
because even the first-line therapies take approximately 30 minutes or more to begin working.
An expert should manage the airway if possible. (See 'Laryngeal attacks' above and 'Airway
management' above.)
● In areas of the world where first-line agents are available:
• For patients with a laryngeal attack of any severity, we recommend treatment with a first-
line therapy (table 1) (Grade 1A). Choice of agent depends mainly upon availability, although
pregnant women are preferentially treated with pdC1-INH. (See 'Laryngeal attacks' above
and 'Pregnant or lactating women' above.)
• For patients with gastrointestinal attacks or cutaneous attacks that will likely result in
dysfunction or lost days from school or work, we suggest treatment with a first-line therapy
(table 2) (Grade 2B). The choice of agent should be based upon availability. (See
'Gastrointestinal attacks' above and 'Cutaneous attacks' above.)
• Mild cutaneous attacks affecting the limbs or trunk can often be observed.
● If none of the first-line agents are available, then the approach to treatment depends upon the
type and severity of attack:
• For patients with any laryngeal edema or moderate-to-severe gastrointestinal attacks, we

suggest solvent-detergent-treated plasma or if not available, fresh frozen plasma (table 1)
(Grade 2C). (See 'Plasma' above.)
• For patients with mild gastrointestinal attacks, we suggest supportive therapy (rehydration
and symptomatic therapy) (Grade 2C). (See 'Rehydration and symptomatic therapy' above.)
2068
• For patients with cutaneous attacks not involving skin adjacent to the airway, we suggest no
treatment (Grade 2C).
● After an HAE attack, the events leading up to the attack should be reviewed to determine the
factors that may have precipitated it. This evaluation is invaluable in helping patients and
clinicians identify triggers that are important for that individual and devise strategies to avoid
these triggers in the future. In addition, the clinician should review whether the patient was able
to access care quickly and improve upon the care plan if necessary. (See 'Care following attacks'
above.)
ACKNOWLEDGMENT
2069
GRAPHICS
2070
Hereditary angioedema (HAE) emergency care wallet card
2071
Acute treatment of angioedema episodes of in adults and children with hereditary angioedema (HAE)
Medication Availability Dosing Precautions
C1 inhibitor concentrate Widely available. Berinert (all ages): 20 units per Do not shake solution, because
(plasma-derived) In United states, Cinryze is not kg body weight given protein will denature.
(Berinert, Cinryze) approved for acute treatment intravenously over 10 minutes.
but is effective. Symptoms usually stabilize in
30 minutes. Second dose
In Europe, Cinryze is approved
uncommonly needed but may
for children.
be given 30 minutes to 2 hours
Despite the differences in after first.
product labeling, both
Cinryze (children): 500 units for
products are effective for acute
body weight <25 kg and 1000
treatment of attacks.
units ≥25 kg; a second dose
should be given if no response.
Relapse of symptoms is
reported in <1% of episodes.
Recombinant C1 inhibitor Europe, United States, some 50 units per kg body weight for Do not shake solution.
Conestat alfa (Ruconest, other countries. patients <84 kg. 4200 units (2
Rhucin) vials) for those ≥84 kg. Relapse
of symptoms in reported in <3%
of episodes.
Bradykinin B 2 -receptor United States and many other Adults: 30 mg slow Caution in patients with
antagonist countries. subcutaneous infusion unstable angina.
Icatibant (Firazyr) Approved in the United States (because of volume) in Mild injection site reactions are
for individuals over the age of abdominal area. common.
18 years. Children: Dosing is weight-
Registered in the European based:
Union for children as young as Administer 10 mg if
2 years of age. weight is 12 to 25 kg
Administer 15 mg if
weight is 26 to 40 kg
Administer 20 mg if
Administer 25 mg if
Administer 30 mg if
weight is >65 kg
Second dose can be given 6
hours after first if symptoms
continue to worsen. Relapse of
symptoms is reported in up to
10% of episodes. Maximum of
three doses in 25 hours.
Kallikrein inhibitor United States only. 30 mg (3 doses of 10 mg each) Rare allergy reaction reported
Ecallantide (Kalbitor) Approved in the United States given at three separate sites usually in <1 hour. Should be
for individuals over the age of subcutaneously in abdomen, administered by a clinician or
12 years. upper arm, or thigh and away nurse in a medical setting
from site of angioedema. equipped to treat anaphylaxis.
Relapse is reported in <3% of
episodes. May be repeated in 1
hour.
Plasma Widely available as solvent 2 units initially. Can be repeated Monitor for volume overload in
2072
detergent-treated plasma every 2 to 4 hours, if needed. patients with underlying
(preferred) or fresh frozen conditions predisposing to
plasma. volume overload. Theoretical
risk of transmission of blood-
borne pathogens.
Rare reports describe
worsening of angioedema after
administration of plasma.
2073
Treatment of acute episodes of hereditary angioedema (HAE)
Cutaneous attack
Laryngeal attack Abdominal attack
Extremities, trunk Face, neck
C1INH concentrate Yes Yes Yes, unless swelling Yes

(plasma-derived or is extremely
recombinant) given mild and not
intravenously causing disability
Ecallantide (United Yes Yes Yes, unless extremely Yes

States only) mild
Icatibant Yes Yes Yes, unless extremely Yes

mild
Plasma Yes, if first-line therapies Yes, if first-line therapies Yes, if severe and first- Yes
(solvent/detergent- are not available are not available line therapies are not
treated or fresh frozen) available
Intubation*, transfer to Yes (consider early Not applicable Not applicable May be necessary if
ICU, rarely emergent intubation if above attack spreads to involve
tracheotomy agents are not available) upper airway
Wait and see Not sufficient Not recommended Acceptable if mild Not sufficient (because
(spontaneous unless symptoms are angioedema can spread
resolution) mild and first- to involve airway)
line therapies are not
available
All acute attacks should be treated as early as possible, at first sign of prodromal symptoms and before the attack becomes fully
established.
C1INH: C1 inhibitor; ICU: intensive care unit.

* Consider intubation early in setting of progressive laryngeal edema or if C1INH preparations, ecallantide, or icatibant are not available.
Modified with permission from: Bowen T, Cicardi M, Farkas H, et al. 2010 International Consensus Algorithm for the Diagnosis, Therapy, and
Management of Hereditary Angioedema. Allergy, Asthma, and Clinical Immunology; 2010; 6:24. Copyright © 2010 BioMed Central Ltd.
2074

Data from:
2075
Risk of viral and bacterial infection following transfusion of blood products
Components prepared from whole blood*

Hepatitis B virus [1] 1:1 million
Hepatitis C virus [2] 1:1.2 million
HTLV [2,3] 1:2.7 million
HIV [2] 1:1.5 million
Solvent/detergent-treated plasma products

Hepatitis C virus Inactivated
Hepatitis B virus Inactivated
HIV Inactivated
Hepatitis A virus Not fully inactivated ¶
Parvovirus B19 Not fully inactivated ¶
Hepatitis E virus Not fully inactivated ¶
Platelets
With automated bacterial culturing methods in place, septic transfusion reactions are estimated to occur at a rate of 1:50,000 to 1:80,000
transfused platelet apheresis units. This is an underestimate, since it relies on passive surveillance data [4].
Cytomegalovirus (CMV) infection

The risk of CMV infection is rare in recipients with selected conditions (eg, bone marrow or solid organ transplants) who are at risk for
severe morbidity from CMV infection and who receive CMV reduced-risk products. Two methods to supply CMV reduced-risk products
that appear to have equal efficacy are CMV seronegative cellular components (red blood cells, platelets) or leukoreduced components.
Numbers reported in this table are estimates for the United States, where blood is routinely screened for infection with syphilis,
hepatitis B virus, hepatitis C virus, HIV-1, HIV-2, HTLV-I, HTLV-II, West Nile virus, Zika virus, and Trypanosoma cruzi. CMV serotesting is
not routine. Only enough products are tested to provide a sufficient inventory of CMV-negative products. Platelets are tested for
bacterial contamination. Refer to UpToDate topics on risks of blood transfusion for further details.
HTLV: human T-lymphotropic virus; HIV: human immunodeficiency virus.

* These estimates apply to red blood cells, platelets, and plasma, with the exception of HTLV, for which there is no risk from plasma.
¶ Plasma products are tested for parvovirus B19, hepatitis A virus, and hepatitis E virus nucleic acid before being used for further
manufacturing into solvent/detergent-treated plasma. Transmission of these agents should not occur (or should be extraordinarily rare) under
these conditions.
References:
1. Stramer SL, Notari EP, Krysztof DE, Dodd RY. Hepatitis B virus testing by minipool nucleic acid testing: Does it improve blood safety? Transfusion
2013; 53:2449.
2. Zou S, Stramer SL, Dodd RY. Donor testing and risk: Current prevalence, incidence, and residual risk of transfusion-transmissible agents in US
allogeneic donations. Transfus Med Rev 2012; 26:119.
3. Stramer SL, Notari EP, Zou S, et al. HTLV antibody screening of blood donors: Rates of false positive results and evaluation of a potential donor
re-entry algorithm. Transfusion 2011; 51:692.
4. Kleinman S, Reed W, Stassinopoulos A. A patient-oriented risk-benefit analysis of pathogen-inactivated blood components: Application to
apheresis platelets in the United States. Transfusion 2013; 53:1603.
2076
Hereditary angioedema: Temporary prophylaxis before

procedures or stress to prevent angioedema episodes
INTRODUCTION
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent angioedema

without wheals [1]. All forms of HAE are characterized by recurrent episodes of angioedema without
pruritus or urticaria, which most often affect the skin or mucosal tissues of the upper respiratory and
gastrointestinal tracts. Although swelling resolves spontaneously in two to four days in the absence
of treatment, angioedema can often be temporarily debilitating, and laryngeal angioedema may
cause fatal asphyxiation. There are several different forms of HAE. The recommendations in this
topic apply to those due to C1 inhibitor (C1INH) deficiency.
Dental and medical procedures can trigger episodes of angioedema. The various prophylactic
therapies that are used prior to dental and medical procedures to prevent attacks will be reviewed
here. Long-term prophylaxis to reduce the frequency and severity of angioedema episodes and other
issues in the diagnosis and management of HAE are discussed separately:
prophylaxis".)
prognosis".)
● (See "Hereditary angioedema with normal C1 inhibitor".)
2077
INDICATIONS FOR SHORT-TERM PROPHYLAXIS
The most common indications for short-term prophylaxis are medical or dental procedures (ie,
"preprocedural" prophylaxis) or anticipated stressful events [2]. Prophylaxis may also be given for a
brief period of time (ie, "extended" short-term prophylaxis) for travel to remote areas or countries in
which there may not be ready access to health care or for a period of weeks or months during which
increased stress is anticipated (eg, students during exam periods) [3]. In contrast, the regular use of
medications over years to reduce the severity or frequency of angioedema episodes is referred to as
long-term prophylaxis and is discussed separately. (See "Hereditary angioedema (due to C1 inhibitor
deficiency): General care and long-term prophylaxis", section on 'Approach to long-term prophylaxis'.)
The need for short-term prophylaxis is influenced by the availability of one of the "on-demand"
treatments: C1 inhibitor (C1INH) concentrates, icatibant, or ecallantide. If none of the on-demand
therapies are available, then preprocedural prophylaxis is especially important. Mechanisms of
action, efficacy, dosing, and administration of on-demand therapies are discussed separately. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents:
Dosing, efficacy, and adverse reactions'.)
Patients already on long-term prophylaxis — For patients already receiving long-term prophylaxis
with intravenous C1INH or androgens, dosing can be modified prior to a procedure. For example,
patients receiving regular intravenous injections of plasma-derived C1INH (pdC1INH) can arrange to
have an injection immediately before the procedure, or patients taking androgens can increase the
dose for five days prior to the procedure. The risk of procedural angioedema in patients using
subcutaneous pdC1INH or lanadelumab is unknown, and because of this uncertainty, the author will
often recommend an injection of intravenous pdC1INH prior to the procedure to be safe.
Risk associated with specific procedures — The highest risk procedures are intubation, oral surgery,
and major dental work (ie, cutting of tissue or injections of anesthetics), which can trigger symptoms
in most patients [4,5]. These procedures can induce both cutaneous and laryngeal edema. Short-
term prophylaxis should always be administered prior to these procedures, even if the patient has
access to acute therapies, as the potential consequence of laryngeal edema is too severe to rely
upon on-demand treatment alone.
In a series of 577 tooth extractions, 37 percent of episodes resulted in angioedema when prophylaxis
was not given, and the swelling was facial, laryngeal, or a combination [6]. Symptoms occurred up to
72 hours after the procedure, with a mean time to onset of 14 hours. Among procedures in which
patients received prophylaxis with C1INH concentrate, 21 percent resulted in swelling, at a mean of
eight hours after the procedure. Some attacks began during the night while the patients were asleep
and were therefore recognized later than if they had occurred during waking hours. The fewest
2078
attacks were seen in patients receiving 1000 units of C1INH concentrate, which was administered
one hour before the procedure.
Minor dental procedures (eg, routine cleanings, filling of cavities, crown placement, restorative work,
etc) are lower risk, and the patient's past response to similar interventions can guide the decision to
give prophylaxis. However, patients vary in their sensitivity to procedure-induced swelling. Those
who have developed swelling in similar situations in the past should receive preprocedural
prophylaxis in the future, even for minor interventions. Those who have tolerated these procedures in
the past are likely to continue to do so. If a patient's tolerance for a given procedure is unknown,
short-term prophylaxis is indicated.
Typical timing of onset of symptoms — Angioedema typically begins within 48 hours of the
intervention but can occur later [5,6]. Patients should be advised that swelling often occurs one day
or so after the procedure, and a specific plan of treatment should be in place for symptoms that arise
during this period, including access to on-demand therapies. In the study of tooth extractions
discussed above, patients who received prophylaxis with C1INH concentrate were at highest risk
during the 12 hours after the procedure [6]. Some attacks began during the night while the patients
were asleep and were therefore recognized later than if they had occurred during waking hours. For
this reason, some experts advise patients to schedule procedures as early as possible in the day.
AVAILABLE AGENTS
The agents that can be used for short-term prophylaxis are C1 inhibitor (C1INH) concentrate,
androgens, and plasma products. These are reviewed here, with availability, efficacy, and adverse
effects [7].
Note that ecallantide (a kallikrein inhibitor) and icatibant (a bradykinin-receptor antagonist), which
are other on-demand therapies, are not used before procedures, because these two agents have
short half-lives (six hours or less). Thus, they are only used to stop an attack once it has
commenced. Their utility as prophylactic agents has not been defined.
Tranexamic acid (TA), an antifibrinolytic agent, has been recommended by some guidelines but
without theoretical rationale or practical evidence of efficacy. Therefore, the authors do not
recommend use of TA for short-term prophylaxis.
Comparative efficacy — Overall, C1INH is likely the most effective therapy for short-term prophylaxis,
followed by androgens [5]. The efficacy of plasma is less clear. Retrospective analyses provide
relative comparisons, but there are no controlled trials directly comparing the effectiveness of
different therapies for short-term prophylaxis.
2079
Evaluation of the efficacy of various agents in short-term prophylaxis is further complicated by the
unpredictability of HAE attacks. Procedures that have triggered attacks in a given patient do not
necessarily do so reproducibly, and major interventions that would be expected to precipitate attacks
in most patients may not, even in the absence of prophylaxis. A registry-based survey has provided
some additional real world data [4]. Because of this inherent unpredictability, it is prudent to give
prophylaxis if there is any uncertainty about the risk of an attack.
C1 inhibitor concentrate — Plasma-derived C1 inhibitor (pdC1INH) concentrate may be administered

intravenously for short-term prophylaxis. Note that subcutaneous administration of C1INH may not
be equivalent if used in this manner, and intravenous preparations are strongly preferred. pdC1INH
concentrate is also the treatment of choice for short-term prophylaxis during pregnancy [8].
● In the United States, two human plasma-derived products (pdC1INH) are available for
intravenous administration, Cinryze and Berinert. Cinryze is US Food and Drug Administration
(FDA)-approved from prophylaxis, although there is no reason to believe that Berinert would not
be equally effective. Berinert P is used throughout Europe, the United Kingdom, Canada, and
Argentina [9,10].
● A recombinant human C1 inhibitor (rhC1INH) preparation, conestat alfa (Ruconest in Europe and
the United States, Rhucin in other countries) is also available. rhC1INH given one hour prior to
the procedure has also been used successfully for short-term prophylaxis in case reports [11].
However, the half-life (three hours) of the recombinant product is significantly shorter than that
of the plasma-derived product (30 to 39 hours), and its efficacy for short-term prophylaxis may
not be identical.
Efficacy — pdC1INH concentrate as a single prophylactic agent is generally accepted as effective

based upon retrospective series and observational studies [6,12-14]. In one series, 33 adults and 8
children received 1000 units of pdC1INH within the 24 hours preceding 91 dental and medical
procedures [12]. Angioedema occurred in only 2 percent of procedures. Another series reported
angioedema in 21 percent of tooth extractions, following prophylaxis with either 500 or 1000 units of
pdC1INH [6].
Dose and timing — Based on a small number of publications, 1000 units is effective in most
children and adults [12]. The risk of angioedema has been shown to be closely linked to the plasma
functional C1INH level, with a level of 50 percent of normal offering near complete protection [15].
Therefore, the authors recommend that the dose of pdC1INH be sufficient to achieve a functional
C1INH level of ≥50 percent at the time of the procedure, an outcome typically achieved immediately
after a dose of 20 IU/kg.
2080
C1INH concentrate is ideally given one hour prior to or immediately before the major procedure.
However, if necessary, dosing can be given further in advance of the procedure. The half-life of a
single weight-based dose of pdC1INH is 30 to 39 hours [16,17], and in the study discussed above,
administration up to 24 hours before was sufficient to prevent attacks [12]. However, a dose of
pdC1INH could conceivably be consumed within 24 hours in some patients, and the median time to
maximal serum concentrations is 0.5 to 1 hour [17]. For these reasons, it is preferable to administer
pdC1INH as close in time to the procedure as possible.
Adverse effects — Side effects of C1INH concentrate are rare and include headache, nausea,
fever, and anaphylaxis [18].
Attenuated androgens — Synthetic 17-alpha-alkylated androgens ("attenuated" or anabolic

androgens) include danazol, stanozolol, oxandrolone, oxymetholone, tibolone, and
methyltestosterone. The choice of androgen is based largely upon availability, since differences
among drugs have not been well-characterized. Danazol is widely available throughout the world.
Stanozolol is not produced commercially in the United States, although it is available by prescription
and can be compounded by individual pharmacies. Tibolone and oxandrolone may be less virilizing
than other agents [19-21]. Methyltestosterone is another alternative [22].
Efficacy — Small, uncontrolled studies and individual case reports suggest that androgens are
effective for short-term prophylaxis [23,24]. As an example, attacks were completely prevented in 12
patients with a history of angioedema after dental procedures who were administered danazol (600
mg/day) four days before and four days after various procedures [23].
Dosing — There are several approaches to dosing androgens for short-term prophylaxis, and no
comparative data exist to recommend one approach over another. Danazol is used in the following
examples, although equivalent doses of other attenuated androgens as well as similar timeframes
are mentioned. In the United States, danazol and stanozolol are FDA-approved for prophylaxis in
patients with HAE, while the other androgens are not. For patients already on long-term androgens,
the doses may be increased temporarily to those described below.
● For patients not already taking androgens, danazol at a dose of 400 to 600 mg/day or an
equivalent androgen at a comparable dose may be given for five days before and three days
after a procedure (table 1) [9]. Lower, weight-based dosing is advised (2.5 to 10 mg/kg) when
children have to be treated, although the use of androgens in children should be avoided
whenever possible.
Other regimens with which the authors of this topic have experience include (adult dosing
shown):
2081
• Stanozolol (4 to 6 mg daily) for five days before and three days after (2 mg stanozolol is
about equivalent to 200 mg of danazol).
• Oxandrolone (5 mg daily) for five days before and three days after (5 mg of oxandrolone is
about equivalent to 200 mg of danazol).
● For patients already taking androgens regularly, the dose may be increased to 400 to 600 mg
daily for five days before and three days after a procedure.
These recommendations are based upon the assumption that for the individual patient in question, a
dose of this magnitude or less has been effective in the past. If not, a higher effective dose must be
determined for that patient.
Adverse effects and contraindications — Short-term androgen therapy (ie, one or two weeks) is
well-tolerated by most postpubertal males and by many female patients as well because the side
effects are of minor significance when androgens are used only briefly. However, elevations in
transaminases have been observed when excessively large doses were given (eg, 4 to 16 mg of
stanozolol daily in adults) [25]. These doses are not routinely used. A pediatric endocrinology
specialist should be consulted if androgens are used in children.
There are no absolute contraindications to short-term prophylaxis with attenuated androgens, except
possibly pregnancy, since androgens can cause virilization of female fetuses. Androgens were even
used successfully in pregnant women with HAE in the past when other options were lacking, with
close collaboration with an obstetrician. However, with the alternative therapies available, androgen
use in pregnancy is best avoided altogether.
Plasma products — Human plasma contains C1INH and can be used for short-term prophylaxis.
However, the efficacy is not as well-established as that of C1INH preparations. Replacement plasma
is available in two forms: fresh frozen plasma (FFP) and solvent/detergent-treated plasma (S/D
plasma).
Dosing and timing — The usual dose is 2 units for adults, 10 mL/kg in children, given one to two
hours before the procedure. Optimal dosing has not been studied.
Efficacy — The efficacy of FFP for short-term prophylaxis is supported by several case reports
and observational series [26-29]. In a review of the literature, 148 cases were identified in which FFP
was administered as short-term prophylaxis, with six instances of angioedema [26]. No controlled
trials have been performed.
The efficacy data on S/D plasma are only anecdotal. Studies would be needed to demonstrate that it
is an equivalent substitute for FFP, since S/D treatment is known to remove some plasma
2082
components, and the effect on C1INH concentration has not been reported.
Adverse effects — FFP has been associated acutely with urticaria, anaphylactic shock, and
hemolysis, although we are not aware of reports of these events in patients with HAE. (See "Clinical
use of plasma components".)
The primary concern with plasma products is disease transmission and the risks of this must be
presented to the patient.
● S/D treatment inactivates enveloped viruses (such as human immunodeficiency virus [HIV],
human T lymphotropic virus, and hepatitis B and C) but not prions or nonenveloped viruses (eg,
hepatitis A, parvovirus).
● FFP does not undergo processing to remove infectious agents. However, it is obtained from
single donor units, rather than pooled plasma, and each unit undergoes serologic testing for viral
markers. The risk of infection for a unit of FFP is identical to that of red blood cells, which are
also obtained from single donors. The issue of disease transmission from red blood cells (and
therefore FFP) is presented in more detail elsewhere. (See "Risk of HIV from blood transfusion"
and "Epidemiology and transmission of hepatitis C virus infection".)
OUR APPROACH
Several guidelines and practice parameters on the treatment of HAE have been published [9,30-35].
However, few studies have evaluated short-term prophylaxis specifically, and recommendations in
the guidelines are largely extrapolated from data of efficacy of different agents in long-term
prophylaxis. The approach presented in this topic review is consistent with available guidelines,
although it is largely based on the experience of the authors and editors.
As mentioned previously, angioedema triggered by a procedure usually occurs within 48 hours of the
procedure, so it is important that plans be made for both the procedure and the postprocedure
period. Because angioedema does not typically develop during or immediately after the procedure,
we do not insist that patients only receive dental care to hospital-based clinics or put other additional
restrictions on them, provided on-demand therapy is accessible.
General precautions
● Communication between the patient, specialist performing the procedure, and

allergist/immunologist (or other HAE expert) is critical. Both the clinician performing the
procedure and the patient should know how to reach the HAE expert clinician in case advice is
2083
needed. A printable form summarizing the acute treatment of HAE is available to assist in this
communication (form 1).
● Ideally, two doses of an on-demand therapy should be available to patients undergoing

procedures, and these doses should be available to the patient both in the clinic and for two to
three days after the procedure.
● We suggest that the patient be observed for at least two hours after the procedure, before being
discharged home. However, as mentioned above, swelling related to the procedure may begin
within the ensuring 48 hours, so patients must also have a plan in place to access on-demand
therapy if needed.
High-risk procedures — There are two principal approaches for preprocedural prophylaxis for high-
risk procedures, such as oral surgery and intubation (table 1) [9].
● Plasma-derived C1INH (pdC1INH) concentrate (20 units per kg) may be given one hour before
the procedure, with two additional doses available for on-demand use if symptoms develop.
Alternatively, ecallantide (a kallikrein inhibitor) and icatibant (a bradykinin-receptor antagonist)
could be used if symptoms develop (although these are not used before the procedure, as their
efficacy as prophylaxis is not known). Dosing of pdC1INH concentrate is discussed above. (See
'C1 inhibitor concentrate' above.)
OR
● If pdC1INH is not available, androgens may be given for five days before and three days after the
procedure, administered as described below This option is usually reserved for patients who are
known to tolerate androgens or have experience taking androgens for long-term prophylaxis and
for countries in which access to C1INH, icatibant, and ecallantide is limited. (See 'Attenuated
androgens' above.)
● A third option, if none of the above therapies is available, is solvent/detergent-treated plasma

(S/D plasma) or fresh frozen plasma (FFP). (See 'Plasma products' above.)
Lower-risk procedures — If on-demand therapies are available, then short-term prophylaxis may not
be necessary. On-demand therapies include C1INH concentrate, icatibant, or ecallantide (United
States only). If on-demand therapies are not immediately available, we would administer androgen
premedication, unless the individual tolerated that specific procedure in the past.
Emergent procedures — In an emergent situation in which prophylaxis is indicated, C1INH

concentrate should be given, if available. If no acute therapies are available and there is not enough
2084
time for androgen pretreatment, plasma products (FFP or S/D plasma) may be given. (See 'Plasma
products' above.)
Travel to remote areas — Patients traveling to remote areas who are not already receiving long-term
prophylaxis may want to take extended short-term prophylaxis (such as androgens) temporarily and
should also have on-demand medications that can be self-administered.
Patients can access detailed, patient-oriented information through the United States Hereditary
Angioedema Association and the International Patient Organization for C1 Inhibitor Deficiencies.
● In patients with hereditary angioedema (HAE), "short-term" or "preprocedural" prophylaxis refers

to the administration of medications briefly before a procedure or stressful event that is likely to
precipitate an episode of angioedema. It may also be given to patients traveling to remote areas
in which they may not be able to access health care. (See 'Indications for short-term prophylaxis'
above.)
● Angioedema typically begins within 48 hours of a triggering event or procedure. Patients should
be advised that swelling often occurs one day or so after the procedure, and a specific plan of
treatment should be in place for symptoms that arise during this period. (See 'Typical timing of
onset of symptoms' above.)
● Some procedures, such as oral surgery, intubation, and dental work that involves injections or
cutting of tissues, reliably trigger symptoms in most patients. However, individuals vary in their
susceptibility to attacks. If a patient has had symptoms with a given procedure, then it should be
considered high risk for that patient, and prophylaxis should be administered for future similar
procedures. (See 'Risk associated with specific procedures' above.)
2085
● None of the available therapies confer complete protection from an attack, and the supervising
clinician must be prepared to recognize and manage angioedema with on-demand therapies
immediately available. (See 'General precautions' above.)
● For patients undergoing high-risk procedures (eg, major dental procedures, surgery, intubation),
we recommend administering prophylactic therapy (table 1) (Grade 1B) (see 'High-risk
procedures' above):
• We suggest giving plasma-derived C1 inhibitor (pdC1INH) concentrate (Grade 2C). We

prefer weight-based dosing (ie, 20 units per kg). This should be injected as close in time to
the procedure as is feasible (preferably within the hour before the procedure). At least two
additional doses of an on-demand therapy (C1INH, icatibant, or ecallantide) should be
available to the patient in case symptoms develop either during the procedure or during the
two to three days following the procedure. (See 'C1 inhibitor concentrate' above.)
• If C1INH concentrate is not available, we suggest premedication with androgens (Grade 2C).
A representative regimen is danazol (10 mg/kg per day to a maximum of 600 mg/day),
beginning five days before and extending for three days after the procedure. (See
'Attenuated androgens' above.)
● For patients undergoing low-risk procedures, we suggest not administering androgens in

advance, provided C1INH concentrate, ecallantide (United States), or icatibant is immediately
available to treat any symptoms that arise (table 1) (Grade 2C). If one of these acute therapies is
not immediately available, we would administer androgen premedication, unless the patient
tolerated that specific procedure in the past. (See 'Lower-risk procedures' above.)
● In an emergent situation in which prophylaxis is indicated but no acute therapies are available
and there is not enough time for androgen pretreatment, plasma products (fresh frozen plasma
[FFP] or solvent/detergent-treated plasma [S/D plasma]) may be given. (See 'Emergent
procedures' above.)
ACKNOWLEDGMENTS
The editorial staff at UpToDate would like to acknowledge John P Atkinson, MD, who contributed to
an earlier version of this topic review.
2086
2087
GRAPHICS
Short-term prophylaxis to prevent angioedema in hereditary angioedema (HAE)
High-risk procedures Lower-risk procedures
Intubation, oral surgery (cutting of tissues), dental procedures Routine dental cleanings.
involving injections of anesthetics, general surgery, other
procedures that precipitated past attacks in that patient.
Option 1: Give plasma-derived C1 inhibitor concentrate one hour No additional treatment in advance but have treatment for acute
before procedure, with two additional doses available on demand*. angioedema immediately available if symptoms develop (ie, C1
inhibitor concentrate, ecallantide, or icatibant).
Option 2: If option 1 is not possible, then give premedication with

androgens for five days before and three days after.
Example: Danazol, 10 mg/kg per day up to 600 mg daily or
equivalent doses of another attenuated androgen
* Ecallantide and icatibant have not been studied for use in prophylaxis, although they can be given if angioedema develops.
2088
2089
Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology,

pathogenesis, and diagnosis
Section Editor: Bruce S Bochner, MD
INTRODUCTION
Acquired angioedema due to deficiency of C1 esterase inhibitor, also called acquired angioedema and abbreviated
C1INH-AAE, is a rare syndrome of recurrent episodes of angioedema, without urticaria, which is associated with B
cell lymphoproliferative disorders in some patients [1]. Angioedema typically affects the skin or mucosal tissues of
the upper respiratory and gastrointestinal tracts. The swelling is self-limited, although laryngeal involvement may
cause fatal asphyxiation. Clinically, this disorder is very similar to hereditary angioedema (HAE), although acquired
angioedema develops in older patients and is frequently associated with underlying disease, whereas the hereditary
disorder presents in younger patients who are otherwise healthy [2].
This topic review will discuss the clinical manifestations, epidemiology, pathogenesis, and diagnosis of C1INH-AAE.
The management and prognosis of this disorder are reviewed separately. (See "Acquired C1 inhibitor deficiency:
HAE is discussed separately. (See "Hereditary angioedema: Pathogenesis and diagnosis" and "Hereditary
angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary
angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency):
General care and long-term prophylaxis".)
EPIDEMIOLOGY
C1INH-AAE, also called acquired angioedema, is rare, and the precise incidence is not known [3-5].
● In the group of patients referred to the author's specialty center in Milan for angioedema due to C1INH
deficiency since 1976, 77 had acquired and 675 had hereditary forms of the disease with a ratio of 1:8.8 [3].
● Two national series found that between 6 and 10 percent of angioedema cases were attributable to C1INH-AAE
[6,7]
However, C1INH-AAE is likely underdiagnosed, and there are several factors that may contribute to this. (See
'Obstacles to diagnosis' below.)
2090
C1INH-AAE is characterized by recurrent episodes of angioedema, without urticaria or pruritus [8]. Episodes of
angioedema typically last two to five days without treatment. Attacks are commonly triggered by trauma and
psychological stress but may also occur without an apparent trigger. As in hereditary angioedema (HAE), swelling
episodes in acquired angioedema can be characterized into three types: cutaneous, gastrointestinal, or upper
airway, and the two disorders have very similar clinical manifestations. The important differences are summarized
here. A more detailed discussion of each type of attack is found elsewhere. (See "Hereditary angioedema:
Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)
Upper airway edema, frequently involving the larynx, is the most severe and potentially lethal site of angioedema in
both disorders. Around 50 percent of patients with acquired angioedema experience upper airway edema, and
anoxic brain injury or death from upper airway obstruction can occur [5,9]. (See "Acquired C1 inhibitor deficiency:
Management and prognosis", section on 'Prognosis'.)
Differences between acquired and hereditary angioedema — The most consistent clinical difference between
hereditary and acquired angioedema (C1INH-AAE) is the age of onset. C1INH-AAE presents in the fourth decade of
life or later [10,11]. In a series of 77 patients with C1INH-AAE from the author's center, the earliest age of
angioedema appearance was 39 years. In comparison, more than 90 percent of patients with HAE experience their
first symptoms before the age of 20 years.
Another important difference is that patients with acquired angioedema are often found to have an underlying
lymphoproliferative, malignant, or autoimmune disorder, whereas most patients with HAE are otherwise healthy.
There are other more subtle differences between the clinical manifestations of the acquired and hereditary
disorders:
● Gastrointestinal attacks appear to be less frequent in acquired angioedema compared with HAE. Angioedema
of the gastrointestinal mucosa, which presents as recurrent colicky abdominal pain, distention, vomiting, and/or
diarrhea, is reported by nearly 80 percent of patients with HAE, while less than 50 percent of our acquired
angioedema patients and around 30 percent of those from other centers reported gastrointestinal attacks
[3,5,12].
● Cutaneous angioedema in acquired angioedema seems to affect the face more than the limbs, while in patients
with HAE, swelling of the extremities is more typical [3,5]. However, both disorders can cause swellings in both
locations.
● Patients with acquired angioedema may report antecedent changes in the skin (ie, similar in appearance to
erythema marginatum) prior to cutaneous or gastrointestinal angioedema episodes, although it is not as
prevalent as in patients with HAE. Skin findings are described elsewhere. (See "Hereditary angioedema:
Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Characteristic features
of angioedema attacks'.)
2091
C1INH-AAE was first described in 1972 in two patients with lymphoma [13]. Since this initial description, the
majority of patients diagnosed with C1INH-AAE have been found to have an underlying disorder [14-18]. Based on
available reports, approximately 30 to 40 percent of patients are found to have some type of malignancy,
predominantly affecting B lymphocytes. Another 30 to 40 percent are found to have monoclonal gammopathy of
undetermined significance (MGUS), and another 5 to 10 percent have autoimmune conditions [19]. A small
percentage of patients have no identifiable associated disorder, at least at the time of diagnosis.
To illustrate this, one extensive review of the literature identified 136 cases of C1INH-AAE [19]. An underlying
disease was identified in 85 percent of patients, including:
● Lymphatic malignancies in 35 percent
● MGUS in 32 percent
● Autoimmune diseases in 8 percent
● Adenocarcinoma and other malignancies in 6 percent (note that other than lymphoma and adenocarcinoma, no
other specific types of malignancies have been reported with regularity)
Lymphoproliferative disorders and B cell malignancies — The most frequently associated disorders are
lymphoproliferative disorders and B cell malignancies (most often non-Hodgkin lymphomas and indolent
lymphomas) [14-18,20,21]. Among patients with MGUS and C1INH-AAE, the rate of progression to multiple myeloma
does not appear to be increased [16,18].
In our series of patients, 24 of 77 had non-Hodgkin lymphoma, and in a French series, 44 of 92 had non-Hodgkin
lymphoma [3,5]. Splenic marginal zone lymphoma was far more frequent (20 of 24 in our series and 24 of 44 in the
French series) than other types [3,5,22]. The predominance of splenic marginal cell lymphoma among patients with
C1INH-AAE was consistent with an earlier study mentioned above and suggests that these individuals may be at
particular risk [23]. (See "Splenic marginal zone lymphoma", section on 'Managing autoimmune complications'.)
An estimate of the prevalence of C1INH-AAE in lymphoma patients was provided by a retrospective study of 131
patients with different types of lymphomas, in which patients were screened at the time of diagnosis for deficiency
and dysfunction of C1INH [21]. Four patients (3 percent) were symptomatic with episodic swelling, and all four had
both functional tests and levels of C1INH that were below 50 percent of normal. Three of these four patients had
splenic marginal cell lymphoma. Another 10 patients had abnormal C1INH function but normal levels and had not
developed angioedema.
Autoimmune disorders — Autoimmune disorders are also identified in patients with acquired angioedema [24].
Reported conditions include systemic lupus erythematosus (SLE), autoimmune hemolytic anemia, and
cryoglobulinemia [25-27].
Other implicated disorders — A small number of case reports have implicated infections, especially Helicobacter
pylori, in the development of acquired angioedema [28-30]. Eradication of H. pylori was followed by reversal of the
clinical symptoms and biochemical abnormalities of acquired angioedema, suggesting the possibility that this
infection could have a pathogenetic role in the development of acquired angioedema. The author has seen a patient
with echinococcus and acquired angioedema who improved after treatment of the infection [31]. However,
2092
infections are unlikely to be related to pathogenesis in most patients, and we do not suggest an exhaustive search
for infections unless there are suggestive clinical and laboratory findings.
Idiopathic cases — In most series, fewer than 10 percent of patients have neither an associated disorder nor
autoantibodies to C1INH [19,31]. The mechanism underlying acquired angioedema remains unknown in such
patients. We can hypothesize that these individuals have antibodies to C1INH that elude detection in plasma
because of a low titer or because they are bound to cell membranes. It is also possible that an entirely different
mechanism exists in such patients.
PATHOGENESIS
C1INH-AAE usually arises in the setting of an uncontrolled clonal proliferation of B lymphocytes. However, the
mechanism by which clonal B cell disorders lead to depletion of C1INH and angioedema remains incompletely
understood. Clonal B cell proliferation appears the pathologic process underlying C1INH-AAE that leads to
production of C1INH-neutralizing autoantibodies and to non-Hodgkin lymphomas. The postgerminal center origin of
non-Hodgkin lymphoma suggests that immune stimulation may contribute to lymphomagenesis [23].
Role of bradykinin — The angioedema of C1INH-AAE appears to be mediated largely by bradykinin, as in hereditary
angioedema (HAE) [32]. Tissue insult or injury normally activates the contact system, leading to the generation of
bradykinin and other proinflammatory mediators. Bradykinin, acting through bradykinin B2-receptors, increases
endothelial permeability via mechanisms involving nitric oxide, cyclic guanosine monophosphate (GMP), and other
effector molecules [33,34]. Bradykinin production is normally regulated by C1INH.
Antibodies to C1 inhibitor — Most (although not all) patients with acquired angioedema have identifiable
autoantibodies against the C1INH protein [25,35-37]. In our patient group, we were able to detect these antibodies in
48 of 73 patients (66 percent) [31]. One theory proposes that pathologic B lymphocyte proliferation results in
expansion of a clone that produces antibodies that bind to C1INH ("neutralizing antibodies"), causing steric
hindrance and a functional deficiency of the C1INH protein. Whether autoreactive clones may then evolve to
lymphoma remains to be established. The unusually high prevalence of splenic marginal zone lymphoma in our
population suggests that immune stimulation of postgerminal center B cells may contribute to the development of
lymphoma [23]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone
lymphoma of mucosa associated lymphoid tissue (MALT)".)
Normally, C1INH interacts with its target proteases and is cleaved in the process. The cleaved and inactive inhibitor
irreversibly binds to the protease and renders it inactive. However, in the presence of anti-C1INH antibodies, C1INH
is still cleaved, but it cannot bind the protease, and the protease continues to function, leading to uncontrolled
generation of bradykinin and angioedema. However, if this theory was correct, then acquired angioedema should
result in essentially the same pattern of complement abnormalities as HAE, but this is not the case. Most patients
with acquired angioedema demonstrate profound depletion of components of the classical complement pathway,
including a low C1q (the measurable component of the C1 complex, C1q-r-s), which is not seen in patients with HAE.
In addition, not all acquired angioedema patients with low C1q values have detectable anti-C1INH antibodies [31].
(See "Complement pathways".)
The relationship between autoantibodies to C1INH and lymphoproliferative disorders in patients with acquired
angioedema is not clear either. An early study identified these neutralizing antibodies in otherwise healthy acquired
2093
angioedema patients and hypothesized that acquired angioedema could arise from an autoimmune mechanism
without an associated lymphoproliferative disease [35]. Based on this, two types of acquired angioedema were
proposed: one paraneoplastic and the other autoimmune [38]. However, subsequent work revealed that patients with
and without autoantibodies to C1INH develop lymphatic malignancies over time and at similar rates, indicating that
this distinction is not clinically or prognostically relevant [11,39]. Thus, the division of acquired angioedema into
these two types has been abandoned [14].
Activation of the classical complement pathway — A second theory proposes that the pathogenesis of C1INH-AAE
involves massive activation of the classical complement pathway by the neoplastic lymphoid tissue or by the
abnormal antibodies and subsequent depletion of normally functioning C1INH [15,26,40,41]. Evidence includes
increased in vivo turnover of radio-labeled C1q and C1INH with concomitant normal C1INH production by
monocytes of the same patient [40,41]. In this theory, anti-C1INH autoantibodies are either an aggravating factor or
purely an epiphenomenon.
An interesting patient was reported who had HAE and then developed non-Hodgkin lymphoma [42]. With the
appearance of the lymphoma, the patient's angioedema markedly worsened, and depletion of classical pathway
complement components was apparent that had not been present before. This patient did not have detectable anti-
C1INH antibodies, and the case supports the role of lymphoma tissue as activator of the classical complement
pathway and as the trigger of angioedema symptoms.
DIAGNOSIS
The diagnosis of C1INH-AAE is based upon a suggestive clinical history and appropriate complement abnormalities.
Clinical history — C1INH-AAE should be considered in patients with the following:
● Episodes of angioedema affecting the cutaneous tissues and mucous membranes of the upper respiratory and
gastrointestinal tracts.
● Symptoms beginning in the fourth decade of life or later.
● No family history of angioedema.
Patients with C1INH-AAE generally demonstrate all three of the above characteristics. Absence of a family history of
angioedema, in isolation, is not diagnostic of acquired angioedema, because more than 25 percent of patients with
HAE carry a de novo mutation in C1INH gene and therefore have no affected ancestors [1]. On the other hand, the
presence of a family member with angioedema essentially excludes the diagnosis of acquired angioedema.
Complement studies — An algorithm for the diagnosis of angioedema due to C1INH deficiency (acquired or
hereditary) was published by an international consensus group (algorithm 1) [43]. In patients with isolated
angioedema who are suspected of having a disorder of C1INH, the following tests should be obtained:
● C4 level
● C1INH antigenic level and function
● C1q level may be obtained initially in patients older than 30 years of age and without a family history of
angioedema
Most patients with acquired angioedema demonstrate the following:
2094
● Low C4
● Low C1q (usually <50 percent of normal)
● Low or normal C1INH antigenic (or quantitative protein) level
If the patient demonstrates these laboratory abnormalities, then a test of C1INH function should be obtained. Low
function is required for the diagnosis, and it is usually <50 percent of normal (table 1).
C1q levels are usually <50 percent of normal in patients with acquired angioedema. However, about 30 percent of
the patients in two large series had C1q levels that were decreased but >50 percent of normal [10,19]. Finally, there
are rare cases in which C1q levels are normal.
Note that complement abnormalities may fluctuate between normal and abnormal when the disorder first develops,
becoming more consistently abnormal over the ensuing months. For this reason, mild abnormalities associated
with a consistent clinical presentation should be followed over time.
Additional studies — Other diagnostic tests are only occasionally required. These include genotyping, detection of
antibodies directed against C1INH, and detection of cleaved C1INH by gel electrophoresis and immunoblotting. The
indications for obtaining these tests are discussed below.
Genotyping — In rare cases of acquired angioedema in which C1q is normal, the complement findings of
acquired angioedema are identical to those in HAE. Genotyping for mutations in the C1INH gene (SERPING1), which
are only found in HAE, would be the only definitive way to differentiate these disorders. However, genetic testing is
not widely available. If testing is not available, we recommend screening and monitoring patients who appear to
develop HAE over the age of 40 years for underlying lymphoproliferative diseases. (See 'Evaluation for underlying
disorders' below.)
Detection of anti-C1INH antibodies — The other biochemical finding that is characteristic of acquired
angioedema is the presence of anti-C1INH autoantibodies in plasma. By comparison, approximately 30 percent of
patients with HAE have these antibodies, as well as 3 percent of normal controls [44]. As with other autoantibodies,
the definition of a pathologic level is relatively arbitrary. In our laboratory, we find clinically irrelevant positive values
at minimal dilutions and consider positive results at dilutions less than 1:20 to be background noise due to natural
autoantibody. No commercial assay for measuring these antibodies is available, although an enzyme-linked
immunosorbent assay (ELISA) system can be set up in specialized laboratories and yields reliable results for
investigational purposes [37,45]. Therefore, the finding of high titers of anti-C1INH antibodies in a patient's serum is
supportive of the diagnosis of acquired angioedema, but the absence of these antibodies does not exclude the
disorder.
Electrophoresis for inactive inhibitor — An additional test that may help to refine the diagnosis of acquired
angioedema is the detection of cleaved C1INH by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-
PAGE) and immunoblotting [38]. C1INH normally interacts with its target protease and is cleaved by this interaction.
Cleaved C1INH then irreversibly binds to the protease, rendering it inactive. However, in the presence of anti-C1INH
antibodies, C1INH is cleaved but cannot bind the protease [46]. The protease then continues to function while
cleaved, but inactive C1INH remains in the circulation. The cleaved, inactive form can be distinguished by
electrophoresis [46]. In contrast, the routine quantitative assay for antigenic levels of C1INH cannot distinguish
between cleaved inactive and uncleaved active C1INH, which explains why patients with acquired angioedema can
have normal C1INH antigenic levels and low function with standard complement tests.
2095
Obstacles to diagnosis — It is our clinical impression that acquired angioedema frequently evades diagnosis for a
period of years. We believe there are several obstacles to diagnosis:
● Even among specialists, awareness of the existence of an acquired form of C1INH deficiency is not widespread,
and uncertainties regarding the pathogenesis and laboratory features of the disorder further complicate
diagnosis.
● Patients with acquired angioedema lack a family history, so cases are not detected through family screenings,
as with the hereditary form.
● The diagnosis of a coexisting lymphoproliferative malignancy can overshadow other medical issues, including
recurrent angioedema, which may be attributed to a paraneoplastic phenomenon and not evaluated further.
● Because the disorder begins later in life, many patients are taking multiple medications, and the episodes of
angioedema are attributed to drug-allergic reactions. Similarly, patients may have multiple comorbidities, and
the evaluation of angioedema may not take precedence until a severe attack occurs.
● Complement abnormalities may fluctuate between normal and abnormal when the disorder first develops,
becoming more consistently abnormal over the ensuing months. For this reason, mild abnormalities associated
with a consistent clinical presentation should be followed over time.
The differential diagnosis of acquired angioedema (C1INH-AAE) includes:
In patients with no complement abnormalities:
● Angioedema induced by angiotensin-converting enzyme (ACE) inhibitors

● Hereditary angioedema with normal C1INH (which has also been called type III HAE or previously, estrogen-
dependent HAE)
● Isolated angioedema as a manifestation of an allergic reaction
● Idiopathic angioedema (ie, angioedema with no associated complement abnormalities)
In patients with complement abnormalities:
● Hereditary angioedema with deficient C1INH (type I HAE)

● Hereditary angioedema with dysfunctional C1INH (type II HAE)
However, most patients with acquired angioedema have low levels of C1q, while patients with HAE have normal C1q
(table 1). Patients with acquired angioedema develop angioedema later in life and do not have a family history of
angioedema, while HAE usually presents in young people, and about 75 percent of HAE patients have a family
history of angioedema.
The differential diagnosis of angioedema, in general, is reviewed separately. (See "An overview of angioedema:
Clinical features, diagnosis, and management", section on 'Differential diagnosis'.)
Low C1q levels — Low levels of C1q are not exclusive to C1INH-AAE. Autoantibodies to C1q causing depressed C1q
levels can be seen in hypocomplementemic urticarial vasculitis syndrome (HUVS) and systemic lupus
2096
erythematosus (SLE). Levels of C1q less than 30 percent of normal are typical of both conditions. However, HUVS
usually includes urticaria, which is not observed with inherited or acquired C1INH deficiency. The diagnosis of HUVS
and SLE are reviewed elsewhere. (See "Urticarial vasculitis" and "Clinical manifestations and diagnosis of systemic
lupus erythematosus in adults".)
There is also congenital C1q deficiency, which is rare (10 to 50 reported cases). More than 90 percent of reported
patients with this have SLE, and the deficiency is also associated with glomerulonephritis and pyogenic infections
[47].
EVALUATION FOR UNDERLYING DISORDERS
All patients with C1INH-AAE disorders should be evaluated for an underlying B cell lymphoproliferative disorder.
This evaluation begins with a thorough review of systems and physical examination. Any abnormalities identified
should be investigated further. Referral to a hematology expert can help with this evaluation. (See "Multiple
myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Clinical presentation and diagnosis of
non-Hodgkin lymphoma" and "Evaluation, staging, and response assessment of non-Hodgkin lymphoma".)
If the review of systems and physical examination is unrevealing, we usually obtain the following studies:
● Complete blood count (CBC), white blood cell differential, platelet count, and examination of the peripheral
smear for the presence of atypical cells.
● Biochemical tests, including blood urea nitrogen (BUN), creatinine, alkaline phosphatase, aspartate
aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH).
● Serum protein electrophoresis and immunofixation.
● Serum-free light chain assay (see "Laboratory methods for analyzing monoclonal proteins", section on 'Serum
free light chains').
● Screening for lymphadenopathy and masses with imaging studies of the chest and abdomen. We usually
perform chest radiograph and abdominal ultrasound, although computed tomography (CT) scans are also an
option.
● All age-appropriate cancer screening (see "Screening for lung cancer" and "Screening for colorectal cancer:
Strategies in patients at average risk" and "Screening for breast cancer: Strategies and recommendations").
If no associated condition is identified, then we monitor patients by repeating studies for B cell malignancies
annually. Monitoring is discussed in more detail elsewhere. (See "Acquired C1 inhibitor deficiency: Management and
prognosis", section on 'Monitoring for development'.)
Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
2097
SUMMARY
● Acquired angioedema, (also known as, acquired C1 inhibitor deficiency [C1INH-AAE]), is a rare disorder
characterized by recurrent episodes of angioedema, without urticaria or pruritus. Swelling most often involves
the subcutaneous tissues of the face and the submucosa of the upper airway and small bowel. Acquired
angioedema presents in the fourth decade of life or later. (See 'Epidemiology' above and 'Clinical
● Approximately 70 percent of patients with acquired angioedema are found to have an associated disorder. In
one-half of these cases, the disorder is malignant (most often non-Hodgkin lymphoma), and in the other one-
half, the associated condition is benign (most often monoclonal gammopathy of undetermined significance
[MGUS]). (See 'Associated disorders' above.)
● Angioedema in C1INH-AAE is bradykinin-mediated, but the precise pathogenesis is undefined. Most patients
have autoantibodies against the C1INH protein. These autoantibodies may impede the normal functioning of
C1INH and cause a functional deficiency. Alternatively, the antibodies, or perhaps neoplastic tissue in some
cases, may cause activation of the classical complement pathway, leading to depletion of normally functioning
C1INH. (See 'Pathogenesis' above.)
● C1INH-AAE should be considered in a patient who presents with isolated angioedema (without urticaria) in the
fourth decade of life or later and has no family history of angioedema. (See 'Diagnosis' above.)
● Initial testing should consist of levels of C4, C1q, and C1INH (antigenic level). If C4 and C1q are low and C1INH
antigenic level is low or normal, then C1INH function should be obtained. Low C1INH function confirms the
diagnosis (algorithm 1 and table 1). Other studies are usually not needed. (See 'Complement studies' above.)
● All patients with acquired C1INH disorders should be evaluated for an underlying B cell lymphoproliferative
disorder at the time of diagnosis. If no disorder is found, we recommend repeating an evaluation annually. (See
'Evaluation for underlying disorders' above.)
ACKNOWLEDGMENT
We are saddened by the death of Marco Cicardi, MD, who passed away in August 2019. UpToDate wishes to
acknowledge Dr. Cicardi's past work as an author for this topic.
2098
GRAPHICS
C1INH deficiency diagnostic algorithm
FXII: factor XII.
Modified with permission from: Bowen T, Cicardi M, Farkas H, et al. 2010 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.
Allergy, Asthma, and Clinical Immunology 2010; 6:24. Copyright © 2010 BioMed Central Ltd.
2099
Angioedema
C4* C1-INH level C1-INH function C1q Other tests
disorder
Hereditary angioedema Low Low Low Normal Genetic testing

with C1-INH deficiency (usually <50% of (not needed for
type I (HAE-C1-INH normal) diagnosis)
type I)
Hereditary angioedema Low Normal or elevated Low Normal Genetic testing

type II (HAE-C1-INH normal) diagnosis)
type II)

with factor XII factor XII
gene mutations
(HAE-FXII)

with angiopoietin-1 gene angiopoietin-1
mutations (HAE-
ANGPT1)

with plasminogen gene plasminogen
mutations (HAE-PLG)

with kininogen-1 gene kininogen-1
mutations (HAE-KNG1)
Hereditary angioedema Normal Normal Normal Normal

of unknown origin (HAE-
U)
Acquired angioedema Low Normal or low Low Normal or low ¶ Anti-C1INH antibodies
(AAE-C1-INH) normal) diagnosis)

acquired angioedema
(histaminergic or
nonhistaminergic)
(AAE-IH or AAE-InH)

Terminology for angioedema disorders is evolving, and the abbreviations HAE-C1-INH and C1INH-HAE are both used for hereditary
angioedema in the literature.
2100
Acquired C1 inhibitor deficiency: Management and prognosis

Section Editor: Bruce S Bochner, MD
INTRODUCTION
Acquired angioedema due to deficiency of C1 esterase inhibitor, also called acquired angioedema
and abbreviated C1INH-AAE, is a rare syndrome of recurrent episodes of angioedema, without
urticaria, which is associated with B cell lymphoproliferative disorders in some patients [1].
Angioedema typically affects the skin or mucosal tissues of the upper respiratory and
gastrointestinal tracts. The swelling is self-limited, although laryngeal involvement may cause fatal
asphyxiation. Clinically, this disorder is very similar to hereditary angioedema (HAE), although
acquired angioedema develops in older patients and is frequently associated with underlying
disease, whereas the hereditary disorder presents in younger patients who are otherwise healthy [2].
This topic review will discuss the management and prognosis of C1INH-AAE. The clinical
manifestations, epidemiology, pathogenesis, and diagnosis of this disorder are reviewed elsewhere.
(See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and
diagnosis".)
HAE, which is caused by mutations in the gene for C1INH, is discussed separately. (See "Hereditary
angioedema: Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical
manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Acute treatment
of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care
and long-term prophylaxis".)
OVERVIEW OF MANAGEMENT
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The management of a patient with acquired angioedema involves several components [3]:
● Educating the patient about the potential triggers and early recognition of angioedema attacks
and ensuring that the patient understands that there is a real risk of fatal asphyxiation with
attacks involving the upper airway. (See 'Patient education about laryngeal edema' below and
'Avoidance of exacerbating factors' below.)
● Providing the patient with written instructions about treatment of acute attacks, which can be
given to other providers in the emergency setting (form 1). (See 'Written treatment plan' below
and 'Airway management in laryngeal edema' below.)
● Prescribing appropriate "on-demand" therapies for attacks of angioedema and ensuring that the
patient is either trained to self-administer these treatments or has access to appropriate
medications at the hospitals nearest to the patient's home. (See 'Pharmacologic treatment of
acute attacks' below.)
● Managing associated diseases, if present, or if none is initially found, monitoring for the
development of an associated disease. (See 'Associated disorders' below.)
● Evaluating the need for prophylaxis to prevent angioedema attacks. (See 'Prophylaxis to prevent
angioedema episodes' below.)
PREPARATION FOR ACUTE ANGIOEDEMA EPISODES
Laryngeal attacks are the most dangerous type of attack in acquired angioedema because edema
can lead to fatal airway obstruction. Upper airway angioedema usually progresses over hours,
although it can occur precipitously. Intubation may become very difficult due to distortion of the
anatomy of the upper airway. Because of the dangers associated with laryngeal attacks, it is
important to make sure that patients are prepared to respond effectively to the development of
symptoms near or in the throat.
Angioedema may also affect the gastrointestinal tract, causing colicky abdominal pain, nausea,
vomiting, and/or diarrhea. Episodes of abdominal angioedema are often debilitating but are not life-
threatening. Angioedema affecting the skin is temporarily disfiguring but rarely dangerous unless it
affects the mouth or lips, since it can compromise the airway in these situations. The approach to
treating abdominal and cutaneous attacks is similar to that used in patients with hereditary
angioedema (HAE), which is reviewed in detail separately. (See "Hereditary angioedema: Acute
treatment of angioedema attacks", section on 'Gastrointestinal attacks' and "Hereditary angioedema:
Acute treatment of angioedema attacks", section on 'Cutaneous attacks'.)
2102
Patient education about laryngeal edema — All patients with C1INH-AAE must be counseled about
the earliest signs of an attack affecting the upper airway, which typically includes the sensation of a
lump or feeling of tightness in the throat or swallowing difficulties. Patients should also have a plan
to get prompt and appropriate treatment. Any patient with throat symptoms should seek emergency
care immediately. The patient should not attempt to manage early laryngeal attacks at home,
although if therapy for self-administration is available and can be given quickly, the patient can
initiate therapy and then call for an ambulance to take him/her to the nearest emergency
department. It is important to discuss that even if the treatment has worked well in the past, the
patient should always proceed immediately to an emergency care setting when the throat is involved
because all of the first-line therapies take approximately 30 minutes or more to begin working. In rare
circumstances, acute treatment, particularly with plasma-derived C1INH (pdC1INH), can be less
effective than in hereditary C1INH deficiency, thus a second dose is occasionally required. In
contrast, abdominal angioedema or cutaneous angioedema can often be managed by patients at
home if they have access to acute treatments. The emergency treatments that are appropriate for
administration at home are discussed elsewhere. (See "Hereditary angioedema: Acute treatment of
angioedema attacks", section on 'Initiating acute treatment of HAE attacks at home'.)
Written treatment plan — C1INH-AAE is a rare disorder, and few emergency department providers are
familiar with the treatment. Patients can be equipped with a document that briefly explains their
diagnosis, outlines the indicated treatment for acute attacks, and provides contact information for
the supervising clinician (form 1).
Airway management in laryngeal edema — Assessment and protection of the upper airway is the
first and most important management issue in the patient with an acute attack involving any part of
the airway because none of the available therapies including C1INH concentrate, icatibant, and
ecallantide can be considered universally effective in all cases. In addition, these agents take time to
work, and the patient's airway must be protected in the interim. Asphyxiation remains an important
and preventable cause of death in patients with this disorder, even in settings with appropriate
medications available. (See 'Prognosis' below.)
Intubation should be performed immediately if stridor or signs of respiratory arrest are present. A
clinician trained in difficult airway management should be summoned if possible because failed
attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required in rare cases.
(See "Approach to the anatomically difficult airway in adults outside the operating room" and
"Emergency cricothyrotomy (cricothyroidotomy)".)
Once the patient is assessed and either intubated or deemed stable, additional therapies can be
considered. Transfer to the intensive care unit should be arranged. Frequent and meticulous
2103
monitoring of airway status should continue throughout the course of the attack until complete
resolution, and patients should not be discharged until all airway symptoms have resolved.
Pharmacologic treatment of acute attacks — There are several medications available for acute
treatment of episodes of angioedema due to genetic C1INH deficiency that can be used for C1INH-
AAE. None of these drugs are registered/approved specifically for C1INH-AAE, and availability varies
around the world (table 1):
● C1INH concentrate, derived from human plasma (pdC1INH) (see 'C1 inhibitor concentrate'
below)
● Recombinant human C1INH (rhC1INH, conestat alfa) (see 'Recombinant C1 inhibitor' below)
● Icatibant, a synthetic bradykinin B2-receptor antagonist (see 'Icatibant' below)
● Ecallantide, a recombinant plasma kallikrein inhibitor (see 'Ecallantide' below)
● Human plasma, either solvent/detergent-treated plasma (S/D plasma) or fresh frozen plasma
(FFP) (see 'Plasma' below)
The therapy with which there is most experience is pdC1INH, followed by icatibant. A clinical
response should be evident within two hours with pdC1INH, icatibant, or ecallantide. Each
medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy
data, and adverse effects.
The treatment of C1INH-AAE is extrapolated from that of HAE [2,4,5]. No controlled studies have
been performed in patients with C1INH-AAE, and no therapies are specifically registered/approved
for treatment of this condition. Based on clinical experience, there appears to be some differences in
the response of these two disorders to the available therapies, as discussed in this section.
C1 inhibitor concentrate — The most widely used therapy for acute laryngeal edema is pdC1INH,
which is available as Cinryze or Berinert (brand names). pdC1INH became available in the United
States in 2009 but has been available in Europe for decades. Observational studies indicate that
pdC1INH is effective in the majority of patients with C1INH-AAE, reducing the average attack
duration by 60 percent or more [6].
Based on the controlled studies performed in C1INH-HAE, an initial dose of 20 units/kg is suggested.
The dosing, administration, and adverse effects of pdC1INH are reviewed elsewhere. (See "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy,
and adverse reactions'.)
Resistance — A small percentage of patients with C1INH-AAE become less responsive to

pdC1INH over time, requiring higher doses to control symptoms [7,8]. As an example, one of the
author's patients required multiple infusions totaling 12,000 units of pdC1INH (the usual initial dose
2104
is 1500 units) over a period of two hours to control laryngeal edema. The newer therapies for
bradykinin-mediated angioedema, ecallantide and icatibant, offer alternatives for the treatment of
patients who become resistant to pdC1INH, and we would suggest trying these if resistance is
suspected. (See 'Ecallantide' below and 'Icatibant' below.)
The mechanism by which resistance to pdC1INH develops appears to involve extremely rapid
catabolism of the inhibitor protein, although this has not been formally demonstrated. In blood
samples collected from the patient described above, no significant increase of C1INH function could
be detected at any point during the multiple infusions, while C1INH antigen normalized due to the
increase in cleaved C1INH. These data suggest that the infused C1INH was rapidly bound by the
autoantibodies and converted in its cleaved inactive form upon interaction with target proteases. The
patient described above had high levels of anti-C1INH antibodies in serum.
Recombinant C1 inhibitor — There are limited data regarding the efficacy of recombinant human
C1INH (rhC1INH) (Ruconest [brand name]) in C1INH-AAE. rhC1INH has a shorter half-life than
pdC1INH. This is a theoretical disadvantage in treating C1INH-AAE, which is characterized by
increased C1INH consumption, although no published data are available to confirm. The dosing and
adverse effects of this agent are discussed elsewhere. (See "Hereditary angioedema: Acute
treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
Icatibant — Icatibant (Firazyr [brand name]) is an antagonist of the bradykinin B2-receptor, which
has also been successful in treating a small number of patients not responsive to C1INH concentrate
[9,10]. It became available in the United States in 2011.
The author has successfully used icatibant to treat angioedema episodes, including laryngeal
edema, in several C1INH-AAE patients, some of whom were not responsive to C1INH [9,10]. Because
icatibant does not depend on C1INH catabolic rate, the author prefers it to C1INH concentrate in his
own practice.
The dosing, administration, and adverse effects of icatibant are reviewed elsewhere. (See "Hereditary
angioedema: Acute treatment of angioedema attacks", section on 'Bradykinin B2-receptor
antagonist'.)
Plasma — Plasma has been used in the treatment of acute laryngeal attacks and severe
abdominal attacks in both acquired and hereditary angioedema, although the efficacy has not been
formally investigated. Where available, S/D plasma is preferred because the risk of disease
transmission is theoretically lower. If not available, FFP may be given. Plasma contains an array of
complement components, including C1INH.
2105
Two units is the usual initial dose for treatment of angioedema. This dose can be repeated every two
to four hours until there is clinical improvement. Once the attack begins to subside, further plasma is
not usually required. If a patient has comorbid conditions that increase the risk for volume overload,
then dosing of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume
status and cardiopulmonary function.
The administration, infection risks, and adverse effects of plasma are reviewed elsewhere. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)
Ecallantide — Ecallantide (Kalbitor [brand name]) is an inhibitor of plasma kallikrein that has been
effective in a small number of case reports of patients with C1INH-AAE [11,12]. Kallikrein is the
enzyme that releases bradykinin, the mediator of angioedema, from high molecular weight
kininogen. Ecallantide is approved by the US Food and Drug Administration (FDA) for acute
angioedema attacks in patients with HAE [13]. It is only available in the United States.
During the first open-label trial, the author's group used this drug in two patients with C1INH-AAE,
one of them resistant to pdC1INH, and observed a prompt resolution of symptoms [11]. Both patients
developed a relapse of angioedema within 12 hours, but the symptoms were mild and resolved
spontaneously without need for further treatment.
The dosing, administration, and adverse effects of ecallantide are reviewed elsewhere. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor
(United States only)'.)
Ineffective therapies — Our and others' experience support the view that antihistamines,
glucocorticoids, and epinephrine are not effective in acute treatment of C1INH-AAE [14]. There are no
trials that directly evaluate the use of these therapies in acquired or hereditary angioedema. We
strongly recommend not relying on these drugs to treat angioedema in patients with C1INH
deficiency. In one review of 22 patients, investigators concluded that "in the acute setting, high-dose
glucocorticoids with or without subcutaneous epinephrine seem to be effective, depending on the
severity of symptoms" [15]. However, they did not provide the data to support the statement, and this
conclusion is not consistent with our clinical experience. On the other hand, these therapies should
be considered if there is any uncertainty about the patient's diagnosis because allergic forms of
angioedema do respond to these therapies.
AVOIDANCE OF EXACERBATING FACTORS
Factors that exacerbate or precipitate attacks include physical or psychological stress and certain
medications.
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Medications that can increase the frequency and/or severity of attacks in acquired angioedema
(C1INH-AAE) include the following:
● Estrogen-containing medications, such as hormone replacement therapy and contraceptives

[16].
● Tamoxifen, a selective estrogen receptor modulator (SERM) that has mixed agonist/antagonist
actions on the estrogen receptor. In one reported case, a patient with hereditary angioedema
(HAE) who developed increased episodes on tamoxifen was successfully treated with the
aromatase inhibitor letrozole [17]. If tamoxifen or another SERM is essential to the patient's
therapy, then worsening symptoms of C1INH-AAE may need to be managed by increasing
therapy to prevent angioedema episodes, rather than discontinuing the SERM.
● Angiotensin-converting enzyme (ACE) inhibitors [18]. In contrast, the experience of the author is
that angiotensin II receptor blockers (ARBs) are well-tolerated.
Monitoring for development — If no associated condition is identified initially, we monitor patients by

performing all age-appropriate cancer screening and repeating studies for B cell malignancies
annually. Specifically, we obtain a complete physical examination, a complete blood count (CBC) with
differential, a serum protein electrophoresis and immunofixation, a chest radiograph, and an
abdominal ultrasound. Although there are limited published data regarding the rate at which
disorders are detected over time, the author has personally followed one patient with no apparent
associated disease for over a decade.
Management of identified disorders — Successful treatment of lymphoproliferative disorders that

are identified in a patient with acquired angioedema usually results in reduction of attacks of
angioedema. Two independent case series provide evidence that partial or complete clinical and/or
biochemical remission of acquired angioedema occurs upon treatment of associated
lymphoproliferative diseases [19,20]. The effect of treating other associated disorders is informed by
single case reports [21-23].
In patients with lymphoma, a variety of therapies, including surgery, chemotherapy, and biologic
agents, such as rituximab, have been reported to be helpful in reducing episodes of angioedema
[19,20]. Responses to treatment range from partial to complete (and apparently stable) remission.
However, treatment of the underlying disorder is not indicated in every case, and the risk-benefit
balance should be considered in each patient. It would not be prudent to risk potential adverse
effects to treat a lymphoproliferative disorder that had a very mild course for the sole purpose of
2107
controlling angioedema attacks, since the latter can often be managed with the therapies discussed
in this review.
Alterations in complement abnormalities are variable following treatment for lymphoma in patients
with acquired angioedema. C1INH levels, C1q, and C4 levels may normalize in concert or
independently. Disappearance of autoantibodies can also occur. We have observed a wide range of
changes in complement studies and autoantibody levels in the patients we manage following
treatment for lymphoma, although we have not detected a consistent pattern [19]. One of the author's
patients had complete reversal of clinical and complement abnormalities but persistence of anti-
C1INH autoantibodies. Such findings highlight the uncertainties regarding the pathogenesis of
acquired angioedema. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology,
pathogenesis, and diagnosis", section on 'Pathogenesis'.)
Monitoring MGUS — Patients with acquired angioedema who are found to have monoclonal
gammopathy of undetermined significance (MGUS) must be followed and evaluated regularly, as
MGUS can transform to a more serious disorder at a rate of approximately 1 percent per year. The
author has followed patients with stable MGUS for over 20 years. It is not known if treatment of
MGUS prior to transformation would impact the patient's outcome. The recommendations for
monitoring are reviewed separately. (See "Clinical course and management of monoclonal
gammopathy of undetermined significance".)
PROPHYLAXIS TO PREVENT ANGIOEDEMA EPISODES
Short-term prophylaxis should always be administered if intubation, oral surgery, or general surgery
is planned. It is often administered prior to lesser dental procedures. Other minimally traumatic
procedures not involving the oral cavity, such as a colonoscopy, may not require prophylaxis,
although it is best to provide prophylaxis if the patient's tolerance to a procedure is unknown. The
approach is identical to that for patients with hereditary angioedema (HAE). Only a few case reports
describe short-term prophylaxis in patients with acquired angioedema specifically, and these have
used either plasma-derived (pdC1INH) or recombinant human C1INH (rhC1INH) concentrates [24,25].
The indications for long-term prophylaxis in patients with acquired angioedema are not well-defined,
and guidelines remain vague. The author's approach is to initiate prophylactic therapy in patients
who cannot control symptoms by "on-demand therapy" and experience several days of disability
each month. The author also administers prophylaxis to patients in whom "on-demand therapy" is
not entirely or consistently effective.
The options for prophylactic therapy in patients with acquired angioedema are the same as those
used in HAE [7,21,26-28]:
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● Antifibrinolytic agents (ie, tranexamic acid [TA])
● Attenuated androgens
● Regular infusions of C1INH concentrate
However, we have concerns about the use of C1INH concentrate for prophylaxis because acquired
angioedema patients sometimes become resistant to it (possibly due to anti-C1INH antibodies), and
we prefer to reserve it for treating acute attacks. Whether regular C1INH infusion increase the levels
of anti-C1INH autoantibody worsening disease course has not been proven, but such possibility
should be considered [29]. (See 'Resistance' above.)
It is the author's approach to start with TA (3 grams daily) [2]. If the patient's episodes of angioedema
stop occurring, the dose of TA may be gradually lowered, although some patients have recurrent
symptoms when this is attempted and need to remain on the full dose indefinitely. If the attacks do
not decrease in number and severity on full-dose TA, the author then changes to danazol (200 mg
daily), adjusting to the lowest effective dose.
Antifibrinolytics — TA is well-tolerated by most patients with acquired angioedema and is available in

many countries [30]. It became available in the United States in oral form in 2009. TA reduces the
frequency and severity of attacks in the majority of patients [2]. As an example, of 13 patients treated
with TA in one series, 8 responded very well and 4 responded partially [7]. Use of TA for the
prevention of angioedema, including dosing and monitoring, is discussed in more detail separately.
prophylaxis", section on 'Antifibrinolytics'.)
It is debated whether or not antifibrinolytics carry an increased risk of thrombosis, particularly in

patients with associated malignancies. Until this question is conclusively answered, we coadminister
antithrombotic therapy only to patients with other reasons for increased risk of thromboembolism
(eg, those with malignancies, coronary heart disease, or history of thromboembolic stroke) who also
need long-term TA for acquired angioedema [31]. We have observed thrombotic events in four
patients on antifibrinolytic agents, and the treatment was discontinued. In three of these patients, the
frequency and severity of angioedema recurrences increased substantially after withdrawal of TA
and could not be controlled by on-demand treatment alone or with danazol. Therefore, after complete
recovery from the acute thrombotic events, antifibrinolytic treatment was resumed with concomitant
oral anticoagulants. No further thrombotic events have occurred in these three patients using this
approach for over 10 years [10].
Androgens — Attenuated androgens, such as danazol, stanozolol, and others, control symptoms in
approximately one-half of patients in our clinical experience [7,21,27,28]. Those who respond well to
this therapy sometimes achieve control of symptoms with very low doses and remain on this agent
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for years. However, in the remaining patients, androgens either do not work from the outset or
become ineffective after a period of time [7]. Use of androgens for the prevention of angioedema is
discussed in more detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency):
General care and long-term prophylaxis", section on 'Attenuated androgens'.)
PROGNOSIS
There are no published studies that provide information about the long-term prognosis of patients
with C1INH-AAE. Among the 77 patients the author has followed since 1975, 16 patients have died
since diagnosis [10]. Eleven deaths were not related to C1INH-AAE, and one patient died of laryngeal
edema. Three patients died from complications of the associated lymphoproliferative disease, and
one died due to hemorrhagic complication of hepatitis C virus cirrhosis, possibly acquired during
treatment with plasma-derived C1INH (pdC1INH) in the 1970s (when viral controls for plasma
products were not available).
The risk of asphyxiation due to upper airway closure remains a real and immediate risk for patients
with acquired angioedema because of the limited knowledge of this condition on the part of
clinicians. In the patient who died due to laryngeal edema, an infusion of 1000 units of C1INH
concentrate was started but too late to prevent progression of the swelling to airway closure.
Attempts at endotracheal intubation failed because of massive laryngeal edema, and permanent
anoxic brain damage was already established by the time a tracheotomy was performed. Our overall
experience with 983 patients diagnosed in Italy since 1974 with C1INH-HAE indicates that 63 died, 5
of them for laryngeal edema.
● Acquired angioedema due to deficiency of C1 inhibitor (C1INH-AAE) is a rare syndrome of

recurrent episodes of angioedema, without urticaria, which is associated with B cell
lymphoproliferative disorders in some patients.
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● Patients should be educated about the risk of fatal laryngeal attacks and instructed on how to
proceed should swelling in the throat develop. Because so few clinicians are familiar with this
disorder, equipping the patient with information about proper treatment is critical. A printable
form is provided (form 1). (See 'Patient education about laryngeal edema' above and 'Written
treatment plan' above.)
● Patients with laryngeal attacks require immediate assessment of the airway. If respiratory
distress or stridor is present, preparations to intubate should be made because even the first-line
therapies take approximately 30 minutes or more to begin working. An expert should manage
the airway, if possible. (See 'Airway management in laryngeal edema' above.)
● For treatment of severe angioedema in patients with C1INH-AAE, we suggest plasma-derived

C1INH (pdC1INH) concentrate (Grade 2C). There is more experience with this therapy than with
any other. Other agents that may be effective based on case reports include the following (table
1):
• Icatibant, a bradykinin B2-receptor antagonist (available in the United States, Europe, and
other countries).
• Ecallantide, a kallikrein inhibitor (available in the United States).
• Recombinant human C1INH (rhC1INH) (available in most of Europe and the United States).
• Plasma (fresh frozen or solvent-detergent treated).
Patients should either be trained to self-administer one of these treatments or have access to
appropriate treatments at the hospitals nearest to the patients' homes. (See 'Pharmacologic
treatment of acute attacks' above.)
● Patients with acquired angioedema can become resistant to C1INH concentrate over time. For
patients with acute angioedema who do not improve in response to an initial dose of C1INH
concentrate, we suggest administering ecallantide or icatibant instead (Grade 2C).
● If an underlying disorder is identified, treatment of that disorder usually reduces the frequency of
angioedema episodes. (See 'Associated disorders' above.)
● We suggest prophylactic therapy for patients with recurrent episodes of laryngeal edema or
angioedema symptoms affecting the gastrointestinal tract or skin, who despite the availability of
on-demand therapies, experience several days of disability per month (Grade 2C). The primary
agents for prevention of attacks are antifibrinolytic agents or attenuated androgens. (See
'Prophylaxis to prevent angioedema episodes' above.)
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ACKNOWLEDGMENT
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GRAPHICS
Instructions for emergency care of acquired angioedema
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Treatment of acute episodes of angioedema in acquired angioedema (also known as acquired C1 inhibitor
deficiency)
Medication Availability Dosing Precautions
C1 inhibitor concentrate In United States: 20 units per kg body weight Do not shake solution, because
(plasma-derived) Berinert given intravenously over 10 protein will denature. Cinryze is
(Berinert, Berinert P, Cinryze) Cinryze minutes. Symptoms usually not FDA-approved for acute
stabilize in 30 minutes. Second attacks but has efficacy.
Other countries:
dose uncommonly needed but
Berinert P
may be given 30 minutes to 2
Cinryze hours after first dose.
Recombinant C1 inhibitor Europe, United States, some 50 units per kg body weight for Patients should be screened for
Conestat alfa (Ruconest, other countries. patients <84 kg. 4200 units (two rabbit allergy prior to receiving
Rhucin) vials) for those ≥84 kg. Second with rabbit-specific IgE
dose rarely needed. immunoassay and should not
receive drug if positive.
Bradykinin B 2 -receptor United States and many other 30 mg slow subcutaneous Caution in patients with
antagonist countries. infusion (because of volume) in unstable angina. Mild injection
Icatibant (Firazyr) Approved in the United States abdominal area. Second dose site reactions are common.
for individuals over the age of needed in about 10% of patients
18 years. and can be given 6 hours after
first dose. Maximum of three
doses in 25 hours.
Kallikrein inhibitor United States only. 30 mg (three doses of 10 mg Rare allergy reaction reported
Ecallantide (Kalbitor) Approved in the United States each) given at three separate usually in <1 hour. Should be
for individuals over the age of sites subcutaneously in administered by a clinician or
16 years. abdomen, upper arm, or thigh nurse in a medical facility
and away from site of equipped to treat anaphylaxis.
angioedema.
Plasma Solvent detergent-treated 2 units initially. Can be repeated Monitor for volume overload in
plasma (S/D plasma) every 2 to 4 hours, if needed. patients with underlying
(preferred) conditions predisposing to
Fresh frozen plasma (FFP) volume overload. Theoretical
risk of transmission of blood-
borne pathogens.
The use of the therapies in the table for acquired angioedema (ie, acquired C1 inhibitor deficiency) is extrapolated from hereditary
angioedema. Evidence supporting the use of the agents in the acquired forms of the disease is limited to case reports and clinical
experience. Plasma-derived C1 inhibitor concentrate is the agent with which there is the most clinical experience.
FDA: US Food and Drug Administration; IgE: immunoglobulin E.
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ACE inhibitor-induced angioedema

Authors: Autumn Chandler Guyer, MD, Aleena Banerji, MD
INTRODUCTION
Angiotensin-converting enzyme (ACE) inhibitors are the leading cause of drug-induced angioedema in the United States because they
are so widely prescribed. Patients most commonly present with swelling of the lips, tongue, or face, although another presentation is
episodic abdominal pain due to intestinal angioedema. Urticaria and itching are notably absent.
This topic reviews the clinical features, diagnostic evaluation, differential diagnosis, pathophysiology, risk factors, and management of
ACE inhibitor-induced angioedema. The use of angiotensin-receptor blockers (ARBs) and related medications in patients who have past
angioedema to an ACE inhibitor is also reviewed. An overview of angioedema from all causes is found separately. (See "An overview of
angioedema: Clinical features, diagnosis, and management" and "An overview of angioedema: Pathogenesis and causes".)
EPIDEMIOLOGY
ACE inhibitors induce angioedema in 0.1 to 0.7 percent of recipients, with data suggesting a persistent and relatively constant risk over
time [1-10]. The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent [11-13].
Although the risk to an individual is relatively low, the large number of people taking these medications means that ACE inhibitors are
the leading cause of drug-induced angioedema in the United States, accounting for 20 to 40 percent of all emergency department visits
for angioedema each year [14-16]. Approximately 35 percent of all prescriptions written for antihypertensive medications in the United
States are for ACE inhibitors [17], and more than 40 million patients globally are taking these agents [1]. ACE inhibitors are routinely
used in patients with hypertension, myocardial infarction, heart failure, diabetes, and chronic kidney disease.
CLINICAL FEATURES
Angioedema is an asymmetric, nonpitting swelling of the subcutaneous or submucosal tissues that most commonly affects
nondependent areas. There is an absence of itching or urticaria in ACE inhibitor-induced angioedema, and the presence of urticaria
suggests a different group of etiologies [18]. The different mechanisms of angioedema and the etiologies associated with each
mechanism are reviewed separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on
'Types of angioedema'.)
Affected areas — ACE inhibitor-induced angioedema most commonly affects the lips, tongue, face, and upper airway. The intestine can
also be involved, presenting as acute abdominal pain with diarrhea or other gastrointestinal symptoms, but this presentation may be
less well recognized. The reason that these particular parts of the body are more often affected is not known.
Face, mouth, and upper airway — The edema that occurs from ACE inhibitors usually affects the lips, tongue, and face (picture 1)
[19]. Angioedema of the pharynx, larynx, and subglottic area have also been reported. Early signs of laryngeal edema may include
hoarseness of the throat and inspiratory stridor, which may progress to airway obstruction in up to 10 percent of cases [14,20]. Rarely,
fatalities due to massive tongue swelling and asphyxiation are reported [14,15,21].
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Intestine — Visceral angioedema due to ACE inhibitors has been described in a handful of case reports and reviews [22-28]. Most
commonly, this presents as diffuse abdominal pain and diarrhea [22-27,29-35]. Other symptoms include vomiting, anorexia, or ascites
[36]. In most of these reports, diagnosis was delayed by months to years, because clinicians were not as aware of this potential
presentation of ACE inhibitor-induced angioedema [22-26].
In more than one-half of the case reports of visceral angioedema, symptoms began within 72 hours of starting ACE inhibitor therapy,
although in other reports, angioedema developed after weeks or years of therapy [28,29,35]. The jejunum is most often involved,
followed by the ileum and duodenum. At least one case report documented swelling of the distal antrum and pylorus of the stomach
[37].
Findings on imaging — Visceral angioedema can usually be visualized using either abdominal computed tomography (CT) or
ultrasound. Typical findings include dilated bowel loops, a "doughnut" or "stacked coin" appearance, thickened mucosal folds,
mesenteric edema, perihepatic fluid, and/or ascites [24,38].
Time course — ACE inhibitor-induced angioedema occurs episodically, but each episode follows a relatively predictable time course of
two to five days in duration. Swelling usually develops over minutes to hours, peaks, and then resolves over 24 to 72 hours, although
complete resolution may take days in some cases [14,30,37]. The pathophysiologic reasons for this pattern are not known. A history of
preceding episodes with long symptom-free intervals is not unusual, especially in the case of abdominal or visceral angioedema
[22,29]. If the ACE inhibitor is not discontinued, the episode will still resolve, although the frequency and severity of future episodes
appears to escalate, and the condition can become life-threatening. (See 'Discontinue ACE inhibitor' below.)
In more than one-half of cases, angioedema occurs during the first week of exposure, although it may occur any time during the course
of therapy from hours to years after treatment [10,31,39,40]. In the large retrospective study mentioned previously, two-thirds of
angioedema episodes occurred within the first three months of therapy [6]. However, case reports have documented episodes of
angioedema related to ACE inhibitor use after years of stable therapy [32,33], with data suggesting a persistent and relatively constant
risk annually [10].
Severity — In most cases, the episode of angioedema resolves without complications. However, endotracheal intubation or emergency
tracheostomy may be necessary for angioedema obstructing the airway, and fatalities have been reported [41,42].
Risk of additional episodes — Some patients will have additional episodes of angioedema even after stopping the ACE inhibitor. For this
reason, it is critical to explain this to patients and provide specific advice about how to proceed if another episode occurs. (See
'Recurrence' below.)
PATHOPHYSIOLOGY
The clinical features of ACE inhibitor-induced angioedema are related to elevated levels of bradykinin, an inflammatory vasoactive
peptide, which leads to vasodilation of blood vessels. The pathways involved in bradykinin generation are described briefly here.
ACE inhibition — ACE inhibitors block the effects of the enzyme ACE, also known as kininase II, and impact both the renin-angiotensin-
aldosterone (RAA) pathway and the degradation of bradykinin. The RAA cascade is important for regulating renal blood flow and blood
pressure. Angiotensinogen, produced in the liver, is converted by renin in the kidney to produce angiotensin I. Angiotensin I is then
metabolized to angiotensin II in the lungs by the enzyme ACE (kininase II). Angiotensin II acts as a vasoconstrictor through stimulation
of angiotensin I and II receptors.
Angiotensin II is also responsible for inactivating bradykinin [43], while ACE (kininase II) is the primary peptidase involved in the
degradation of bradykinin. Bradykinin is a peptide made of nine amino acids that increases capillary permeability and acts as a potent
vasodilator. The production of bradykinin occurs after the precursor kininogen is cleaved by kallikrein, which leads to production of the
active form of bradykinin (figure 1).
Bradykinin has a very short half-life (approximately 17 seconds) and is metabolized primarily by ACE (kininase II), neutral
endopeptidase (NEP), and aminopeptidase P (APP) and secondarily by the enzymes dipeptidyl peptidase-4 (DPP-4) and kininase I. Des-
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Arg9-BK is an active metabolite of bradykinin formed primarily due to the kininase I enzyme. The pharmacologic activities of des-Arg9-
BK, similar to those of bradykinin, are short-lived because of its breakdown by ACE and APP.
Thus, ACE inhibitor therapy has the following effects in all patients:
● Initially, vasodilation due to inhibited production of angiotensin II
● Chronically, angiotensin II returns to pretreatment levels through alternative pathways of production by tissue chymases [44]
● Bradykinin levels become elevated due to impaired metabolism, which leads to release of nitric oxide and prostaglandins and
results in vasodilatation and hypotension [45]
● Levels of des-Arg9-BK, the breakdown product of bradykinin, become elevated
In addition, a small study found that serum levels of 6-keto-prostaglandin F1-alpha, a breakdown product of prostaglandins with a longer
half-life, increased significantly with 10 mg/day doses as a result of ramipril therapy [46]. Further studies are necessary to determine if
this will be a clinically useful biomarker in the future.
Role of bradykinin in angioedema — Elevated plasma bradykinin activity has been demonstrated in patients with ACE inhibitor-induced
angioedema [47]. A case report demonstrated a 10-fold increase in bradykinin levels during an episode of angioedema due to use of the
ACE inhibitor captopril and returned to normal levels during remission [43,48]. High levels of bradykinin stimulate vasodilation and
increased vascular permeability of the postcapillary venules and allows for plasma extravasation into the submucosal tissue, leading to
angioedema [43,49]. Substance P can also increase vascular permeability, leading to angioedema.
ACE inhibitor-induced angioedema is thought to result from defective degradation of at least three vasoactive peptides: bradykinin, des-
Arg9-BK (a metabolite of bradykinin), and substance P [50,51].
Normally, bradykinin is inactivated by ACE, APP, DPP-4, and NEP, as mentioned previously. The APP-inactivated bradykinin metabolite,
des-Arg9-BK, is also degraded by DPP-4 [52]. Substance P is inactivated primarily by the enzyme DPP-4, although ACE and NEP play a
secondary role [52,53]. Decreased activity of DPP-4 correlated to a prolonged half-life of substance P but only in the presence of ACE
inhibition, suggesting a requirement for multiple enzyme defects to inhibit degradation.
When ACE is inhibited by drug therapy, the secondary bradykinin metabolic enzymes (APP, kininase I, NEP, and DPP-4) play a relatively
larger role in degrading bradykinin, des-Arg9-BK, and substance P. Thus, defects or deficiencies in these enzymes theoretically
predispose patients to developing angioedema when taking an ACE inhibitor. Studies that support this mechanism include the
following:
● Decreased APP activity was demonstrated in the sera of 39 Caucasian patients with a history of ACE inhibitor-induced
angioedema, as compared with 39 ACE inhibitor-exposed controls [54].
● Decreased DPP-4 antigen and activity levels were found in the sera of 50 patients with a history of ACE inhibitor-induced
angioedema, as compared with 176 ACE inhibitor-exposed controls [55].
In addition to the above, approximately one-half of patients experiencing ACE inhibitor-induced angioedema also have an enzyme
defect involved in des-Arg9-BK metabolism, leading to its accumulation when ACE is inhibited [56].
RISK FACTORS
Both environmental and genetic factors have been shown to influence the development of ACE inhibitor-induced angioedema [11-14,52-
55,57-61]. However, there is no standardized genetic or laboratory evaluation that can identify (in advance) individual patients who are
at an increased risk for developing ACE inhibitor-induced angioedema.
Possible risk factors — Potential risk factors include the following:
● History of previous episodes of angioedema [11,14,57].
● Age older than 65 years [11].
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● Aspirin or other nonsteroidal anti-inflammatory (NSAID) use [11,14,57].
● History of angioedema related to NSAID use [10].
● Female sex [11,14,57].
● Smoking [55].
● Seasonal allergies [11].
● Use of the mechanistic target of rapamycin (mTOR) inhibitors, sirolimus or everolimus, has been shown to predispose to
angioedema when combined with ACE inhibitor use in renal transplant recipients, due to reduced metabolism of bradykinin [58,62].
Increased rates of angioedema have also been reported in cardiac transplant patients taking everolimus and ACE inhibitors [63].
Ramipril was restarted at lower doses in all patients at lower sirolimus levels with no adverse effects, suggesting a dose-dependent
effect of this combination of drugs on the development of angioedema. In general, transplant patients are thought to be at
increased risk of ACE inhibitor-induced angioedema because of the effects of immunosuppressants on decreasing the activity of
circulating levels of dipeptidyl peptidase-4 (DPP-4) [64].
● Underlying C1 inhibitor deficiency or dysfunction predisposes individuals to episodes of bradykinin-mediated angioedema,

independently of ACE inhibitors, although some patients are asymptomatic until exposed to these drugs [47]. Both hereditary
(hereditary angioedema [HAE]) and acquired forms of C1 inhibitor disorders exist. Patients already known to have these rare
disorders should not be given ACE inhibitors. (See "Hereditary angioedema: Pathogenesis and diagnosis" and "Acquired C1
inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
● History of ACE inhibitor-induced cough was found to be an independent risk factor for developing ACE inhibitor-related angioedema
in one retrospective cohort study [47]. The mechanism of ACE inhibitor-induced cough is not precisely known, although it may
involve increases in bradykinin, prostaglandins, thromboxanes, and/or substance P [65,66]. (See "Major side effects of angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)
In contrast, the risk of angioedema is not related to the specific agent administered or to dose [2,40]. There appears to be a reduced risk
of angioedema due to ACE inhibitors in people with diabetes [3,55].
Predisposing genetic factors — The following genetic factors are believed to impact the risk of ACE inhibitor-induced angioedema:
● The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent, as mentioned
previously [11-13]. (See 'Epidemiology' above.) One possible explanation for this heightened susceptibility is the presence of
genetic polymorphisms in the enzymes aminopeptidase P (APP) and neutral endopeptidase (NEP), which occur at a greater rate in
African Americans [54]. These polymorphisms lead to lower circulating levels of these enzymes, which are responsible for
degradation of bradykinin and its active metabolite, des-Arg9-BK [52]. Levels of bradykinin are further increased in the presence of
an ACE inhibitor [52,55]. Despite these polymorphisms, ACE inhibitors are considered beneficial in the treatment of hypertension in
patients of African descent. (See "Treatment of hypertension in black patients", section on 'ACE inhibitors'.)
● In other populations, genetic polymorphisms in the gene that encodes APP (XPNPEP2) lead to decreased APP activity and higher
levels of bradykinin and des-Arg9-BK, which have been associated with a higher prevalence of ACE inhibitor-induced angioedema
[59,60,67].
● Insertion/deletion polymorphisms have been described in the ACE gene and have been associated with reduced expression of ACE
and a decrease in the degradation of bradykinin. Although theoretically relevant, there does not appear to be a link between ACE
gene polymorphisms and the occurrence of ACE inhibitor-induced angioedema [61].
● Genetic variations in the enzyme neprilysin have been preliminarily implicated. In a genome-wide association study (GWAS) of 175
individuals with ACE inhibitor-induced angioedema and 489 ACE inhibitor-exposed controls, genotyping was performed for
polymorphisms in genes encoding the bradykinin-degrading or substance P-degrading enzymes (carboxypeptidase N, neprilysin,
APP, DPP-4, bradykinin B1-receptor, and the neurokinin 1 [NK1] receptor) [68]. No single gene appeared to have a large effect size,
suggesting that ACE inhibitor-induced angioedema behaves like a complex trait. There were two single nucleotide polymorphisms
(SNPs) that were modestly associated with an increased rate of angioedema. Using a candidate gene approach, a polymorphism in
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the first intron of the neprilysin gene was detected that was associated with an increased risk of angioedema in two subjects.
Additional evidence implicating neprilysin was found in the OCTAVE trial (discussed above) [5]. Patients treated with omapatrilat, a
combined inhibitor of ACE and neprilysin, demonstrated a threefold increased risk of angioedema, compared with those treated
with enalapril alone. (See 'Epidemiology' above.)
DIAGNOSIS
The diagnosis of ACE inhibitor-induced angioedema is made clinically, based on the presence of angioedema, without itching or
urticaria, affecting a characteristic anatomic site, in a patient taking ACE inhibitors. In this scenario, the ACE inhibitor should be
discontinued and assumed to be the cause until proved otherwise.
The diagnosis is confirmed when the ACE inhibitor is discontinued and no further angioedema episodes occur. However, the impact of
discontinuation may only be clear after several months, as some patients will have a small number of recurrent episodes, particularly in
the first few months after the ACE inhibitor was discontinued. (See 'Recurrence' below and 'Referral' below.)
Laboratory evaluation — There are no definitive laboratory tests to diagnose ACE inhibitor-induced angioedema. ACE inhibitor-induced
angioedema is far more common than any of the other rare angioedema disorders [69]. However, obtaining a serum level of
complement protein 4 (C4) is reasonable if there is any clinical suspicion that another cause of bradykinin-mediated angioedema could
be present. A C4 is definitely indicated if the patient has a family history of angioedema or has an underlying lymphoproliferative
disorder (such as monoclonal gammopathy of uncertain significance or lymphoma) or other malignancy [69,70]. In addition, patients
with rare angioedema disorders are at higher risk of developing angioedema with ACE inhibitor therapy, such that ACE inhibitors can
"unmask" an underlying disorder. A low C4 level requires further evaluation. (See 'Referral' below.)
A low C4 should prompt a more complete laboratory evaluation, including C1 inhibitor function and protein levels, C4 level, and C1q
levels. The complement abnormalities seen in these different angioedema disorders are summarized in the table (table 1).
Discontinuation of the ACE inhibitor and monitoring for resolution of symptoms confirms the diagnosis. However, the impact of
discontinuation may only be clear after several months, as some patients will have a small number of recurrent episodes, particularly in
the first few months after the ACE inhibitor was discontinued. Such patients should remain off ACE inhibitors. Referral to an allergy
expert should be considered for patients who continue to have episodes of angioedema after six months. (See 'Recurrence' below and
'Referral' below.)
Evaluation of abdominal symptoms — If visceral angioedema is suspected in a patient taking an ACE inhibitor and presenting with
acute abdominal pain, noninvasive imaging, such as ultrasonography or computed tomography (CT), should be performed to confirm
bowel edema and/or ascites [37]. CT or abdominal ultrasound are diagnostic in most cases. Magnetic resonance imaging (MRI) and
invasive endoscopy should be reserved for cases in which ultrasound and CT are nondiagnostic and there is still a high clinical
suspicion [22]. (See 'Findings on imaging' above.)
In general, angioedema can be caused by either the generation of bradykinin or by activation of mast cells and release of various mast
cell mediators (including histamine). Mast cell-mediated angioedema is reviewed separately. (See "An overview of angioedema:
Pathogenesis and causes", section on 'Causes'.)
Other rare disorders of bradykinin-mediated angioedema present similarly to ACE inhibitor-induced angioedema, and include (algorithm
1):
● Hereditary angioedema (HAE) (see "Hereditary angioedema: Pathogenesis and diagnosis")

● HAE with normal C1 inhibitor (see "Hereditary angioedema with normal C1 inhibitor")
● Acquired angioedema with deficiency of C1 inhibitor, which is associated with lymphoproliferative disorders (see "Acquired C1
inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis")
● Angioedema induced by other medications [71]
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MANAGEMENT
The primary treatments of ACE inhibitor-induced angioedema are acute airway management if the mouth or throat is involved (until the
angioedema episode has resolved) and discontinuation of the drug.
Airway monitoring — If the mouth or throat is involved, the airway should be immediately evaluated and repeatedly monitored until the
swelling is clearly resolving. Prompt intubation and mechanical ventilation may be required. (See "Approach to the anatomically difficult
airway in adults outside the operating room" and "Devices for difficult emergency airway management in adults outside the operating
room" and "Approach to the failed airway in adults outside the operating room".)
Discontinue ACE inhibitor — Angioedema caused by ACE inhibitors usually resolves within 24 to 72 hours. If ACE inhibitors are
continued, there is an increased and unpredictable rate of angioedema recurrence, and attacks may become more severe or life-
threatening [34,72]. Patients who have experienced angioedema attributed to an ACE inhibitor should never again be treated with this
group of medications.
If the cause of a patient's angioedema is unclear, we would still advise discontinuation of ACE inhibitors. If the patient experiences
recurrent episodes of angioedema beyond several months, then the cause of the angioedema is likely not the ACE inhibitor, and other
etiologies should be explored. (See 'Referral' below.)
Therapies of unproven efficacy — There are several therapies that are effective for aborting attacks of angioedema in hereditary
angioedema (HAE), which is the best studied form of bradykinin-mediated angioedema. These include C1 inhibitor concentrate,
ecallantide, icatibant, and possibly fresh frozen plasma. In theory, these therapies should also be helpful in ACE inhibitor-induced
angioedema, but available studies are conflicting [73-75]. There may be several reasons for this:
● There is no quick diagnostic test to determine if a patient's angioedema is bradykinin-mediated or mast cell/histamine-mediated.
The diagnosis of ACE inhibitor-induced angioedema is presumptive in a patient with angioedema who is taking an ACE inhibitor, so
there are likely patients in each of these trials who are incorrectly categorized as having ACE inhibitor-induced angioedema.
● Although both HAE and ACE inhibitor-induced angioedema are believed to be bradykinin-mediated, the angioedema attacks are
likely different in other ways. Patients with HAE have repeated attacks of angioedema and learn to recognize prodromal symptoms
and self-administer treatment or seek emergency care in the earliest stages of an attack. Studies demonstrating efficacy of HAE
therapies have required that patients present in the first few hours of symptoms. In contrast, most patients with ACE inhibitor-
induced angioedema have not experienced angioedema before and thus present significantly later for care.
For these reasons, the utility of HAE therapies for patients with ACE inhibitor-induced angioedema may be limited, and we cannot
recommend their use in most situations. However, we propose that there are uncommon scenarios in which the clinician may consider
their use. As an example, if a patient presents with severe angioedema that is threatening the airway and actively worsening, has no
history of previous angioedema, is on ACE inhibitor therapy, and can receive one of the HAE therapies within the first few hours from
symptom onset, then we would advocate its use.
A more detailed discussion of each of the therapies, including dose, administration, and adverse effects, is found separately. (See
"Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse
reactions'.)
Tranexamic acid — A retrospective review evaluated 33 patients presenting for emergency care with severe angioedema while taking
an ACE inhibitor, who were treated with either intravenous or oral tranexamic acid as an initial therapy [76]. Doses ranged from 0.5
grams to 4 grams, with most patients receiving 1 gram. Improvement was observed within one hour in 13 of 33 patients, and
tranexamic acid was sufficient to manage the angioedema in 27, while 6 showed partial improvement and were then given either
icatibant (5) or C1 inhibitor concentrate (1). None required intubation.
Ecallantide — Ecallantide is a recombinant protein that is approved for use in acute treatment of HAE attacks. Ecallantide inhibits the
conversion of high molecular weight kininogen to bradykinin by inhibiting plasma kallikrein (figure 1). However, ACE inhibitor-induced
angioedema is caused by the persistence of bradykinin due to lack of metabolism, rather than overproduction, so it is not entirely
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intuitive that ecallantide would be effective [32]. The evidence that ecallantide is of benefit in the treatment of ACE inhibitor-induced
angioedema is mixed [77,78]:
● One randomized trial found no difference in the amount of time required for patients to be safely discharged following treatment
with either ecallantide (at doses of 10 mg, 30 mg, or 60 mg) or placebo [78]. The study included 76 adults who developed
angioedema while taking an ACE inhibitor and presented for emergency care within 12 hours of symptom onset.
● Another randomized trial of 50 adults assigned subjects to ecallantide (30 mg) or placebo (in addition to conventional therapy with
glucocorticoids and antihistamines), required that subjects presented within 12 hours of symptom-onset and developed worsening
symptoms or did not improve during two hours of initial observation [77]. The primary endpoint was eligibility for discharge within
four hours of treatment. Discharge criteria were met in 31 versus 21 percent of subjects receiving ecallantide and placebo,
respectively (95% CI, –14 to 34 percent). Thus, there appeared to be some benefit to therapy, although confidence intervals
overlapped no effect.
(See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor (United States only)'.)
Purified C1 inhibitor concentrate — Purified C1 inhibitor concentrate has appeared helpful for ACE inhibitor-induced angioedema in
case reports [79-83]. One of the functions of C1 inhibitor is the inhibition of kallikrein. Similar to icatibant, this therapy is most likely to
be beneficial if given within a few hours of symptom onset. (See 'Icatibant' below.)
Dosing is reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'C1 inhibitor (plasma-
derived)' and "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)
Fresh frozen plasma — Plasma (solvent detergent-treated plasma or fresh frozen plasma) contains the enzyme ACE, and the
administration of plasma is thought to degrade high levels of bradykinin with subsequent resolution of angioedema. The usual dose of
plasma is 2 units for adults. In the reports described, swelling usually resolved within two to four hours of plasma administration. Case
reports have described administration of fresh frozen plasma leading to rapid improvement of ACE inhibitor-induced angioedema
without further recurrence of symptoms [84-86]. However, the levels of ACE in individual units of plasma can vary significantly [87]. The
usual dose of plasma is 2 units for adults. In the reports described, swelling usually resolved within two to four hours of plasma
administration. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)
Icatibant — Icatibant is a synthetic bradykinin B2-receptor antagonist that is approved for the acute treatment of HAE attacks (figure
1). Case reports, small series, and one randomized trial initially provided initial support for the use of icatibant for ACE inhibitor-induced
angioedema [62,73,88-94]. However, this was followed by two larger randomized trials with negative results, such that the cumulative
data do not support the use of icatibant [74,75].
DISCHARGE COUNSELING
Patients who have experienced ACE inhibitor-induced angioedema should be educated about the following:
● The need to avoid all ACE inhibitors in the future.

● The risk of recurrent episodes of angioedema in the first few months after the ACE inhibitor is discontinued. (See 'Recurrence'
below.)
● The need to determine if a replacement therapy is needed for the condition that the ACE inhibitor was treating.
Written instructions — A handout for patients who have experienced ACE inhibitor-induced angioedema is provided. (See 'Information
for patients' below.)
RECURRENCE
Some patients experience one or more recurrent angioedema episodes in the months after the causative ACE inhibitor has been
discontinued. In a long-term retrospective study, 111 patients with ACE inhibitor-induced angioedema were followed for at least 1 year
and up to 14 years [34]. After stopping the ACE inhibitor, 46 percent had recurrences of angioedema. In 88 percent of patients with
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recurrences, episodes occurred within the first month after the ACE inhibitor was discontinued, although recurrences continued for six
months or more in other patients. However, in cases where angioedema persisted beyond several weeks, it is also possible that ACE
inhibitors were not the true culprit or that the patient had an underlying predisposition to develop angioedema that was exacerbated
(but not entirely caused) by the presence of an ACE inhibitor.
FUTURE USE OF RELATED DRUGS
Drugs mechanistically related to ACE inhibitors include angiotensin-receptor blockers (ARBs), the combination of an ARB and a
neprilysin inhibitor (known as angiotensin receptor-neprilysin inhibitor or ARNI), renin inhibitors, and dipeptidyl peptidase-4 (DPP-4)
inhibitors.
Angiotensin II receptor blockers — Angiotensin-II receptor blockers (ARBs) have cardioprotective effects that are similar to those of
ACE inhibitors. Although earlier systematic reviews described a 1.5 to 10 percent rate of recurrent angioedema in patients with a history
of ACE inhibitor-induced angioedema who were switched to an ARB [95,96], subsequent studies have not found ARBs to be associated
with higher rates of angioedema than other antihypertensives (eg, beta blockers) [6,9,97]. The findings of earlier studies may be
attributable to the phenomena discussed previously, ie, that patients with ACE inhibitor-induced angioedema who are switched to ARBs
may have one or more additional episodes of angioedema in the ensuing weeks to months that are still due to the lingering effects of
the discontinued drug. (See 'Recurrence' above.)
From a pharmacologic perspective, ARBs do not interfere as directly with bradykinin metabolism (figure 1). Therefore, we do not believe
that ARBs should be avoided in patients with ACE inhibitor-induced angioedema if ARB therapy offers an advantage over other
antihypertensives for that individual patient.
The following studies found a low incidence of angioedema in patients receiving ARBs [6,9,97]:
● A nationwide cohort study found that among 5507 patients with prior ACE inhibitor-induced angioedema, the incidence of
angioedema was significantly lower in patients treated with ARBs than in those treated with other antihypertensive agents (beta
blockers, calcium channel blockers, or thiazides) (adjusted hazard ratio 0.39; 95% CI 0.30-0.51) [97].
● In a meta-analysis of data from 19 trials, the overall incidence of angioedema with ARBs was not significantly different from
placebo [9]. This analysis included 35,479 patients (mean age 61 years, 59 percent men) of whom 52 developed angioedema
during a mean duration of 120 weeks, for a weighted incidence of 0.11 percent (95% CI 0.09-0.13).
When changing patients from an ACE inhibitor to an ARB, we specifically explain that they could have a recurrence of angioedema and
review with them how to proceed if this should occur. Written instructions are provided. (See 'Information for patients' below.)
Another approach is to wait four to six weeks after an ACE inhibitor is discontinued before starting an ARB. However, this is only
appropriate if the patient can safely go without the medication for this period of time.
ARNIs — Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor combination drug (ARNI) used in the management of heart
failure with reduced ejection fraction. ARNIs should not be given to patients with previous angioedema to an ACE inhibitor, because
they cause angioedema at rates similar to ACE inhibitors (0.5 percent versus 0.2 percent with enalapril in the PARADIGM-HF trial) [98].
The incidence of angioedema in Black patients was significantly higher (2.4 percent with sacubitril-valsartan and 0.5 percent with
enalapril). (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Angioedema'.)
Renin inhibitors — More clinical experience with the use of renin inhibitors is needed to understand the risk of angioedema with these
agents. Until more information is available, caution is warranted. Aliskiren was the first oral direct-renin inhibitor approved by the US
Food and Drug Administration (FDA) in 2007 for the treatment of hypertension, and several other direct-renin inhibitors are in the early
stages of development [99]. Renin inhibitors are thought to provide a more comprehensive inhibition of the renin-angiotensin system
compared with ACE inhibitors and ARBs and appear to have different safety profiles. Theoretically, aliskiren should not confer a risk of
bradykinin-induced angioedema, because unlike ACE inhibitors, it has no known effect on bradykinin metabolism. In a case series, a
patient with life-threatening angioedema while receiving an ACE inhibitor did not experience subsequent angioedema episodes when
treated with long-term aliskiren [100].
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Despite the above conceptual differences between ACE inhibitors and renin inhibitors, angioedema has been reported with aliskiren
[6,9,101,102]:
● In a meta-analysis that pooled data from 12 randomized-controlled trials of 12,188 patients treated with aliskiren for hypertension,
the incidence of angioedema with aliskiren treatment was 0.4 percent and similar to the risk with ACE inhibitors [102].
● A subsequent study followed 4867 adult patients initiated on aliskiren therapy, among whom there were seven associated
angioedema events and one case of serious angioedema [6].
● In a meta-analysis of 5141 patients on aliskiren, 7 developed angioedema during a mean duration of 24 weeks with an incidence of
0.13 percent (95% CI 0.07-0.19) [9].
(See "Renin-angiotensin system inhibition in the treatment of hypertension", section on 'Direct renin inhibitors'.)
Dipeptidyl peptidase-4 inhibitors — The dipeptidyl peptidase-4 (DPP-4) inhibitors are a group of medications used in the management
of type 2 diabetes. Sitagliptin, saxagliptin, and linagliptin are available in the United States and often used in combination with ACE
inhibitor and ARB therapy [103,104]. The incidence and prevalence of DPP-4 inhibitor-associated angioedema is unknown. However,
health care providers should be aware that angioedema has been associated with DPP-4 inhibitors, either alone or when used
concomitantly with certain classes of medications, including ACE inhibitors and ARBs [103,105-107]. The proposed mechanism is
reduced clearance of bradykinin, because DPP-4 is an enzyme that is involved in bradykinin metabolism (figure 1). (See "Dipeptidyl
peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
NSAIDs — Nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate some bradykinin-mediated forms of angioedema, but clear
evidence of this in patients with an episode of ACE inhibitor-induced angioedema is lacking. Therefore, we do not counsel patients to
avoid NSAIDs in the future, unless the episodes of angioedema continue to occur after approximately six months. (See 'Recurrence'
above.)
REFERRAL
Indications for referral to an allergy specialist include the following:
● Patients in whom complement protein 4 (C4) levels were measured and found to be low.
● Patients in whom angioedema continues to occur beyond the first few months after ACE inhibitor discontinuation, as such patients
may have underlying disorders that predispose to angioedema (eg, acquired C1 inhibitor deficiency). (See 'Differential diagnosis'
above.)
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients.
(You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
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● Basics topics (see "Patient education: Angioedema caused by ACE inhibitor medicines (The Basics)")
● The overall incidence of angioedema in patients receiving angiotensin-converting enzyme (ACE) inhibitors is between 0.1 and 0.7
percent. ACE inhibitors are the leading cause of drug-induced angioedema, accounting for up to 40 percent of emergency visits for
angioedema. (See 'Epidemiology' above.)
● ACE inhibitor-induced angioedema usually affects the lips, tongue, and face, although visceral edema presenting as acute
abdominal pain is also possible. Urticaria and itching are absent. Symptoms typically begin during the first week of treatment,
although some cases develop after years of uneventful therapy. (See 'Clinical features' above.)
● The clinical features of ACE inhibitor-induced angioedema are related to elevated levels of bradykinin, an inflammatory vasoactive
peptide, which leads to vasodilation of blood vessels. The risk of angioedema with an ACE inhibitor is not related to agent or dose.
Lower levels or defects in enzymes that degrade bradykinin and similar compounds may predispose certain patients to
angioedema, which is one identified reason that patients of African descent are more susceptible. (See 'Pathophysiology' above
and 'Risk factors' above.)
● The diagnosis of ACE inhibitor-induced angioedema is made clinically, as there are no definitive laboratory tests that are routinely
available to diagnose ACE inhibitor-induced angioedema. Resolution following discontinuation of the ACE inhibitor confirms the
diagnosis. (See 'Diagnosis' above.)
● The primary acute treatment of ACE inhibitor-induced angioedema is supportive care until the angioedema resolves. Careful
attention to the airway is critical if tongue or laryngeal swelling is present, because airway obstruction occurs in up to 10 percent of
cases. Intubation and mechanical ventilation may be required. (See 'Management' above.)
● Therapies for hereditary angioedema (HAE), a disorder that is also bradykinin-mediated, may be beneficial in ACE inhibitor-induced
angioedema, but studies are conflicting and early administration appears to be critical, such that the real world utility of these
agents is limited. Thus, we do not advocate using them in most situations. However, for the rare patient who presents with severe
and worsening angioedema potentially compromising the airway, in whom symptoms began no more than approximately six hours
earlier, bradykinin-targeting therapies may be beneficial. (See 'Therapies of unproven efficacy' above.)
● Patients should be counseled that angioedema can recur in the first few months after stopping an ACE inhibitor and given advice
about how to proceed if symptoms develop again. A patient handout is provided. (See 'Information for patients' above.)
● In patients with a history of ACE inhibitor-induced angioedema, we suggest not avoiding angiotensin-receptor blockers (ARBs) if an
ARB has advantages over other agents for that patient (Grade 2C). (See 'Angiotensin II receptor blockers' above.)
● Angioedema has been reported with angiotensin receptor-neprilysin inhibitor (ARNIs) at rates comparable with those with ACE
inhibitors, and ARNIs should not be given to patients with previous ACE inhibitor-induced angioedema. Caution is warranted with
several other related drugs, including renin inhibitors and dipeptidyl peptidase-4 (DDP-4) inhibitors (eg, sitagliptin, saxagliptin, and
linagliptin), although data are limited. (See 'Future use of related drugs' above.)
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GRAPHICS
ACE inhibitor-induced angioedema
ACE: angiotensin-converting enzyme.
From: Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced
angioedema. Otolaryngol Head Neck Surg 2007; 137:931. Copyright © 2007. Reprinted by permission of SAGE
Publications.
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Pathways involved in bradykinin (BK)-mediated angioedema
Demonstration of the pathways involved in BK-mediated angioedema and the medications that target their peptidases. When the drugs in orange circles inhibit these peptidases, they
prevent the breakdown of BK, allowing BK to accumulate and stimulate its receptor B2, leading to vasodilation, increased vascular permeability, and angioedema. The drugs in blue
rectangles are inhibitors of BK accumulation and can be used for the treatment of BK-mediated angioedema.
BK: Bradykinin; B2: bradykinin type 2 receptor; ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker.
Original figure modified for this publication. From: Hudey SN, Westermann-Clark E, Lockey RF. Cardiovascular and Diabetic Medications That Cause Bradykinin-Mediated Angioedema. J Allergy Clin Immunol Pract
2017; 5:610. Illustration used with the permission of Elsevier Inc. All rights reserved.
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Angioedema disorder C4* C1-INH level C1-INH function C1q Other tests
Hereditary angioedema with Low Low Low Normal Genetic testing

C1-INH deficiency type I (usually <50% of normal) (not needed for diagnosis)
(HAE-C1-INH
type I)
Hereditary angioedema with Low Normal or elevated Low Normal Genetic testing
C1INH deficiency type II (usually <50% of normal) (not needed for diagnosis)
(HAE-C1-INH type II)
Hereditary angioedema with Normal Normal Normal Normal Mutations in gene for factor
factor XII gene mutations XII
(HAE-FXII)
angiopoietin-1 gene angiopoietin-1
mutations (HAE-ANGPT1)
plasminogen gene plasminogen
mutations (HAE-PLG)
kininogen-1 gene mutations kininogen-1
(HAE-KNG1)
Hereditary angioedema of Normal Normal Normal Normal

unknown origin (HAE-U)
Acquired angioedema with Low Normal or low Low Normal or low ¶ Anti-C1INH antibodies
C1INH deficiency (AAE-C1- (usually <50% of normal) (not needed for diagnosis)
INH)

acquired angioedema
(histaminergic or
nonhistaminergic)
(AAE-IH or AAE-InH)

Terminology for angioedema disorders is evolving, and the abbreviations HAE-C1-INH and C1INH-HAE are both used for hereditary angioedema in the
literature.
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Types of bradykinin-mediated angioedema
Differential diagnosis of bradykinin-mediated angioedema.
HAE: hereditary angioedema; ACE: angiotensin-converting enzyme.
Reproduced from: Vasekar M, Craig TJ. ACE inhibitor-induced angioedema. Curr Allergy Asthma Rep
2012; 12:72. Copyright © 2012; with kind permission from Springer Science + Business Media B.V.
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Physical (inducible) forms of urticaria

Authors: John P Dice, MD, Erika Gonzalez-Reyes, MD
Section Editors: Sarbjit Saini, MD, Craig A Elmets, MD
INTRODUCTION
Physical urticarias are disorders in which urticaria (ie, hives or wheals) are induced by environmental
stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. The
term "inducible urticaria" was preferred by a 2018 international guideline [1]. These disorders
probably result from heightened sensitivity by the mast cell to environmental conditions, although
the exact pathogenesis is unknown.
An urticarial lesion is an intensely pruritic, circumscribed, raised, erythematous plaque, which can
range in diameter from a few millimeters to many centimeters (picture 1 and picture 2). Urticaria may
enlarge, sometimes developing central pallor, and coalesce with other adjacent lesions. They usually
appear in crops and are typically short-lived, expanding and then resolving over a few hours without
leaving residual marks on the skin (unless there is trauma from scratching).
Inducible urticarias, except cold urticaria, will be discussed in this topic review. Other disorders of
acute and chronic spontaneous urticaria and cold urticaria are reviewed separately. (See "New-onset
urticaria" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and
natural history" and "Chronic spontaneous urticaria: Standard management and patient education"
and "Cold urticaria".)
GENERAL POINTS ABOUT INDUCIBLE URTICARIAS
Before discussing individual syndromes, it is helpful to review some observations about the inducible
urticaria disorders as a group.
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Inducible urticarias are considered subtypes of chronic urticaria. In some patients, a specific
physical stimulus is the only trigger for hives, whereas in others, a physical stimulus is an identifiable
factor in a case of otherwise idiopathic chronic urticaria (also called chronic spontaneous urticaria).
A minority of patients have hives triggered by multiple physical stimuli.
Prevalence — The inducible urticarias, considered as a group, are present in a subset of patients with
chronic urticaria, which afflicts approximately 1 percent of adults. Inducible urticarias are present in
20 to 30 percent of adults with chronic urticaria and also occur in children, although there are fewer
reports about this population [2]. The overall prevalence in the general population is not well-defined,
and many cases may be mild and easily managed in the primary care setting. In contrast, most
published reports are based upon patient populations referred to specialty centers, and so they may
overestimate the severity and persistence of these disorders.
Classification — There are differences among experts concerning the best manner of classifying the
inducible urticarias. Guidelines for classification and diagnosis have been published by an
international expert panel [1]. The material in this topic review is similar, although not identical.
Variations in clinical presentation and severity — Inducible urticarias vary widely in severity. The
symptoms of each syndrome can range from mild to disabling, with some patients experiencing
potentially dangerous systemic symptoms.
Testing — Specific testing procedures are presented in the discussions of each disorder below and
summarized in the table (table 1) [3]. However, there are some general points to consider in
performing challenge procedures for inducible urticarias.
Precautions — Physical challenges are not always needed for diagnosis, although they are
sometimes invaluable in clarifying or confirming the diagnosis. These challenges are usually
performed by allergy specialists with training in the management of the systemic allergic reactions
that could conceivably result in anaphylaxis. Proper access to the staff and equipment necessary to
treat a potentially life-threatening allergic reaction is essential. This is especially true if the patient
has experienced systemic symptoms in the past (eg, bronchospasm or hypotension).
During these challenges, physical stimuli are applied to the skin for a specified amount of time
(usually a few minutes) and then removed. Urticaria typically develops after removal of the stimulus.
Leaving the stimulus in contact with the skin until urticaria or angioedema actually appear can result
in excessive exposure and systemic symptoms. Similarly, exposure time may need to be reduced in
patients who describe unusual levels of sensitivity.
When to refer — Patients suspected of having a syndrome of inducible urticaria should be referred to
an allergy or dermatology specialist with experience in these disorders in the following situations:
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● The diagnosis is not apparent.
● The condition does not respond adequately to initial therapy.
Referral is usually appropriate if a challenge procedure is being considered. Patients with past
systemic reactions/anaphylaxis should be referred to allergists specifically because there is
potential risk involved in challenging such patients and because they can educate patients about
how to manage possible recurrent anaphylaxis, including use of an epinephrine autoinjector. (See
"Long-term management of patients with anaphylaxis", section on 'Preparing the patient to treat
possible recurrences'.)
OVERVIEW OF TREATMENT APPROACH
The treatment of inducible urticarias should be approached in a stepwise manner. Avoidance of the
physical stimuli that induce symptoms should always be considered initially, although complete
avoidance may not be possible or practical.
Pharmacologic therapy is often required but variably successful. Certain types of inducible urticarias
(eg, dermographism) are responsive to antihistamines, while other forms (eg, local heat urticaria) are
typically resistant. However, therapy must be individualized in each case, often by trial and error. In
addition, most studies of therapy in these disorders were performed with first-generation, sedating
H1 antihistamines, and the relative effectiveness of the newer second-generation drugs has not been
evaluated.
Antihistamines — In patients with an inducible urticaria disorder who cannot avoid the stimulus, a
trial of antihistamines is warranted. The approach outlined here is opinion-based, since trials
comparing different regimens are lacking.
● Second-generation H1 antihistamine – We usually begin with a second-generation H1

antihistamine at standard doses but quickly increase to double the standard dose (eg, cetirizine
10 mg twice daily, fexofenadine 180 mg twice daily, or loratadine 10 mg twice daily), if needed. In
chronic spontaneous urticaria, doses up to four times the standard have been shown to be safe
and effective, and this can be applied to more difficult cases of inducible urticaria also [4].
● H2 antihistamine – If symptoms are not controlled, we add an H2 antihistamine at standard

dose (eg, famotidine 20 mg twice daily). If there is no detectable improvement, the H2
antihistamine can be discontinued.
● Hydroxyzine – This agent may be dosed once at bedtime or alternatively in divided doses
throughout the day. Adults may be given 10 or 25 mg initially at bedtime and increased in weekly
increments as tolerated, typically up to a maximum of 100 mg as a single dose before bedtime.
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Alternatively, total daily doses of up to 100 to 200 mg may be given, divided into three or four
doses in a 24-hour period. Sedating antihistamines may be used cautiously in children. Children
≥6 years of age may be given up to 50 to 100 mg per day in divided doses.
● Doxepin – Doxepin is a tricyclic antidepressant with antihistaminergic properties at low doses.

In adults, doxepin may be initiated at 10 or 25 mg and increased in weekly increments up to 100
to 150 mg, given once at bedtime or alternatively in divided doses throughout the day. Doxepin is
generally avoided in children <12 years of age due to limited clinical experience. (See "Chronic
antihistamines'.)
Symptoms refractory to antihistamines — The US Food and Drug Administration (FDA) approval of
the monoclonal antibody omalizumab in 2014 for patients with chronic idiopathic urticaria refractory
to antihistamines has given providers a new option for disease management. Patients who fail to
respond to avoidance of the triggering stimulus combined with safe and practical doses of a second-
generation antihistamine should be considered candidates for chronic therapy with omalizumab. A
number of case series or case reports have demonstrated that omalizumab is safe and effective in
patients with a wide variety of inducible urticarias. The most impressive data have been found for
patients with dermatographism, cold urticaria, delayed-pressure urticaria, and solar urticarias [5].
Data are more limited for other types of inducible urticarias, but omalizumab should remain an
option for these patients. Nonresponders sometimes occur despite the therapy. Other therapies for
refractory disease, depending upon the specific disorder, include glucocorticoids, phototherapy,
physical desensitization protocols, and immunomodulatory agents (eg, cyclosporine, dapsone).
Case reports for each type of inducible urticaria are discussed in the appropriate sections below. It is
the practice of the authors to use omalizumab for inducible urticaria in patients who have failed to
respond adequately to a trial of avoidance of the offending trigger combined with a safe and
practical dose of a second-generation antihistamine (ie, typically four times the standard dose).
Oral glucocorticoids may be used for short-term treatment and are usually very effective. This is
most commonly appropriate for the persistent symptoms of delayed-pressure urticaria, as the
urticarial lesions of many of the other types of inducible urticarias are short-lived. We typically
continue antihistamines and begin glucocorticoid therapy with prednisone, 0.5 to 1.0 mg/kg daily.
Symptoms usually improve within days. The dose can then be tapered gradually over two to four
weeks to discontinuation or at least to <10 mg per day. If the prednisone cannot be reduced to <10
mg per day after two to four weeks or stopped entirely within two to three months, then an alternate,
steroid-sparing agent should be considered, as the long-term side effects of glucocorticoids make
chronic therapy undesirable. (See "Major side effects of systemic glucocorticoids".)
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Agents that have been found to be useful for particular inducible urticaria syndromes are discussed
in the sections below, as are alternate therapies for refractory disease. The treatment of chronic
spontaneous urticaria is reviewed in detail separately. (See "Chronic spontaneous urticaria: Standard
management and patient education" and "Chronic spontaneous urticaria: Treatment of refractory
symptoms".)
DERMOGRAPHISM
Dermographism (also called dermatographism, urticaria factitia, or dermographic urticaria) literally

means to "write on the skin." Patients with this condition develop the rapid onset of a wheal-and-flare
reaction after firm stroking, scratching, or the application of pressure to the skin. Dermographism is
the most common of the inducible urticarias and is often an incidental finding in the evaluation of
other skin conditions, most commonly atopic dermatitis, chronic spontaneous urticaria, and the
other inducible urticarias discussed in this topic.
There are several forms of dermographism (picture 3 and picture 4):
● Simple dermographism is the more common disorder, in which raised urticarial welts form on
the skin with scratching or other stroking, but the skin is not pruritic.
● Symptomatic dermographism is less common. In this disorder, the affected skin shows
urticarial welts and is pruritic.
Epidemiology — Simple dermographism is thought to occur in approximately 2 to 5 percent of the

general population [6,7]. The symptomatic forms of dermographism are much less common and
usually occur sporadically, although there is a single case report of familial dermographism [8].
Clinical features — In simple dermographism, a wheal is provoked by stroking, scratching, or rubbing

the skin. The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30 minutes later
[6]. Symptomatic dermographism is only slightly different, with lesions appearing in less than 5
minutes and lasting 30 minutes [9]. In addition to classic wheals, variants of symptomatic
dermographism have been described in which the reactions are follicular [10] or inflamed and
swollen (red dermographism) [11].
Although a purposeful stroking of the skin is the most common way to elicit symptoms, patients
often are unaware of the inciting action. Occasionally, idiopathic pruritus or pruritus caused by dry
skin can be the event that elicits scratching and subsequent dermographism. In this setting, the
wheals are typically linear. Simple actions, such as scratching, leaning against a solid object, or
irritation from clothes or bed sheets, may provoke whealing. In one case series, dermographism
could be exacerbated by hot water, emotion, exercise, or cold exposure [12].
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Dermographism is typically idiopathic and begins without a clear inciting event. However,
inflammatory perturbations may occasionally precede onset, as cases have been described in which
symptomatic dermographism appeared to be triggered by infections with bacteria, fungi, viruses, and
scabies [13,14] or after receiving penicillin [15] or famotidine [16].
Pathogenesis — The cause of dermographism is unknown. The release of vasoactive mediators from
cutaneous mast cells is assumed to be involved, and elevated levels of serum histamine have been
demonstrated after a whealing episode [17]. Experiments in which serum from a dermographic
patient injected intradermally into a monkey transferred dermographism suggest that the reaction
may be immunoglobulin (Ig)E-mediated, although no allergen has been identified [17,18].
Diagnostic testing — In simple dermographism, a wheal is provoked by stroking the skin with a clean,
firm object (table 1). The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30
minutes later [6]. Special testing devices are available [3,19]. The patient should refrain from taking
antihistamines for several days before the test.
Treatment — Simple dermographism that is nonpruritic requires no therapy, and treatment involves
avoidance of inciting triggers. If the skin appears dry, emollients (such as hydrated petrolatum
applied daily immediately after bathing) can be helpful.
Therapies for symptomatic dermatographism:
● H1 antihistamines have been shown to be effective for treatment of pruritus and reduction of
whealing and are the initial drug of choice. Both first-generation antihistamines, such as
hydroxyzine, and second-generation H1 antihistamines, such as cetirizine, have demonstrated
benefit, although studies comparing different antihistamine regimens are lacking [11,20-22].
It is the authors' practice to initiate therapy for symptomatic dermographism with second-
generation H1 antihistamines as described above. (See 'Overview of treatment approach'
above.)
● The addition of an H2 antihistamine was beneficial in several studies [21,23,24], although not all
concluded that there was an additive effect [17]. A trial of combination therapy with an H1 and
H2 antihistamine is warranted if the response to H1 antihistamines alone is inadequate.
● Some patients report that sun exposure improves the condition, and one uncontrolled study of
43 patients reported that 39 improved or cleared with ultraviolet B light treatment [25]. Such
aggressive therapy could be considered in a patient refractory to standard medications and with
a severe decrease in quality of life (eg, poor sleep, poor performance at work or school, negative
effect on social life).
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● Case reports describe successful treatment with omalizumab [26].
DELAYED-PRESSURE URTICARIA/ANGIOEDEMA
Delayed-pressure urticaria/angioedema (which is sometimes classified as a delayed form of

symptomatic dermographism) presents most commonly as an erythematous swelling of the skin
that develops four to six hours after sustained pressure has been applied to the area.
Clinical manifestations — The leading presentation is erythematous swelling of the skin 4 to 6 hours
after the application of pressure, although the time to onset of symptoms may be as little as 30
minutes or as long as 12 hours. Less often, patients develop urticaria with prominent swelling. The
amount of pressure that is needed to induce symptoms varies among different individuals. Patients
often describe burning and pain instead of, or in addition to, pruritus, and the swelling can last
several hours to several days [3,6]. There may be accompanying arthralgias [13].
Activities that typically induce symptoms in patients with delayed-pressure angioedema include
wearing tight clothing (affecting areas of constriction), sitting for prolonged periods of time on a hard
surface (affecting the buttocks), an extended period of walking (affecting the soles and feet), or
carrying heavy bags of groceries (affecting the palms and hands). Some patients will wake up with
facial swelling on the side of the face that was compressed against the pillow.
Diagnosis — Delayed-pressure urticaria/angioedema can often be accurately diagnosed based upon

historical features alone. Devices called dermographometers have been used in research protocols
in the past but are not widely available [27,28]. Diagnostic maneuvers are not standardized, and the
amount of weight used varies, but one approach is to attach a sling to a 10-pound weight and place
this over the patient's arm for 20 minutes [29]. Alternatively, a 5-kg rod may be laid across the
patient's forearms for 20 minutes [3]. Once the weight is removed, the patient is instructed to observe
the compressed skin for symptoms over the next 24 hours (table 1). The delayed appearance of
erythematous palpable swelling is a positive result. The patient should refrain from taking
antihistamines for several days before the test.
Treatment — Delayed-pressure urticaria/angioedema can be challenging to treat, and symptoms

often do not respond to antihistamines alone. Antileukotriene agents have also shown utility [30-32].
In a randomized trial of 36 patients with delayed-pressure urticaria confirmed by challenge with a

dermographometer (18 of whom had concomitant chronic spontaneous urticaria), patients were
assigned to one of three treatment groups [32]:
● Oral desloratadine (5 mg once daily) plus oral placebo

● Oral desloratadine (5 mg once daily) plus montelukast (10 mg once daily)
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● Oral placebo alone
Subjects were rechallenged after two weeks of therapy. Patients in both active treatment groups
showed a significant reduction in the mean diameter of the induced wheals compared with placebo,
and patients in the group receiving montelukast were significantly better than those receiving
desloratadine alone, with fewer episodes and reduced symptoms. The use of other antihistamines in
combination with montelukast has not been studied, although different agents are probably also
effective.
Several case studies describe successful treatment with omalizumab, although nonresponders are
common [33,34].
Other agents that have been used with some success to manage this disorder include montelukast,
dapsone, chloroquine, sulfasalazine, intravenous immune globulin, nonsteroidal anti-inflammatory
drugs, tumor necrosis factor inhibitors, and omalizumab [30,35-41].
CHOLINERGIC URTICARIA
Cholinergic urticaria (sometimes called generalized heat urticaria) describes hives with a
characteristic appearance that are precipitated by active or passive heating of the body, exercise,
strong emotions, and bathing in hot water [42]. Some classification systems do not include
cholinergic urticaria with other forms of inducible urticaria, because the trigger is internal rather than
environmental [3].
Epidemiology — Cholinergic urticaria is believed to account for approximately 30 percent of all cases
of inducible urticaria and approximately 5 percent of all cases of chronic spontaneous urticaria [43].
Cholinergic urticaria typically has its onset during the second or third decade of life [44-46]. Whereas
one study noted a predominance in male patients [44], others have found that both sexes are
affected equally [45,46]. Familial cases are rare but have been reported (in which all affected
individuals were male) [47].
Clinical features — The classic initial appearance of cholinergic urticaria is that of numerous, small
(1 to 3 mm) punctate wheals surrounded by large flares (picture 5). Many patients note a tingling,
itching, or burning sensation of the skin before the appearance of the hives [44]. As the response
progresses, the flares may coalesce to form large areas of erythema. The wheals typically begin on
the trunk and neck and spread distally to involve the face and extremities, although lesions may
begin anywhere on the body. Uncommonly, cholinergic urticaria may progress to include systemic
symptoms, such as hypotension, angioedema, and bronchospasm [44,48-50]. In a series of 19
patients with cholinergic urticaria associated with anaphylaxis, the majority of patients were young
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women. Patients experienced a mean of nine episodes per year, triggered most consistently by high
ambient temperatures, strenuous exertion, and stress [50].
Any trigger that results in an elevation of core body temperature may provoke the onset of
cholinergic urticaria. Exercise and hot, humid environments are some of the most common triggers.
Other typical inciting factors for cholinergic urticaria include hot baths or showers, strong emotional
feelings, and ingestion of spicy or hot foods [44,45]. In one study, a patient with pre-existing
cholinergic urticaria experienced a flare of his condition while undergoing dialysis treatments [51]. A
decrease in the patient's dialysate temperature by 1.5°C (2.7°F) led to resolution of his symptoms,
and rechallenge with fluid at a higher temperature reproduced his urticaria.
Theories of pathogenesis — As with many of the other inducible urticarias, a variety of pathogenetic
mechanisms have been postulated in cholinergic urticaria, and there may be different mechanisms
at work in different patients. Elevated levels of histamine have been detected in the serum during an
attack [49]. The precise trigger for the onset of urticaria is not clear.
● One theory of pathogenesis proposed that urticaria in this condition was caused by the
cholinergic nervous system [48]. In some patients, the injection of methacholine intradermally
induces urticaria, which can be reversed by administration of atropine [44,52,53]. Patients with
cholinergic urticaria have been shown to have an increased number of muscarinic receptors on
cutaneous mast cells in areas that demonstrate hives [54].
● The presence of a more typical antigen-antibody reaction or a transferable serum factor has
been investigated in a series of passive transfer experiments using sera from patients with
cholinergic urticaria that were injected into the skin of a primate [55]. When the primate was
subsequently injected with acetylcholine, a cutaneous reaction was observed with 7 of 16
patient sera. (See 'Diagnosis and testing' below.)
● Many of the triggers for cholinergic urticaria also lead to increased sweating, and it is possible
that the immediate trigger for urticaria formation is something that occurs during sweating,
rather than shifts in core body temperature [56].
Several studies have suggested that cholinergic urticaria might be caused by an IgE-mediated
allergy to some component of human sweat [57-60]. Some patients demonstrate immediate
reactions to skin testing with their own diluted sweat [57,60,61]. An IgE-mediated mechanism
was also implicated in a case report of a patient successfully treated with anti-IgE therapy [59].
Another found that a group of 18 patients with cholinergic urticaria appeared to have two
separate mechanisms for their condition [58]. One subset of patients had positive skin test
results to his/her own sweat and had a positive acetylcholine skin test, whereas these tests
were negative in the other patients.
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● There have been several reports of patients with cholinergic urticaria that was associated with
hypohidrosis [62,63]. An explanation was proposed that occlusion of the pores of the stratum
corneum could cause hypohidrosis and subsequent abnormal leakage of inflammatory sweat
materials into the upper dermis, resulting in a whealing reaction [63].
Diagnostic testing — The presentation of the lesions of classic cholinergic urticaria in the context of
typical inciting triggers is often sufficient to make the diagnosis, and a clinical diagnosis is usually all
that is required in routine practice. However, several methods of provocation testing have been
proposed, which are largely used in research settings (table 1):
● Passive heat challenge – Another diagnostic strategy used in research protocols involves
nonexertional elevation of the patient's core body temperature. Patients may have one or both
arms submerged in a 40°C (104°F) hot water bath until the core body temperature has increased
at least 0.7°C (33.3°F) [64]. The appearance of generalized urticaria (ie, not limited to the water-
exposed skin) confirms the diagnosis of cholinergic urticaria.
● Exercise challenge – One group has described the measurement of both core temperature and
skin temperature while subjects perform 30 minutes of exercise on a stationary bicycle to
achieve a specified heart rate [56]. In a group of 10 patients with cholinergic urticaria, onset of
urticaria was found to correlate with sweating, rather than rise in temperature. These results
warrant replication in larger numbers of patients.
● Combination challenges – A two-step approach to differentiating cholinergic urticaria from

exercise-induced urticaria has been proposed [3]. This involves first performing an exercise
challenge (treadmill or stationary bicycle) to the point of sweating and for 15 minutes beyond.
Wearing warm clothing and/or keeping the room warm facilitates the elicitation of symptoms. A
positive test consists of the appearance of suggestive skin changes. If the exercise challenge is
positive, then the next step is to perform a passive heat challenge. This should take place no
earlier than 24 hours later. For this step, the patient's torso and limbs are submerged in a 42°C
(107.6°F) bath for up to 15 minutes while recording body temperature to ensure a rise of ≥1°C
(≥33.8°F). The development of symptoms with both types of challenge is diagnostic of
cholinergic urticaria, while the elicitation of symptoms only with exercise is diagnostic of
exercise-induced urticaria.
● Intradermal methacholine – An intradermal injection of 0.01 mg of methacholine in 0.1 mL

saline that produces a local area of hives is diagnostic. However, only about one-third of patients
with cholinergic urticaria demonstrate a positive test, so this procedure cannot be used to
exclude the diagnosis [44,52]. In addition, there are no injectable forms of methacholine
commercially available in the United States.
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Differential diagnosis — Cholinergic urticaria/anaphylaxis may be confused with exercise-induced
urticaria or anaphylaxis if other triggers are not considered. However, the two conditions can usually
be distinguished because a variety of triggers precipitate cholinergic urticaria, including passive
heating of the body, while exercise or exertion is the primary trigger for exercise-induced urticaria or
anaphylaxis. (See 'Exercise-induced urticaria/anaphylaxis' below.)
Treatment — Identification and avoidance of known triggers are the first steps in controlling
cholinergic urticaria. Bathing in hot water and performing strenuous exercise during hot weather are
to be avoided.
The following pharmacotherapies have been studied:
● Medical therapy consists predominantly of oral H1 antihistamines. Typically, these are taken
daily, although as-needed administration is possible if triggers are easy to identify in advance.
We usually initiate therapy with a second-generation antihistamine, as described previously.
Cetirizine, a less sedating metabolite of hydroxyzine, has shown efficacy at doses twice normal
(10 mg twice daily). (See 'Overview of treatment approach' above.)
● If cetirizine at twice normal dose is not effective, we typically change to the first-generation
antihistamine, hydroxyzine, which has been used successfully for decades [7,45]. This agent is
highly sedating for some patients. Therapy should be initiated with a low dose, which is
increased gradually until the urticaria is controlled. This typically occurs at doses of 100 to 200
mg divided over 24 hours. Studies comparing the hydroxyzine with cetirizine have not been
performed, but clinical experience suggests that some patients who do not respond to cetirizine
do respond to hydroxyzine.
● Omalizumab has been used successfully in the treatment of cholinergic urticaria [59,61],
although failures are also reported [65].
● Ketotifen (not available in the United States) has also shown efficacy in treating cholinergic
urticaria at doses of 3 to 8 mg daily [66,67]. This agent is highly sedating for some patients.
● Oral anticholinergic agents have also been evaluated. An initial report described no consistent
benefit with atropine and hexamethonium [45]. However, in two case reports, scopolamine
butylbromide (10 mg orally, three times daily) was effective in combination with antihistamines
[68,69].
● The anabolic steroid, danazol, can be effective [70,71]. This agent is postulated to correct the
low blood levels of protease inhibitors that occur in some patients with cholinergic urticaria [72].
Given its potential for adverse effects, however, this medication should be reserved only for
severe cases refractory to antihistamines.
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Desensitization may be possible, as patients will sometimes experience a period of latency after an
episode of cholinergic urticaria. In most cases, these relatively symptom-free periods lasted only a
few hours but could last more than 24 hours if the initial episode was severe. One study described
two patients who treated themselves on a nightly basis using a dose of antihistamine that was
followed three hours later by a hot bath [45].
Prognosis — The prognosis for cholinergic urticaria is generally favorable. One study reported only
31 percent of patients with a persistence of symptoms greater than 10 years [44]. Another estimated
that the average duration of symptoms is 7.5 years (range, 3 to 16 years) [73].
EXERCISE-INDUCED URTICARIA/ANAPHYLAXIS
Urticaria with exercise has been shown to occur in two distinct situations.
● Cholinergic urticaria – Patients with cholinergic urticaria develop hives after exercising or after
experiencing any other trigger that elevates core body temperature. Systemic symptoms are
uncommon but can occur. (See 'Cholinergic urticaria' above.)
● Exercise-induced anaphylaxis – Urticaria with exercise may also be an early manifestation of

exercise-induced anaphylaxis. Unlike in cholinergic urticaria, exercise is the only trigger in
exercise-induced anaphylaxis, and passively raising the core body temperature is not sufficient
to induce symptoms. In addition, the hives of exercise-induced anaphylaxis are typically larger in
size than those of cholinergic urticaria. This disorder is reviewed in detail elsewhere. (See
"Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and
diagnosis".)
LOCAL HEAT URTICARIA
Local heat urticaria describes a rare disorder in which a warm stimulus must come into direct
contact with the skin and results in the formation of a wheal at the heated site within minutes [29].
The pathogenesis involves histamine release, implicating the mast cell in the cause of this condition
[74]. Passive transfer experiments, however, have been negative. There is one case report of a
familial, delayed-type variant of local heat urticaria [75].
Diagnostic testing is conducted by the application of a test tube containing water at 44°C (111.2°F)
to the arm for four to five minutes [29]. Other protocols use a cylinder heated to 50 to 55°C (122 to
131°F) (table 1) [64]. A localized hive should develop within a few minutes after removal of the
heated object. The patient should refrain from taking antihistamines for several days before the test.
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Occasionally, a positive test can only be obtained on specific areas of skin that have displayed
symptoms in the past [76].
Therapy using antihistamines and oral cromolyn has generally not been effective for local heat
urticaria [29]. However, there may be individual patients who respond to the combination of H1 and
H2 antihistamines [77]. Desensitization using daily hot baths was successful in one patient but
carries some risk for a systemic reaction [78].
AQUAGENIC URTICARIA
Aquagenic urticaria is a rare condition in which urticaria develop as a result of direct skin contact
with water.
Epidemiology — There are fewer than 50 cases of aquagenic urticaria reported in the medical
literature [9,79-83]. Women seem to have a slightly higher incidence than men, and in most cases, the
age of onset is during or slightly after puberty. Familial occurrences have been reported on several
occasions [80-82,84]. In one report, the condition existed across three generations of a single family
[80].
Clinical features — In aquagenic urticaria, hives appear rapidly after direct contact with various
sources of water (ie, distilled, tap, or saline), regardless of the temperature of the water. The lesions
of aquagenic urticaria are characteristically small, punctate (1 to 3 mm), perifollicular wheals that
may occur on all parts of the body, although generally not on the palms and soles. In appearance,
they are indistinguishable from the wheals of cholinergic urticaria.
In some patients, salinity appears to be important. One patient experienced urticaria after exposure
to tap water, snow, and sweat but did not develop symptoms after exposure to sea water [85].
Another developed hives on exposure to sea water but not fresh water, although over time, she also
became sensitive to tap water as well [86]. Hive formation is not influenced by the temperature or pH
of the water [83]. Alcohol and other liquid organic solvents applied to the skin do not lead to wheal
formation [82,83]. However, they can potentiate the reaction to water, possibly by enhancing the
permeability of the skin [87].
Wheals appear rapidly within 20 to 30 minutes following exposure to water. Once the water source is
removed from the skin, the wheals generally fade within 30 to 60 minutes [9]. Systemic symptoms
are rare but have been reported [81,88]. A refractory period lasting several hours has been
demonstrated after an attack [89]. Repeated, short, purposeful exposures to water can lead to
exhaustion of the wheal response [87].
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Aquagenic urticaria is occasionally associated with other forms of inducible urticaria. Case reports
describe patients with aquagenic urticaria and coexisting dermographism [81,90], cholinergic
urticaria [82,89,90], or cold urticaria [91].
Pathogenesis — The pathogenesis of this condition is poorly understood and may not be the same in
all patients. Several theories have been proposed based upon studies in small numbers of subjects.
Serum histamine levels are variable from patient to patient, as is the response to pretreatment with
oral antihistamines. The studies reviewed below were performed before the publication of those
implicating hypersensitivity to sweat allergens in cholinergic urticaria, and comparative mechanistic
studies of the two conditions have not been undertaken. (See 'Cholinergic urticaria' above.)
The following mechanisms have been postulated:
● Several researchers have proposed that water is primarily acting as a solvent in aquagenic
urticaria, solubilizing an antigen that then permeates the skin and activates dermal mast cells.
Water may interact with sebum (the oily substance produced by sebaceous glands in the skin)
to form a substance capable of acting as a direct mast cell degranulator, resulting in histamine
release [79]. One study demonstrated that patch testing with a patient's sweat produced only
erythema, whereas testing with sweat and sebum produced marked urticaria [83]. Others have
proposed that the causative antigen(s) normally resides at the epidermal layer of the skin, and
solubilization in water allows this antigen to diffuse more deeply into the skin [82]. It is possible
that different antigens in different skin layers are involved.
In another study, removal of the stratum corneum layer of the skin enhanced reactivity upon
contact with water [87]. Similarly, pretreatment of the skin with organic solvents enhanced wheal
formation to water. These investigators concluded that enhancing the ability of water to
penetrate the stratum corneum layer of the skin increases the wheal-provoking effects of water
in these patients.
● Another theory suggested that activation of the cholinergic pathway was essential for the
formation of aquagenic urticaria, based upon the ability of scopolamine (an acetylcholine
antagonist) to suppress wheal formation when applied to the skin before water exposure in two
patients [87]. However, other studies did not find evidence for a cholinergic mechanism, as
pretreatment with atropine did not suppress subsequent wheal formation [82]. In addition,
methacholine injection testing, often positive in cholinergic urticaria, was negative in a series of
patients with aquagenic urticaria [83].
Diagnostic testing — The standard test for aquagenic urticaria is the application of a compress of
35°C (95°F) water to the upper body for 30 minutes (table 1). Although water of any temperature can
provoke aquagenic urticaria, using ambient-temperature water avoids confusion with cold-induced or
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local heat urticaria. The upper body is chosen as the preferred site because other areas, such as the
extremities, are affected less commonly in aquagenic urticaria [92]. The patient should refrain from
taking antihistamines for several days before the test.
In some case reports, rinsing specific areas of the body with water or performing direct bath and
shower challenges has been attempted. Use of these approaches may be required when localized
testing using a small water compress is negative, although it should be avoided in patients with a
history of significant systemic symptoms.
Differential diagnosis — Aquagenic pruritus, cholinergic urticaria, cold-induced urticaria, and local
heat urticaria may have inciting factors that can be confused with those of aquagenic urticaria.
● Aquagenic pruritus is itching of the skin upon contact with water, without the development of
actual hives or other objective findings [93].
● Cholinergic urticaria can be elicited by sweating, exercise, heat, and strong emotions, whereas
aquagenic urticaria requires the skin to be in direct contact with water. (See 'Cholinergic
urticaria' above.)
● Cold-induced urticaria can be differentiated from aquagenic urticaria by the history of reactions
upon exposure to cold air and tolerance of warm or hot water. (See "Cold urticaria".)
● Local heat urticaria can be distinguished from aquagenic pruritus by reactions to warm but dry
triggers (heating pad or test tube filled with warm water). (See 'Local heat urticaria' above.)
Treatment — A trial of H1 antihistamines is warranted in all patients as an initial intervention,

although the success of these agents is variable [87,94,95]. Other reported therapies include the
following:
● A single case report on the use of omalizumab in aquagenic urticaria reported success in a
patient with a refractory condition. The patient responded after only two doses and remained
symptom-free even when all other medications were discontinued [96].
● Propranolol at doses of 10 to 40 mg daily was reported to be effective in five of six patients in a

small series [97]. In another report, two patients were successfully treated [98].
● Ultraviolet B light treatments twice per week in a child with coexisting aquagenic urticaria,
cholinergic urticaria, and dermographism resulted in improvement by 20 weeks [90]. Two reports
have documented the benefits of psoralen plus ultraviolet A therapy [99,100].
● Stanozolol was effective in a patient with HIV infection, hepatitis C virus infection, and
aquagenic urticaria, who had failed therapy with oral antihistamines [88]. Symptoms recurred
2143
when stanozolol was stopped.
● Barrier creams were reported to be effective in a small number of patients, although this may
only be practical in very specific circumstances [87,92,101].
● A low dose of a selective serotonin reuptake inhibitor, in combination with cyproheptadine and
methscopolamine, was effective in one case report [102].
SOLAR URTICARIA
Solar urticaria involves the induction of urticaria, most commonly following direct exposure of the
skin to sunlight [103]. The number of patients affected by this condition is small, and most data are
case reports and small series [104-107]. The largest series included 87 cases confirmed by
phototesting [108].
Epidemiology — Retrospective reviews of patients with urticaria found that only approximately 0.5
percent were classified as solar urticaria [104,105]. There is a higher incidence in women [106,108].
Patient age at onset, atopic history, and the wavelength of light responsible for the reaction may vary
significantly. Geographic and racial differences have not been described.
Clinical features — Solar urticaria generally presents with classic-appearing urticarial lesions,
developing within minutes after exposure to direct sunlight and occurring on skin that was
uncovered (picture 6). However, in the series of 87 cases, 76 and 83 percent developed symptoms
through thin clothing and glass, respectively [108]. Limited exposures provoke only itching or burning
erythema, while more prolonged exposures lead to typical wheals. A more delayed onset of
symptoms (several hours after light exposure) has been reported in a few patients [109,110].
The severity of the symptoms generally increases with the intensity of the sun exposure. Areas of
skin that frequently are exposed to sunlight are less sensitive than areas that are usually covered
[111]. The exact mechanism of this "hardening" phenomenon remains unknown [112]. A more severe
reaction may be provoked by purposeful sunbathing rather than by normal daily sunlight exposure.
Systemic anaphylactic reactions are possible if the exposed body surface area is large enough [7].
When the patient is removed from the sun exposure, symptoms usually fade rapidly. Most patients
note disappearance of the urticaria within 24 hours.
Pathogenesis — It has been hypothesized that solar urticaria is dependent on the presence in the
skin of a precursor molecule that is activated by exposure to a particular wavelength of light and
becomes a photoallergen. This antigen can be activated in vivo or in vitro by irradiating a sample of
the patient's serum [106]. The origin of the precursor molecule has not been determined. The fact
2144
that passive transfer is not always successful could indicate that there are different photoallergens
at work in different patients. Different classification systems have been proposed [113]. One group
has suggested that the disorder be divided into two subtypes: type I solar urticaria, due to IgE
antibodies directed against an abnormal photoallergen present only in affected patients and type II
solar urticaria, due to circulating IgE antibodies against a normal photoallergen present in most
people [114].
Diagnosis and testing — Clinical history may be sufficient to differentiate solar urticaria from other
conditions. If there is clinical uncertainty, the diagnosis can be established using phototesting (table
1). The patient should refrain from taking antihistamines for several days before the test.
A simple form of testing may be performed by exposing a small area of the patient's skin to natural
sunlight, which induces erythema or urticaria. The reaction generally fades quickly after the test is
halted. However, patients with cholinergic or local heat urticaria might react to this type of testing as
well.
More formal evaluation is performed with light sources that emit specific wavelengths of light.
Ultraviolet A (UVA) and ultraviolet B (UVB) light sources are available for this purpose. In certain
instances, it may be necessary to evaluate visible light sources as well [115]. Most patients
demonstrate a threshold wavelength at which symptoms develop, which is referred to as the action
spectrum. In some patients, testing with monochromatic light failed to provoke urticaria, although
exposure to other light sources, such as natural sunlight, high-intensity ultraviolet light, or slide-
projector light, did cause symptoms [107]. These methods are unlikely to be practical for most
clinicians but are mentioned for academic and research interest.
In some patients, there is a spectrum of light (an inhibition spectrum), which when applied to the skin
during or immediately after the action spectrum, inhibits the development of wheals [116]. However,
application of the inhibition spectrum before the action spectrum does not prevent symptoms [106],
so this phenomenon has no immediate clinical utility.
Differential diagnosis — A variety of photosensitive disorders has been described. The symptoms of
solar urticaria could initially be mistaken for common sunburn. However, the lesions of solar urticaria
develop within minutes of sun exposure. Two other disorders that can present with symptoms
similar to solar urticaria are polymorphous light eruption and erythropoietic protoporphyria:
● Polymorphous light eruption – In this idiopathic condition, which is far more common than solar
urticaria, pruritic, papular, and papular-vesicular lesions appear on sun-exposed areas, although
there is less of a predilection for the face (picture 7 and picture 8). In northern climates, patients
may develop symptoms with the first full sun exposure of the season. The lesions of
polymorphous light eruption tend to last two to six days, which usually allows differentiation
2145
from solar urticaria, in which lesions resolve within 24 hours. (See "Polymorphous light
eruption".)
● Erythropoietic protoporphyria – Erythropoietic protoporphyria (EPP) can present as acute,

nonblistering induration and swelling of sun-exposed skin, although the skin is typically painful
(often extremely so) rather than pruritic. EPP usually presents in early childhood, and there may
be a family history of the disorder. The cutaneous lesions of EPP can develop within minutes of
sun exposure, and diffuse edema of the skin in sun-exposed areas may resemble angioedema.
Petechiae and purpuric lesions may be seen (picture 9). With time, the skin may become
lichenified and leathery, with labial grooving and nail changes. This disorder is reviewed
separately. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)
● Drug-induced phototoxicity – Phototoxicity results from direct tissue or cellular damage

following ultraviolet irradiation of a phototoxic agent that has been ingested or applied to the
skin. The reaction is not immune-mediated and can occur in any individual in whom the
threshold concentration of the chemical or drug has been reached. Common culprits include
tetracyclines and thiazides. Phototoxic reactions appear as an exaggerated sunburn (picture
10A-C). In severe cases, vesicles or bullae may form. The reaction usually evolves within
minutes to hours of sun exposure and is restricted to exposed skin. Drug-induced toxicity can
usually be distinguished from solar urticaria, as patients with the former are taking a
photosensitizing medication and complain of burning rather than pruritus. In some situations,
phototesting may be necessary to differentiate between the two disorders. (See
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and
treatment", section on 'Phototoxicity'.)
● Photoallergic reactions – Photoallergic reactions are a form of contact dermatitis caused by an

antigen that has become allergenic as a result of exposure to ultraviolet radiation. Photoallergic
reactions are typically pruritic, eczematous eruptions in sun-exposed areas of skin. The
responsible mechanism is delayed-type hypersensitivity, with symptoms developing 24 to 48
hours after sun exposure, which is significantly more delayed than solar urticaria. Photoallergic
reactions are most common with topical agents (eg, sunscreen, antimicrobials), although
systemic agents (eg, quinidine) can also cause these reactions (picture 11). (See
"Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and
treatment", section on 'Photoallergy'.)
● Cutaneous lupus erythematosus – Cutaneous forms of systemic lupus erythematosus (SLE)

may develop initially after exposure to ultraviolet light and appear years before other
manifestations of the disease. Cutaneous SLE most commonly presents with a characteristic
facial eruption (butterfly rash) or (less commonly) as a generalized eruption. Biopsy of affected
2146
skin can distinguish this from solar urticaria. In addition, lesions of cutaneous lupus are more
persistent than solar urticaria. (See "Overview of cutaneous lupus erythematosus".)
● Brachioradial pruritus – Brachioradial pruritus presents as localized pruritus involving the

proximal dorsolateral forearm. The pathogenesis is unclear, although it is often thought to be a
localized neuropathic pruritus of the arms and forearms that can also involve the shoulders and
neck. Symptoms may be intermittent, unilateral, or bilateral. Sun exposure may be a contributing
factor, as affected individuals often state that sun exposure provokes the disease. People with
brachioradial pruritus complain of burning and stinging rather than pruritus and do not have any
cutaneous lesions, only the discomfort. (See "Pruritus: Etiology and patient evaluation", section
on 'Brachioradial pruritus'.)
Treatment — H1 antihistamines provide symptomatic treatment and can be used orally or topically.
These medications are effective in reducing pruritus and wheal formation but may not eliminate the
erythema. In most of the initial studies, terfenadine was used, and higher than standard doses often
were required to achieve symptom relief [115,117]. Whether this finding is true for all antihistamines,
including some of the newer agents, remains to be determined. Topical and systemic glucocorticoids
can be used if antihistamines are insufficient. (See 'Overview of treatment approach' above.)
When antihistamines provide inadequate relief, other treatment approaches may be considered:
● Omalizumab (anti-IgE therapy) has been shown to be of benefit in multiple studies [34,118-121].
Solar urticaria can be particularly difficult to treat as sun avoidance is extremely difficult to
manage, and antihistamines are often of limited benefit. With its high likelihood of benefit and
low risk of adverse effects compared with other agents, the use of omalizumab should be
considered early in the treatment plan.
● Desensitization may be useful in some cases [122]. It has been demonstrated that skin that is
regularly exposed to sunlight becomes less reactive than that which is usually covered [111].
Patients may be repeatedly exposed to ultraviolet light sources, although the desensitized state
typically lasts only a few days.
● The use of psoralen plus ultraviolet A (PUVA) radiation and narrowband UVB has been shown to
induce a longer-lasting effect, although the potential long-term adverse effects are greater
[117,123].
● Intravenous immune globulin at doses ranging from 1.4 to 2.5 g per kg given over two to five
days has been reported as helpful in a small number of patients, although not in others
[124,125].
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● At least one instance of the successful use of cyclosporine (4.5 mg per kg per day) for refractory
solar urticaria has been reported [126].
● Plasmapheresis has been used alone and in conjunction with PUVA therapy [127-129]. This
modality has been reported to improve symptoms in the few patients included in these studies.
One study failed to demonstrate a lasting benefit with plasmapheresis [130]. The effectiveness
of this therapy may depend on the characteristics of the specific photoallergen at work (ie,
circulating antigen versus cutaneous antigen).
● Future possible therapeutic options include a melanocyte-stimulating hormone that has shown
an ability to decrease hive formation under laboratory conditions [131].
Prognosis — The long-term outlook for patients with solar urticaria has been uncertain because of
the small number of cases. A review of 87 patients found that 25 percent of 60 subjects who were
available for follow-up reported complete resolution of their conditions [108]. An additional 32
percent reported improvement, whereas 35 percent were unchanged, and 8 percent believed that
their conditions had worsened. Most of the original case reports indicated that the condition was
persistent, and although many experienced overall improvement in symptoms, few patients
experienced complete resolution.
VIBRATORY ANGIOEDEMA AND URTICARIA
Vibratory angioedema refers to the development of pruritus and swelling after the application of a
vibratory stimulus to the skin. Hives are usually not observed in this syndrome. Vibratory urticaria, in
which patients do have distinct hives, sometimes accompanied by systemic symptoms, has also
been described [132].
Epidemiology — Vibratory angioedema and urticaria are rare disorders. Familial forms of the
condition, with autosomal dominant inheritance, have been reported [133,134]. Other case reports
describe patients with vibratory symptoms that are not familial but rather related to the subject's
occupation.
Clinical features — Common triggers for vibratory angioedema or urticaria include mowing the lawn,
riding a motorcycle, horseback riding, or mountain biking. At-risk occupations include jackhammer
operator, machinist [135], carpenter [135], and metal grinder [136]. Patients generally complain of
local pruritus, erythema, and swelling arising within a few minutes after exposure to vibration and
affecting the area that was most exposed to the stimulus (often the hands). There are rare cases of
delayed-onset symptoms beginning 1 to 2 hours after exposure [137]. Symptoms peak in severity at
4 to 6 hours and typically resolve by 24 hours. In some episodes, the symptoms may persist for
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several days. The severity and duration of the symptoms may vary and seem to be proportional to
the intensity and duration of the applied vibratory stimulus and to the area of exposed body surface.
An early report described systemic symptoms of headache and generalized erythema [133]. Another
report described a severe case with accompanying dizziness, tachycardia, and hypotension [138].
One patient developed carpal tunnel syndrome and slowed median nerve conduction that was
documented only during episodes of edema [136].
In autosomal dominant vibratory urticaria, a mutation was found in three unrelated Lebanese
families with multiple members exhibiting vibratory urticaria symptoms [132]. All patients
experienced localized, pruritic urticaria in response to repetitive mechanical stimulation of the skin.
Some patients also experienced facial flushing, headache, or the sensation of a metallic taste. All
patients tested negative for dermographism using standard protocols.
Pathogenesis — The pathogenesis of sporadic vibratory angioedema has not been satisfactorily
elucidated. Elevated levels of serum histamine and mast cell degranulation have been documented
during symptomatic episodes [135,137,139]. Most investigators favor a nonimmunologic reaction
(eg, direct mast cell stimulation from the vibration causes degranulation and local release of
histamine), and passive transfer experiments have been negative [133,139]. In a study of vibration
exercise in 37 healthy subjects, approximately one-half developed a pruritic erythematous eruption
[140].
In autosomal dominant vibratory urticaria, a gain-of-function mutation in the gene ADGRE2 (adhesion
G protein-coupled receptor E2, also called EMR2) has been implicated [132]. ADGRE2 encodes a cell
surface receptor that is normally inhibitory on mast cells, but the mutated form renders the cell
susceptible to degranulation following exposure to vibration. This receptor may be a component of
an innate immune response to noxious physical stimuli.
Diagnostic testing — Several methods for reproducing the vibratory stimulus and classifying the
reaction have been used in the literature [9]. The patient should refrain from taking antihistamines for
several days before the test. The subject's arm is held on a level plane, and a vortex mixer is placed
in contact with the skin (table 1). The vibratory stimulus is applied for 10 minutes, although this may
need to be reduced for very sensitive patients, and the site is observed for five to six hours. The test
is considered positive if the area becomes erythematous, pruritic, and edematous around the full
circumference of the arm, although one study found that this test also induced a positive response in
7 of 20 normal volunteers [141], suggesting that this response may not be entirely abnormal. In
patients with vibratory urticaria the same protocol is used to elicit characteristic wheals.
Dermographism should be excluded using the appropriate tests. At the present time, testing for the
novel genetic mutation is not commercially available. (See 'Dermographism' above and 'Delayed-
pressure urticaria/angioedema' above.)
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Treatment — Patient avoidance of specific vibratory stimuli is the first line of therapy, although this
may not be possible in occupational cases.
H1 antihistamines have been used successfully [142]. In another report, symptoms were refractory to
multiple antihistamines, antileukotriene agents, dapsone, cyclosporine, prednisone, and omalizumab
but eventually responded partially to ketotifen, a strong antihistamine and mast cell stabilizer. This
was given at a dose of 1 to 2 mg twice daily. Ketotifen (not available in the United States) is highly
sedating for some patients.
A state of tolerance was achieved in one patient by using twice daily vibration challenges until
symptoms were delayed in onset and reduced in duration [139]. The patient eventually attained
complete control of her symptoms by using a five-minute desensitization protocol every five to seven
days. However, a state of tolerance could not be induced in another case report [142].
● Basics topic (see "Patient education: Inducible hives (The Basics)")
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● Inducible urticarias are forms of chronic urticaria in which hives (sometimes with angioedema)
are elicited by physical or environmental stimuli. These syndromes often occur in children and
adults with chronic spontaneous urticaria. (See 'General points about inducible urticarias'
above.)
● The more common inducible urticaria syndromes include dermographism, cholinergic urticaria,
and delayed-pressure urticaria/angioedema. (See 'Dermographism' above and 'Delayed-pressure
urticaria/angioedema' above and 'Cholinergic urticaria' above.)
● Rare disorders include urticaria/angioedema following exposure to heat, exercise, water,

sunlight, or vibration. (See 'Local heat urticaria' above and 'Exercise-induced
urticaria/anaphylaxis' above and 'Aquagenic urticaria' above and 'Solar urticaria' above and
'Vibratory angioedema and urticaria' above.)
● Inducible urticarias can often be diagnosed based upon history and physical examination. In
some cases, physical challenge procedures are needed to clarify or confirm the responsible
trigger (table 1). (See 'Testing' above.)
● The management of inducible urticaria begins with accurate identification and avoidance of the
triggering stimulus. (See 'Overview of treatment approach' above.)
● For initial pharmacotherapy for the majority of patients with an inducible urticaria, we suggest a
less sedating, second-generation antihistamine (Grade 2C). Options include cetirizine (10 mg
daily), loratadine (10 mg daily), or fexofenadine (180 mg daily). Many patients will require a
doubling of the standard dose to impact symptoms significantly (eg, cetirizine, 10 mg twice
daily). (See 'Overview of treatment approach' above.)
● If symptoms do not respond adequately to antihistamines, management proceeds in a stepwise

manner and includes H2 antihistamines, first-generation H1 antihistamines, and in some cases,
limited courses of systemic glucocorticoids. (See 'Overview of treatment approach' above.)
● Patients who fail to respond to avoidance of the triggering stimulus combined with safe and
practical doses of a second-generation antihistamine should be considered candidates for
chronic therapy with omalizumab. Other therapies for refractory disease, depending upon the
specific disorder, include phototherapy, physical desensitization protocols, and
immunomodulatory agents. (See 'Symptoms refractory to antihistamines' above.)
2151
2152
GRAPHICS
Urticaria
Urticaria is characterized by circumscribed, raised, erythematous, and extremely pruritic

lesions. They typically appear in one area, resolve over the course of several hours, and
then reappear elsewhere. Individual lesions may enlarge and develop central pallor before
fading.
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Urticaria
Dermal vasodilatation occurs with no epidermal change (scale).
Wilkins.
2154
Inciting factors and diagnostic tests for physical and other inducible urticarias
Disorder Inciting trigger(s) Diagnostic test
Symptomatic Firm stroking, scratching, pressure Moderate stroking of the skin with a blunt, smooth object (eg, closed
dermographism ballpoint pen tip, wooden tongue depressor) or dermographometer.
(urticaria factitia)
Delayed-pressure Application of pressure 0.5 to 12 Sling with weights placed over arm or shoulder for 15 minutes (7 kg
urticaria/angioedema hours before onset of symptoms weight on 3 cm wide shoulder strap). Patient reports symptoms over
next 24 hours.
Dermographometers are used in research (100 grams/mm 2 for 70
seconds).
Cholinergic urticaria Elevation of body temperature Exercise using a machine (stationary bicycle or treadmill) to the point
(exercise, hot water, strong emotion, of sweating. Then, continue for 15 minutes. If this test is positive, then
hot or spicy food) passive heating of one/both arms in 42°C warm water bath to cause
increase in body temperature of ≥1°C.
Some patients may react to skin testing with own sweat.
Cold contact urticaria Exposure of skin to cold air, cold Ice cube test - Melting ice cube in thin plastic bag for 5 minutes.
liquids, or cold objects TempTest where available to determine patient's threshold.
Heat contact urticaria Warm object in direct contact with Application of test tube containing 45°C water or metal cylinder heated
affected skin to 45°C to skin for 5 minutes.
Exercise-induced Physical exertion Treadmill testing.

urticaria/anaphylaxis
Aquagenic urticaria Skin contact with water of any Application of 35°C water in compress to upper body for 30 minutes.
temperature
Salinity of water important in some
cases
Solar urticaria Exposure of skin to sunlight Exposure of normally covered skin to UVA (6 J/cm 2), UVB (60
(triggering wavelengths vary) mJ/cm 2), and visible light (projector).
Vibratory Lawn mowing, riding a motorcycle, Vortex mixer is held against skin for 10 minutes.
urticaria/angioedema horseback riding, mountain biking,
exposure to vibrating machinery,
holding some steering wheels
UVA: ultraviolet A radiation therapy; UVB: ultraviolet B radiation therapy.
Consistent with the recommendations in: Magerl M, Altrichter S, Borzova E, et al. The definition, diagnostic testing, and management of chronic inducible
urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy 2016; 71:780.
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Urticaria: Dermatographism
These lesions of dermatographism developed five minutes after stroking the skin with a
wooden stick.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al. (Eds). Color Atlas and
2156
Dermatographism ("skin writing")
These lesions occurred three minutes after stroking with the wooden tip of a cotton swab.
Wilkins.
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Cholinergic urticaria
Small urticarial papules on red skin (axon reflex erythema) occurring on the neck within 30
minutes of vigorous exercise.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds). Color Atlas and
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Solar urticaria induced by ultraviolet A light
(A) Shoulder before sun exposure.

(B) Shoulder after 15 minutes of sun exposure through a glass window. The glass window filters out
ultraviolet B light.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin Disorders, 2nd Edition.
Philadelphia: Lippincott Williams & Wilkins, 2003. Copyright © 2003 Lippincott Williams & Wilkins.
2159
Polymorphic light eruption
Clusters of confluent, extremely pruritic papules and vesicles on the exposed chest
occurred the day following the first sun exposure of the season. The eruption involved the
dorsum of the arms but spared the face and dorsal hands.
Reproduced with permission from: Fitzpatrick T, Johnson R, Wolff K, et al. Color atlas and synopsis of
clinical dermatology: Common and Serious Diseases, Third Edition, McGraw Hill, New York, 1997.
Copyright © 1997 McGraw-Hill Companies, Inc.
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Polymorphic light eruption
Clusters of pruritic papules and vesicles on the dorsal wrist and arm and an erythematous
plaque on the dorsum of the hand following first sun exposure of the season. The face and
dorsal hand are typically spared.
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Erythropoietic protoporphyria
Diffuse erythematous infiltration of the nose with edema, petechial hemorrhage, and
scattered atrophic scars on the side of the face with telangiectasia.
2162
Phototoxic eruption
Diffuse, sunburn-like erythema is present on the face and ears.
2163
Phototoxic eruption
A bright red, confluent rash on the "V" of the neck of a patient with drug-induced photosensitivity reaction.
2164
Phototoxic eruption
Confluent erythema on the dorsum of the hands following sun exposure in a child taking doxycycline. Note initial
blistering on the right hand and the sparing of the area covered by a watch.
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Photoallergic eruption
This 45-year-old woman developed an acute, well-demarcated, erythematous plaque with

vesicles after topical application of ketoprofen gel followed by sun exposure. The patient
wore socks, which protected the foot from the sun, creating the line of demarcation that is
visible in the image.
2166
Cold urticaria
Author: Marcus Maurer, MD
INTRODUCTION
Cold urticaria, or cold contact urticaria, is a subtype of physical urticaria (table 1) [1-3]. The physical
urticarias are forms of inducible urticaria, in which there is a specific and definite stimulus that
triggers the development of symptoms. Cold urticaria is characterized by pruritic wheals (hives)
and/or angioedema due to cutaneous mast cell degranulation and release of proinflammatory
mediators after cold exposure of the skin. Triggers include skin contact with cold objects, cold
liquids, and cold air. The underlying pathophysiology is largely unknown but is likely to involve
immunoglobulin E (IgE)-mediated mast cell activation [4,5].
Cold urticaria is reviewed here. Other urticaria disorders, including acute and chronic spontaneous
urticaria and other forms of inducible urticaria, including physical urticaria, are discussed separately.
(See "Physical (inducible) forms of urticaria" and "New-onset urticaria" and "Chronic spontaneous
urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Clinical
EPIDEMIOLOGY
Cold urticaria most frequently affects young adults [6,7]. Both sexes are affected with similar
frequency in most studies [6,8-10], although one study reported that females were affected twice as
often as males [7]. Up to one-half of patients with cold urticaria are atopic, and one-fourth have other
types of inducible urticaria, most commonly symptomatic dermographism and cholinergic urticaria
[8,10,11].
2167
The incidence of cold urticaria was estimated to be 0.05 percent in Central Europe [8]. The frequency
of cold urticaria among physical urticaria subtypes varies between 5 and 34 percent, partly
depending on the geographic region (ie, higher incidences are found in regions with colder climates
and lower rates are seen in regions with a warmer climate) [6,8,12,13].
Natural history — Cold urticaria is a self-limited disorder in many patients. Remission, or at least
improvement of symptoms, occurs in 50 percent of patients within five to six years [3,6-8,14]. The
mean time to resolution in one study was 5.6±3.5 years [6]. Recurrence of cold urticaria after
remission is rare. However, some patients have the disorder for many years, and there are variant
forms that appear to be lifelong (eg, familial atypical cold urticaria). (See 'Variant forms' below.)
PATHOGENESIS
Cold urticaria symptoms result from the activation of mast cells, their degranulation, and subsequent
release of histamine and other proinflammatory mediators. Following a cold stimulation test (CST),
cutaneous mast cells in patients with cold urticaria show signs of degranulation, and serum levels of
mast cell mediators are increased [15-17]. This results in pruritus, burning, and erythema from
activation of skin nerves and vasodilation of skin vessels with extravasation causing wheals and
angioedema. On skin biopsy, cold urticaria lacks a late-phase cellular infiltrate, similar to most other
forms of physical urticaria (except delayed pressure urticaria) [18].
A variety of laboratory abnormalities have been found in patients with cold urticaria, including the
following:
● In a small series, the majority of patients with cold urticaria exhibited mast cell-activating anti-
immunoglobulin E (IgE) antibodies [19].
● Associations noted in case reports include cryoglobulinemia, cold agglutinins, anti-lamin-B

antibodies, reduced levels of C1 esterase inhibitor and C4 and increased levels of platelet-
activating factor and platelet factor 4 [20-24].
Associated disorders — A number of diseases have been anecdotally associated with cold urticaria,
largely in case reports. The causal relationship between these various disorders and cold urticaria is
unknown.
● Associations have been reported with various infections, including viral, parasitic, and bacterial
infections. Specific disorders include Lyme disease, hepatitis, infectious mononucleosis, acute
toxoplasmosis, Helicobacter pylori colonization, and human immunodeficiency virus (HIV)
infection [25-29].
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● Cold urticaria has been associated with antecedent Hymenoptera stings, food and drug
intolerance [30], and hematologic, lymphatic, or neoplastic conditions [31,32].
The clinical manifestations of the most common form of cold urticaria consist of cutaneous wheals
and/or angioedema, which form after cold exposure of the skin. A subset of patients develops
systemic reactions. Variant forms have specific characteristic features that can be elicited by a
careful clinical history and provocation testing.
Cutaneous signs and symptoms — Cold urticaria is characterized by the development of wheal-and-
flare skin reactions and/or angioedema after the skin is exposed to cold air, liquids, or objects
(picture 1) [14]. Wheals and angioedema typically develop minutes after exposure and are usually
limited to cold-exposed skin areas. Exposure to cold weather is one of the most common triggers for
symptoms, with variables that include temperature, humidity, and wind chill factor.
Systemic reactions — Extensive cold contact, such as swimming in cold water, may result in
systemic reactions, ranging from generalized urticaria to anaphylaxis, with symptoms involving the
respiratory, gastrointestinal, and/or cardiovascular systems [9]. In a series of 30 children with cold
urticaria seen in a tertiary referral center, one-third had a history of cold-induced anaphylaxis [11]. In
another series of mostly adult patients, also from a tertiary referral clinic, nearly one-third
experienced at least one severe systemic reaction with hypotension and/or respiratory compromise,
and approximately one-half of patients reported milder cutaneous systemic reactions [6]. In these
two studies, almost all patients reported either cutaneous or systemic symptoms triggered by
aquatic activities, whereas only 30 percent experienced symptoms after touching a cold object.
Patients with cold urticaria who participate in aquatic activities (eg, swimming in cold water) are at
risk of death both directly from anaphylaxis and indirectly from drowning during a reaction [7,9,33].
Patients with cold urticaria are also at risk of suffocation due to oropharyngeal angioedema after
consuming cold foods or beverages, although it is unclear how commonly this occurs.
Risk factors for systemic reactions — Some risk factors or predictors of systemic reactions have
been identified:
● In the pediatric study described above, the only risk factor identified was a history of a previous
cold-induced systemic reaction [11].
● In another study, patients with a history of cold-induced oropharyngeal angioedema were at

greater risk of a systemic reaction triggered by swimming, compared with those with a history of
only a few hives after swimming [33].
2169
● Severe systemic reactions may be more frequent in patients <30 years old at disease onset [6].
Physical variables associated with systemic reactions include a greater surface area of skin
exposed, exposure to lower temperatures, and longer duration of cold exposure. Exposure to cold
water or solid objects that are cold is more likely to elicit symptoms than exposure to cold air. We
also advise patients to pay attention to the wind chill factor during cold months, as symptoms will be
more easily triggered on days when the wind chill is significant.
Variant forms — There are several variant forms of cold urticaria (atypical cold urticarias). In a
retrospective review of 74 patients referred to a specialty center, nearly 30 percent of cold urticaria
patients had atypical cold urticaria [34]. In all of these disorders, the standard cold stimulation test
(CST) is negative. Each involves urticarial lesions, although the specific triggers, timing, or location of
the lesions are different from classic cold urticaria. Some are acquired and others are hereditary
[17,35]. Modified types of CST are needed to elicit the signs and symptoms. (See 'Cold stimulation
test' below.)
● Delayed cold urticaria – There are both acquired and hereditary forms of delayed cold urticaria,
all of which are rare. In these disorders, the wheal-and-flare reaction occurs up to 24 hours after
cold exposure [36,37]. Patients have no immediate response to CST but will develop a wheal-
and-flare response at the test site, usually 18 to 24 hours later. In the familial form,
hyperpigmentation typically develops at the site of lesions following resolution.
● Familial atypical cold urticaria – In this disorder, symptoms begin in early childhood and are life-
long [38]. Localized urticaria typically develops on areas exposed to cold air, water, or objects.
Symptoms triggered by cold food and beverages are also common. Systemic inflammatory
symptoms are absent. CSTs were negative in the small number of patients described.
A syndrome of familial cold urticaria related to deletions in the gene for phospholipase C (PLC)-
gamma-2 was described in 2012 [39]. Affected individuals have cold urticaria from childhood,
although symptoms are elicited by evaporative cooling (eg, exposure to cold air or wind), rather
than touching cold objects or water, and autoimmunity and immunodeficiency are each present
in about one-half of patients. Investigators suggested the condition be called PLC-gamma-2-
associated antibody deficiency and immune dysregulation, or PLAID.
● Cold-dependent dermographism – In this variant, the skin becomes dermographic when cooled
[40,41]. To reproduce this, the skin should be stroked firmly while cool and then rewarmed.
● Cold-induced cholinergic urticaria – Patients with this variant develop hives only when
exercising in cold environments [42]. The diagnosis is often made by clinical history alone and
would be confirmed by exercise challenge in a cold room.
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● Systemic cold urticaria – In this form of cold urticaria, generalized urticaria is seen after
systemic cold exposure. This form is not associated with exercise [43]. CST is negative, and the
diagnosis is usually based on clinical history and confirmed by cold exposure in a cold room.
● Localized cold urticaria – Patients with localized cold urticaria develop hives following cold
exposure but only at defined skin sites, such as the face [44,45]. Thus, the CST is positive only if
performed at these sites.
● Food-dependent cold urticaria – Hives develop at the site of the ice cube challenge, but only
after the intake of food [46].
EVALUATION
In a patient with a suggestive clinical history, evaluation consists of a cold stimulation test (CST)
[17,47,48]. Modified types of testing are often needed for variant forms. Laboratory testing is not
needed in routine cases of cold-induced urticaria in children or adults, although it is appropriate if the
patient's symptoms are not typical for cold-induced urticaria or suggest the presence of systemic
disease or an associated condition. (See 'Associated disorders' above and 'Differential diagnosis'
below.)
Cold stimulation test — A CST can be performed by several different methods. All methods involve
the application of a cold object to the skin and then removing the stimulus and allowing the skin to
rewarm. The test is considered positive if the test site shows a palpable and clearly visible wheal-
and-flare skin reaction upon rewarming. The affected site is pruritic and/or associated with a burning
sensation in most cases. The test is considered negative if there is no reaction or erythema or
pruritus/burning only.
Ice cube test — The ice cube test, which requires no special equipment, involves placing an ice
cube and a small amount of water in a thin plastic bag, allowing a few minutes for the ice and water
temperatures to equilibrate and then placing the bag against the skin (usually of the volar forearm)
for 5 minutes [33]. The bag is then removed and response is assessed 10 minutes after removal
(picture 2). This method is readily performed in most offices and has a sensitivity of 83 to 90 percent
and a specificity of 100 percent [7,47]. Longer periods of exposure are rarely needed.
If no wheal has developed, we revisit the history. Sometimes, a variant form of cold urticaria is
present. As an example, we might ask the patient again if there are only certain areas of the body on
which cold-induced wheals and/or angioedema have formed in the past (suggesting localized cold
urticaria). Modified testing can sometimes elicit a positive test. (See 'Variant forms' above.)
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Testing methods that are not recommended — Cold provocation testing using cold packs or cold
water baths is not recommended for first-line screening, because these methods expose larger areas
of skin to cold and may induce systemic reactions [9,17]. Rather, they are usually used to evaluate
patients in whom the ice cube or TempTest method was negative.
Natural exposure testing — In some situations, the most logical way to diagnose a cold-induced
disorder is to ask the patient to re-expose himself/herself to the conditions (eg, cold wind, cold
water) that elicited the signs and symptoms in the first place, if safe and feasible.
Specialized testing devices — TempTest 4.0 is a thermoelectric device that was developed,
validated, and licensed as a commercially available medical product. TempTest 4.0 allows for CSTs,
including threshold measurements, with a continuous gradient of temperatures ranging from 4 to
44°C (39 to 111°F) (picture 3). (See 'Threshold testing' below.)
Threshold testing — The author's approach in patients who show a positive initial test reaction is to
further define a temperature threshold for the individual patient using the TempTest 4.0 device. The
critical temperature threshold is the highest temperature sufficient to induce a positive test reaction
(picture 4) [35]. Threshold testing is not necessary for the diagnosis, although the information can
help patients avoid risky situations by knowing what temperatures are likely to elicit symptoms. It
can also be used to monitor treatment responses without repeatedly exposing the patient to
situations that induce symptoms [49,50].
A study of 45 patients with cold urticaria found a mean (+ standard error of the mean) critical
temperature threshold of 17 (+ 6°C) or approximately 63 (+ 11°F) (range 4 to 27°C or approximately
39 to 81°F) [51]. Thus, patients' thresholds may vary significantly. Patients with higher threshold
temperatures are considered to have more severe disease, although disease severity does not
appear to predict response to antihistamine therapy. (See 'Dose' below.)
One important caveat about threshold determinations is the following. There are no data indicating
that threshold levels are the same whether the area of exposure is localized, such as exposure of the
face to a cold wind, versus a large area, such as submersion in cold water. We advise patients that if
they are faced with a situation in which symptoms might occur (such as swimming in a pool), they
can expose a limited area of the body first (eg, submerge a hand) and then wait to see if symptoms
appear before exposing the rest of the body.
DIAGNOSIS
In a patient with an appropriate clinical history, the diagnosis of cold urticaria is confirmed by the
presence of a positive cold stimulation test (CST). (See 'Cold stimulation test' above.)
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Other disorders in which symptoms are induced by cold exposure include familial cold
autoinflammatory syndrome (FCAS), disorders caused by cold-induced abnormal serum proteins,
and cold-induced urticarial vasculitis (rare) [52]. Cold stimulation tests (CSTs) would be negative if
performed in patients with these disorders. Patients do not develop typical urticaria, distinguishing
these disorders from typical or variant forms of cold urticaria.
● Patients with FCAS present within the first few months of life. The development of a papular
rash after cold exposure is often delayed by up to several hours. This form is associated with
systemic inflammatory symptoms, including fever, conjunctival injection, and arthralgias. The
presence of systemic symptoms distinguishes this disorder from simple cold urticaria. FCAS is
considered a hereditary periodic fever syndrome. (See "Cryopyrin-associated periodic
syndromes and related disorders", section on 'Familial cold autoinflammatory syndrome'.)
● Several other diseases involve abnormal cold-dependent immunoglobulins, including

cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease, and paroxysmal cold
hemoglobinuria. Patients with these disorders do not present with cold urticaria but rather with
signs and symptoms of cutaneous (ie, purpura) or systemic vasculitis, renal disease, or other
organ system manifestations. (See "Overview of cryoglobulins and cryoglobulinemia" and
"Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and
"Cryofibrinogenemia" and "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria".)
REFERRAL
Straightforward cases of cold urticaria may be diagnosed and managed by generalists. We suggest
referral to an allergy/immunology expert if the clinician is not comfortable performing diagnostic
testing and in cases involving systemic symptoms or atypical symptoms or if symptoms prove
difficult to manage. Patients with cold-induced symptoms that are suggestive of an
autoinflammatory or vasculitis disorder should be referred to a specialist.
MANAGEMENT
The management of cold urticaria consists of the following elements:
● Education about the risks of systemic reactions

● Preparation for treatment of acute symptoms
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● Practical advice to avoid cold exposure
● Antihistamine therapy for prophylaxis
Several other adjunctive therapies may also be helpful. (See 'Other pharmacotherapy' below.)
Successful desensitization protocols have been described, but this approach requires daily cold
exposure to maintain the desensitized state and is impractical for most patients. (See 'Cold
desensitization' below.)
Education about high-risk activities and cold avoidance — As soon as the diagnosis has been made,
the clinician should begin to educate the patient about the activities and procedures that may trigger
systemic reactions or serious localized reactions:
● Swimming - Swimming is the activity that most commonly induces systemic symptoms [6,11].
Patients who chose to continue to participate in aquatic activities should expose a limited area
of the body first (eg, submerge a hand) and then wait to see if symptoms appear before
exposing the rest of the body. If a threshold temperature is known for that patient, then they can
more easily avoid lower temperatures. A water temperature above 25°C (77°F) is safe for most
patients [11]. Wetsuits may be helpful, although this has not been formally studied.
● Cold foods and beverages - Consumption of cold foods or beverages can induce oropharyngeal
angioedema or anaphylaxis.
● Surgery - Surgery is another setting in which patients with cold urticaria can develop systemic
reactions [53,54]. The surgery and anesthesia teams should be informed about the patient's
condition and should make efforts to keep the patient sufficiently warm throughout the
procedure. Treatment for any symptoms that may develop should be immediately available.
Premedication with antihistamines could be considered in patients with past systemic reactions
to cold exposure.
● Intravenous fluids and injections - Administration of cold intravenous solutions or injections can
induce symptoms in some patients. Symptoms can develop with vaccines, biologics, and other
injections given intramuscularly or subcutaneously, depending on the temperature and volume.
Intravenous fluids pose the greatest risk and should be prewarmed.
General cold avoidance is recommended, since it is the most logical way to prevent symptoms.
However, avoidance is not always possible. Knowledge of their temperature threshold can help
patients to recognize and avoid critical cold exposure in their daily lives [47]. (See 'Threshold testing'
above.)
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Pretreatment with an antihistamine prior to predictable cold exposure is recommended, because
clinical experience suggests that antihistamine pretreatment can prevent skin reactions and
systemic reactions. In addition, patients of all ages at increased risk of systemic reactions should
have an epinephrine autoinjector readily available and should be trained in its use or in the case of
children, be accompanied by an adult who is trained in its use. (See 'Epinephrine for systemic
symptoms' below.)
Treatment of acute signs and symptoms
Epinephrine for systemic symptoms — Epinephrine is an effective treatment for anaphylaxis

caused by other triggers, and it appears to be effective in this setting as well, based on clinical
experience and case reports [55,56]. We recommend that patients with cold urticaria who have a
history of anaphylaxis, systemic symptoms, frequent and unavoidable cold exposure, and/or a high
temperature threshold be prescribed and carry an epinephrine autoinjector and be taught how and
when to use this device. (See "Prescribing epinephrine for anaphylaxis self-treatment" and
"Anaphylaxis: Emergency treatment" and "Anaphylaxis: Confirming the diagnosis and determining the
cause(s)" and "Patient education: Use of an epinephrine autoinjector (Beyond the Basics)".)
Treatment of milder symptoms — We also recommend that patients carry a few doses of H1
antihistamine for use in treating systemic symptoms that do not require therapy with epinephrine
(eg, extensive urticaria and/or angioedema not involving the airway). Patients with significant
angioedema may benefit from a short course of oral glucocorticoids.
Preventative therapies — Aside from avoidance of cold exposure, H1 antihistamines are the primary
prophylactic therapy for cold urticaria. Other therapies have been reported to be helpful in small
series.
The goal of treatment is to restore a quality of life that is acceptable to that patient. For example,
patients who are content to avoid swimming and other high-risk activities may require minimal
pharmacotherapy, while those who are committed to these activities or have occupations that
routinely expose them to cold may require more extensive therapy. Patients with cold urticaria who
are incompletely treated not only experience avoidable impairment in their quality of life but may also
be at greater risk of developing life-threatening reactions upon cold exposure if they have a history of
systemic reactions. However, the extent to which antihistamines prevent cold-induced systemic
reactions is difficult to predict. The effects of antihistaminic treatment on histamine-induced wheals
do not predict the clinical benefit of treatment in patients [57]. Therefore, patients must also be
prepared to treat these reactions with epinephrine.
H1 antihistamines — H1 antihistamines have been shown in small randomized trials to reduce the
frequency and severity of urticaria/angioedema episodes, as with other forms of chronic urticaria
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[58-63]. (See "Chronic spontaneous urticaria: Standard management and patient education", section
on 'H1 antihistamines'.)
Choice of agent — Nonsedating second-generation H1 antihistamines are preferred for chronic

treatment, although some of these medications may be sedating at higher doses. Several H1
antihistamines have demonstrated efficacy in patients with cold urticaria (eg, loratadine, cetirizine,
desloratadine, ebastine, rupatadine, and bilastine; the last three are not available in the United
States), whereas others have not been studied (eg, levocetirizine and fexofenadine) [58-61,63,64].
Cyproheptadine was commonly used in the past for treatment of cold urticaria. However, this drug is
not known to be superior to other antihistamines for the treatment of cold urticaria, and it has the
well-known adverse effects of the older first-generation antihistamines (eg, sedation, anticholinergic
effects) [65].
Dose — A higher than usual dose of antihistamine (eg, up to four times the daily recommended
dose) is required for sufficient protection from urticarial symptoms in many patients with cold
urticaria [59,60,62,63,66]. We start with the standard daily dose of a nonsedating second-generation
antihistamine and increase it up to four times that dose if the patient continues to experience
symptoms. Recent systematic reviews confirm that greater doses of nonsedating antihistamines are
more effective than standard doses in controlling symptoms and that increasing the dose is not
significantly associated with higher adverse event rates [67].
Studies evaluating the effects of various doses of antihistamines in patients with cold urticaria
● The need for higher than standard doses was demonstrated in a randomized, three-way
crossover trial of 30 patients with cold urticaria who were treated with 5 or 20 mg of
desloratadine or placebo daily (each for 7 days separated by 14-day washout periods) [59].
Response to therapy was assessed by CST using TempTest 4.0. Both antihistamine doses
decreased wheal size 15 and 90 minutes after cold provocation testing, improved the critical
temperature threshold, and increased the critical stimulation time compared with placebo. The
20 mg dose was significantly more effective than the 5 mg dose for each of the endpoints.
Even with higher antihistamine doses, responses are variable and difficult to predict. This was
shown in a subsequent randomized study of 30 patients, in which one-half received 5 mg
desloratadine daily for six weeks, while the other one-half had the dose of desloratadine
increased every two weeks to a maximum of 20 mg daily if symptoms were not controlled [62].
The severity of disease (ie, the higher the eliciting temperature, the more severe the disease)
was assessed at baseline and monitored throughout by CST using the TempTest 4.0 device. No
patient became symptom-free on 5 mg desloratadine, while two became symptom-free on 10
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mg and a further three on 20 mg desloratadine daily. About 20 percent of patients did not
experience any significant improvement, and there was no correlation between initial severity
and response to therapy.
● In a randomized, double-blind trial of 20 patients with cold urticaria, subjects were treated with
different doses of bilastine or placebo in a 12-week crossover study. They received placebo, 20,
40, or 80 mg of bilastine daily, each for 7 days with 14-day washout periods. Bilastine 20 mg (the
standard dose) was highly effective in reducing critical temperature thresholds. Sequentially
increasing the dose to 80 mg significantly increased its effectiveness. At this higher dose, 19 of
20 (95 percent) patients responded to treatment, and 12 of 20 (60 percent) became symptom-
free. Only one patient was refractory to treatment. Microdialysis levels of histamine, interleukin-6
(IL-6), and interleukin-8 (IL-8) assessed one to three hours after cold challenge were significantly
decreased following up-dosing with 80 mg bilastine. Bilastine treatment was well-tolerated
without evidence of increased sedation with dose escalation [63]. Bilastine is not available in the
United States.
● Rupatadine, a nonsedating H1-antihistamine with additional antagonist effects on platelet-

activating factor (PAF), was shown in randomized trials and observational trials to reduce
symptoms of cold urticaria at doses of 20 mg or 40 mg daily [60,68-70]. Rupatadine is not
Treatment of refractory symptoms — In patients with continued symptoms interfering with work
or valued activities despite high-dose H1 antihistamines, treatment options include anti-
immunoglobulin E (IgE) therapy (omalizumab) or cyclosporine.
● Omalizumab has been reported to control symptoms in multiple case reports [4,71-75] and a
placebo-controlled trial [5]. However, omalizumab is only approved in the United States and in
Europe for the treatment of asthma and chronic spontaneous urticaria. Reimbursement for this
costly therapy by third-party payers for use in cold urticaria must be arranged on a patient-by-
patient basis. We initiate therapy at 300 mg every four weeks. Patients who respond to
omalizumab typically do so within a couple of weeks, at which point antihistamines can be
tapered down and discontinued. For patients who do not respond to 300 mg every four weeks,
we increase the dose up to 600 mg. When a patient has responded fully, we typically extend the
dosing interval (to five weeks or six weeks, for example) to see if the patient begins to react to
cold again. If patients appear to be in remission, omalizumab can be discontinued after 12
months. Some patients only need omalizumab in the coldest months of the year. (See "Chronic
spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)
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● Cyclosporine (3 mg/kg daily) with subsequent dose reduction after the first month of treatment
was successful in controlling symptoms in a patient refractory to high-dose antihistamines and
glucocorticoids [76]. The use of cyclosporine in chronic urticaria, including dosing and
monitoring, is reviewed separately. (See "Chronic spontaneous urticaria: Treatment of refractory
symptoms", section on 'Cyclosporine'.)
Other pharmacotherapy — Several other therapies have been administered to patients with cold
urticaria, as noted in case reports:
● Antibiotic therapy was reported to be effective for some patients with cold urticaria in three
observational studies [8,77,78]. In one of these series, 46 percent (13 of 28) of patients treated
with high-dose oral penicillin or tetracycline for two to four weeks went into remission and an
additional 29 percent noted attenuated symptoms [8]. The explanation for the apparent benefit
of antibiotics is unclear, since patients responded regardless of whether an underlying infection
could be detected, and the anti-inflammatory properties of some antibiotics would explain a
temporary benefit but not remission of disease.
In the author's clinic, patients are treated initially (ie, even before prescribing daily
antihistamines) with a three-week course of doxycycline (100 mg twice daily), followed by three
weeks of observation, since the response to treatment usually occurs in the weeks after the
antibiotics are finished. We initially chose doxycycline, because it is safe and inexpensive.
Randomized-controlled trials are needed to assess the efficacy of this treatment, and until better
data are available, we are reluctant to promote the wider use of this approach [78].
● H2 antihistamines (such as famotidine 20 mg twice daily) added to H1 antihistamines are

helpful in some patients [79]. However, other patients experience no apparent benefit, and more
conclusive studies are lacking.
● The addition of the leukotriene antagonists montelukast or zafirlukast appeared to be beneficial

in some patients [80,81], although not in others [82].
● Etanercept and benralizumab have been reported to be of benefit in a single case report each
[83,84].
● Treatment with topical capsaicin, derived from chili peppers, prevented cold urticaria symptoms
for four to seven days in a small case series [85]. Capsaicin treatment results in the depletion of
neuropeptides from sensory nerve fibers that may contribute to the induction of cold urticaria
skin reactions. However, it causes local irritation at the site of application.
● Response to systemic glucocorticoids is variable [76,86]. Most patients do not report

improvement, and this may be related to the absence of a late-phase cellular infiltrate. Those
2178
who do respond usually report only temporary improvement [87]. Thus, glucocorticoids are not
recommended for routine treatment of cold urticaria.
Adjustment and discontinuation of therapy — For patients who have been entirely protected from
cold-induced symptoms for at least six weeks on a higher than standard dose, the dose is then
decreased over several months to the lowest level that provides complete protection. Patients are
continued on a prophylactic antihistamine until they go into remission. The author typically
discontinues the medication after six months to determine if remission has been achieved. Patients
who participate in aquatic activities in the summer usually require year-round treatment, whereas
others may need protection only during the winter months. The author routinely performs threshold
tests with TempTest 4.0 to assess the efficacy of antihistamine therapy.
Cold desensitization — Desensitization to cold (cold "tolerance" induction or hardening) by

repeatedly exposing the patient to baths/showers in cold water is another option for treatment,
although it carries the risk of inducing systemic symptoms and must be performed under a
clinician's supervision. In addition, it is not practical for most patients, because daily cold
showers/baths are required to maintain the desensitized state. Still, several case series suggest that
cold desensitization can be used as therapy [88-90]. Patients are desensitized to the cold by
repeatedly exposing increasingly larger skin areas to incrementally colder water, starting with above-
threshold temperatures. This therapy decreases the critical temperature threshold and protects the
patient from future cold-induced symptoms.
Cold-tolerance induction needs to be initiated with great caution and under a clinician's supervision
because of the risk of severe systemic reactions. While the term "tolerance" is used, "desensitization"
is more appropriate, since discontinuation for as little as a few days results in a complete loss of
protection. Patients need to be informed that daily cold showers/baths are required to maintain the
desensitized state. For this reason, most patients do not continue this therapy for more than a few
weeks to months.
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● Basics topic (see "Patient education: Inducible hives (The Basics)")
● Cold urticaria is a subtype of physical urticaria, characterized by itchy wheals and/or

angioedema due to skin mast cell activation and the release of proinflammatory mediators after
cold exposure (picture 1). The underlying causes are largely unknown. (See 'Epidemiology'
above and 'Pathogenesis' above.)
● Cold urticaria symptoms are usually limited to cold-exposed skin areas and develop within
minutes of cold exposure. However, extensive cold contact may result in systemic reactions.
Occurrence of severe anaphylactic reactions or suffocation due to oropharyngeal edema is
possible. (See 'Clinical manifestations' above.)
● In a patient with an appropriate clinical history, the diagnosis of cold urticaria is confirmed by
the presence of a positive cold stimulation test (CST) (picture 2). In patients with a positive CST,
temperature threshold testing is suggested. Laboratory testing is not needed in routine cases.
(See 'Evaluation' above and 'Diagnosis' above.)
● Most cases of cold urticaria are idiopathic, although a minority is related to an underlying
disorder, such as an infection or a hematologic disorder. Cold-induced systemic inflammation
(eg, fever, arthralgias) or purpuric lesions in response to cold suggest other disorders. (See
'Associated disorders' above and 'Differential diagnosis' above.)
● Avoidance of cold exposure is the best prophylaxis, although complete avoidance is difficult for
most patients. Patients should be educated about high-risk activities and situations, such as
swimming, surgery, and ingestion of cold foods and beverages. (See 'Education about high-risk
activities and cold avoidance' above.)
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● We prescribe epinephrine autoinjectors for those patients with a history of anaphylaxis,
systemic symptoms, frequent or unavoidable cold exposure, and/or a high temperature
threshold. We advise such patients to carry epinephrine at all times and periodically review how
and when to administer it. (See 'Epinephrine for systemic symptoms' above.)
● We recommend nonsedating second-generation H1 antihistamines for patients with cold

urticaria who are unable to sufficiently avoid cold exposure and have frequent symptoms (Grade
1B). We typically begin with the standard dose and increase up to four times this dose, as
needed, to control symptoms. Most patients respond, although some have residual symptoms.
(See 'H1 antihistamines' above.)
● For patients with symptoms refractory to higher doses of H1 antihistamines, we suggest

omalizumab (Grade 2C). Successful treatment with several other therapies has been described
in case reports and may be used if omalizumab is not available. (See 'Treatment of refractory
symptoms' above.)
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GRAPHICS
Inciting factors and diagnostic tests for physical and other inducible urticarias
Disorder Inciting trigger(s) Diagnostic test
Symptomatic Firm stroking, scratching, pressure Moderate stroking of the skin with a blunt, smooth object (eg, closed
dermographism ballpoint pen tip, wooden tongue depressor) or dermographometer.
(urticaria factitia)
Delayed-pressure Application of pressure 0.5 to 12 Sling with weights placed over arm or shoulder for 15 minutes (7 kg
urticaria/angioedema hours before onset of symptoms weight on 3 cm wide shoulder strap). Patient reports symptoms over
next 24 hours.
Dermographometers are used in research (100 grams/mm 2 for 70
seconds).
Cholinergic urticaria Elevation of body temperature Exercise using a machine (stationary bicycle or treadmill) to the point
(exercise, hot water, strong emotion, of sweating. Then, continue for 15 minutes. If this test is positive, then
hot or spicy food) passive heating of one/both arms in 42°C warm water bath to cause
increase in body temperature of ≥1°C.
Some patients may react to skin testing with own sweat.
Cold contact urticaria Exposure of skin to cold air, cold Ice cube test - Melting ice cube in thin plastic bag for 5 minutes.
liquids, or cold objects TempTest where available to determine patient's threshold.
Heat contact urticaria Warm object in direct contact with Application of test tube containing 45°C water or metal cylinder heated
affected skin to 45°C to skin for 5 minutes.
Exercise-induced Physical exertion Treadmill testing.

urticaria/anaphylaxis
Aquagenic urticaria Skin contact with water of any Application of 35°C water in compress to upper body for 30 minutes.
temperature
Salinity of water important in some
cases
Solar urticaria Exposure of skin to sunlight Exposure of normally covered skin to UVA (6 J/cm 2), UVB (60
(triggering wavelengths vary) mJ/cm 2), and visible light (projector).
Vibratory Lawn mowing, riding a motorcycle, Vortex mixer is held against skin for 10 minutes.
urticaria/angioedema horseback riding, mountain biking,
exposure to vibrating machinery,
holding some steering wheels
UVA: ultraviolet A radiation therapy; UVB: ultraviolet B radiation therapy.
Consistent with the recommendations in: Magerl M, Altrichter S, Borzova E, et al. The definition, diagnostic testing, and management of chronic inducible
urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy 2016; 71:780.
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Urticaria
Skin-colored wheals are present.
Wilkins.
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Ice cube test for cold urticaria
This series of photographs illustrates a positive ice cube test in a patient with cold
urticaria. A plastic bag containing an ice cube and a small amount of water is applied to the
volar aspect of the patient's forearm for 5 minutes and then removed. The area of
application is observed and the response is recorded 10 minutes after removal. It is
preferable to use a bag with ice and water rather than applying an ice cube directly to the
skin, since some patients can sustain skin damage at temperatures below 0°C. Refer to the
UpToDate topic on cold urticaria for further discussion of this test and its interpretation.
Courtesy of Marcus Maurer, MD.
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Temperature testing in a patient with cold urticaria using TempTest 4.0
(A) The TempTest 4.0 is a thermoelectric device that is commercially available. It contains a U-shaped
metallic element that is placed against the skin and generates temperatures varying from 4 to 44°C. It is used
to diagnose cold urticaria (and heat urticaria) and to determine critical temperature thresholds.
Threshold information is useful in monitoring a patient's response to therapy.
(B) To perform provocation testing, the volar side of the forearm is laid firmly onto the device along the
temperature applicator so that there is no airspace between the device and the forearm and the temperature
applicator has close contact to the skin along its entire length. The application time is 5 minutes, after which
the patient removes the forearm from the device and the marks from the temperature curve (warm end of
applicator and cold end of the applicator) are noted using a skin marker.
(C) The reading is performed 10 minutes after the end of the test procedure. An evaluation template
(transparent film) is laid on the patient's forearm based on the position of the temperature applicator so that
2185
the markings on the skin and the film are lined up. The contours of the wheal are traced onto the evaluation
template using a waterproof permanent marker.
(D) The transparent film then serves as a permanent record of the test results. The threshold temperature or
the temperature below which symptoms appeared was 18°C in this patient.
Reproduced with permission. Copyright © 2014 Moxie GmbH.
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Photo of cold testing with TempTest 4.0 in a patient with cold urticaria
This photograph shows the forearm of a patient with cold urticaria after the application of the TempTest 4.0 testing
device. This device contains a U-shaped metallic element that generates differential temperatures (from 4 to 44°C). In
this patient, whealing is triggered by temperatures of 24°C and lower.
Courtesy of Marcus Maurer, MD.
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Authors: Jerry D Brewer, MD, MS, FAAD, Mark DP Davis, MD, FAAD
Deputy Editors: Monica Ramirez Curtis, MD, MPH, Abena O Ofori, MD
INTRODUCTION
Urticarial vasculitis (UV) is considered a clinicopathologic entity consisting of two elements:
● Clinical manifestations of urticaria

● Histopathologic evidence of cutaneous leukocytoclastic vasculitis (LCV) of the small vessels,
largely involving the postcapillary venules [1-4]
UV may predominantly involve the skin or affect other organ systems [5]. Hypocomplementemia,
when present, may be associated with extensive vasculitis and systemic features that most
commonly involve the musculoskeletal, pulmonary, renal, and/or gastrointestinal systems. Although
UV is most commonly idiopathic, it can occur in association with autoimmune diseases, drug
reactions, infections, or malignancy. Discussion of UV is confounded by the lack of accepted criteria
for distinguishing UV from other cutaneous vasculitides and associated conditions.
The epidemiology, clinical features, laboratory and biopsy findings, differential diagnosis, treatment,
and prognosis of UV are reviewed here. A more general discussion of urticaria and related conditions
is presented elsewhere. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis,
pathogenesis, and natural history".)
TERMINOLOGY
Urticarial vasculitis (UV) is characterized by a variety of cutaneous, systemic, and serologic features,
which have resulted in a confusing array of names for the disorder(s) [6].
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UV likely represents a continuum of disease, ranging from urticaria with minimal vasculitis, to life- or
organ-threatening systemic vasculitis with minimal urticaria. Some patients have low complement
levels, a feature that is associated with more severe disease and with systemic involvement. By
comparison, patients with normal complement levels are more likely to have mild disease
(sometimes referred to as normocomplementemic urticarial vasculitis [NUV]). The annual incidence
of hypocomplementemic urticarial vasculitis syndrome (HUVS) per million inhabitants in a Swedish
study was estimated to be 0.7 (95% CI 0.4–1.1), 1.3 (95% CI 0.6–1.9) for men and 0.2 (95% CI 0-0.4)
for women [7].
Urticarial vasculitis is sometimes discussed as a clinical feature that is part of another diagnosis,
and sometimes as a primary diagnosis or syndrome. Based upon complement levels and presence
and/or absence of specific systemic findings, the terms that appear with UV as a distinct diagnostic
entity are:
● Hypocomplementemic urticarial vasculitis syndrome (HUVS) [8]

● Hypocomplementemic urticarial vasculitis (HUV) [9]
The distinctions between these two syndromes are discussed below.
Hypocomplementemic urticarial vasculitis syndrome — HUVS has been recognized as a specific

autoimmune disorder involving six or more months of urticaria with hypocomplementemia, in the
presence of various systemic findings [1,8,10-16].
These systemic findings typically include:
● Arthritis or arthralgias
● Mild glomerulonephritis
● Uveitis or episcleritis
● Recurrent abdominal pain
HUVS can occur independently or can be associated with other conditions [5]. (See 'Associated
conditions' below.)
Diagnostic criteria for HUVS have been proposed (table 1) [13]. However, these criteria lack
specificity, and a diagnosis of HUVS should not be made without a skin biopsy. (See 'Diagnosis'
below.)
A biopsy showing cutaneous small vessel vasculitis with a characteristic immunofluorescence

staining is essential to the diagnosis (see 'Immunofluorescence' below). When measured, C1q levels
are frequently found to be low, although the specificity and positive predictive value of this finding
are not clear and patients with systemic lupus erythematosus may also have decreased C1q levels
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[13]. Thus, whether a depressed C1q level is necessary to diagnose HUVS is unresolved. Antibodies
to the collagen-like region of C1q (C1q precipitins) are present in most patients with HUVS. Although
this test is not clinically available , the C1q solid-phase test for immune complexes and the enzyme-
linked immunosorbent assay (ELISA) for anti-C1q autoantibodies give nearly equivalent results
[17,18]. (See 'Pathophysiology' below.)
Hypocomplementemic urticarial vasculitis — HUV is the term used to describe patients with UV and
hypocomplementemia who do not meet diagnostic criteria for HUVS. In general, patients with HUV
have cutaneous disease and few or no systemic manifestations.
PATHOPHYSIOLOGY
Urticarial vasculitis (UV) is believed to result from the formation of immune complexes in the blood
that then deposit in vessel walls. In support of this hypothesis are the findings on skin biopsy (see
'Histology' below), the association of UV with some disorders in which the antigen-antibody
complexes are well defined (eg, hepatitis B, hepatitis C), and the observation that removal of immune
complexes by plasmapheresis is temporally associated with the resolution of the urticarial lesions
[19-21].
The antigens eliciting the formation of antibodies are not known in many cases of UV. Medications
and viruses (particularly hepatitis B and C) have been implicated as the target antigen in some cases
[22,23]. There have also been reports demonstrating the development of UV in association with
infliximab, glatiramer acetate, and the injection of hyaluronic acid dermal filler agents [24-26].
In some patients with UV (particularly those with hypocomplementemic urticarial vasculitis

syndrome [HUVS]), a collagen-like region on C1q has been implicated as the antigenic target [5,19].
The autoantibody is referred to as a C1q precipitin. A causative role of these specific autoantibodies
in the pathogenesis of UV has not been established [8,17,21,27-29].
Once antigen-antibody complexes have formed, they can activate the classical complement pathway.
This generates C3a and C5a, which cause mast cell degranulation resulting in urticarial eruptions.
C3a and C5a also cause increased vessel permeability and chemotaxis of neutrophils. Infiltrating
neutrophils release proteolytic enzymes, causing further tissue destruction and edema [20].
It has been hypothesized that IL-1 may play a role in the pathogenesis of UV. This is based on both
the theoretical observation that features of UV have been noted in autoinflammatory disorders in
which IL-1 is thought to play a role, as well as and practical observations in which anakinra (an IL-1
antagonist) and canakinumab (a long-acting fully humanized monoclonal anti-IL-1-beta antibody)
have been reported to successfully treat UV [30,31]. (See 'Severe systemic disease' below.)
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In addition to environmental factors, genetic factors are thought to play a role in the development of
HUVS. A study including two families with autosomal-recessive HUVS found that mutations in
DNASE1L3 were associated with a familial form of HUVS and HUVS associated with SLE [32]. (See
'Systemic lupus erythematosus' below.)
HISTOLOGY
Histologic findings in leukocytoclastic vasculitis (LCV), which are observed in urticarial vasculitis
(UV) as well as other disorders, include the following [2,4,22,33-35]:
● Injury and swelling of endothelial cells, usually of the postcapillary venules

● Extravasation of red blood cells
● Fragmentation of leukocytes with nuclear debris (leukocytoclasis)
● Fibrin deposition in and around the vessels
● Perivascular infiltrate composed mostly of neutrophils
Leukocytoclasis and fibrinoid deposits are probably the most important aspects of LCV, as they
represent direct signs of vessel damage.
A continuum exists in the amount and type of blood vessel inflammation seen histologically in UV,
ranging from a sparse perivascular infiltrate with no leukocytoclasis to a dense infiltrate with frank
leukocytoclasis and fibrin deposition in the most severe forms [21,33,36]. These more severe
findings, typically with a neutrophilic infiltrate, are seen in patients with hypocomplementemic
urticarial vasculitis syndrome (HUVS). Rarely, lymphocytic, as opposed to leukocytoclastic, vasculitis
may be observed [37].
Immunofluorescence — Direct immunofluorescence reveals deposits of immunoglobulins,

complement, or fibrin around blood vessels in most patients with UV [19,38]. Deposits also may be
present in the basement membrane zone of the dermal-epidermal junction (picture 1A-B). Active
urticarial lesions stain positive for immunoglobulin and complement deposits approximately 80
percent of the time [39]. The findings can also be seen in nonlesional skin.
These findings are not specific to UV and are also frequently seen in patients with systemic lupus
erythematosus (SLE) [33]. Thus, the finding of immunoglobulin and complement deposits within the
basement membrane zone should prompt consideration of both diagnoses [36].
EPIDEMIOLOGY
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Urticarial vasculitis (UV) is a rare diagnosis. In a study from Sweden, the annual incidence rate per
million inhabitants was estimated as 0.7 (95% CI, 0.4, 1.1), and the point prevalence on 31 December
2015 was 9.5 per million (95% CI, 4.5, 14.5) [40].
As an example, the prevalence of UV in patients with chronic urticaria varies from 5 to 20 percent in
adults, depending on the definition of vasculitis used [3,19,33,41-45]. (See "Chronic spontaneous
Women comprise 60 to 80 percent of reported patients [19,39,46]. The peak reported incidence is in
the fourth decade of life [36,39].
UV has also been described in children; the youngest reported case occurred in a patient one year of
age [47]. In a study of children with leukocytoclastic vasculitis, UV accounted for only 9 percent of
cases [48].
Dermatologic findings — The urticarial plaques (or wheals) of urticarial vasculitis (UV) can be found
anywhere on the body (picture 2A-E). In a series of 57 patients with hypocomplementemic UV,
urticarial lesions were typically more pruritic than painful and were associated with angioedema in
51 percent of patients, purpura in 35 percent, and livedo reticularis in 14 percent [49]. Several of the
following features can help distinguish UV wheals from those in common urticaria (table 2), although
none is diagnostic:
● Common urticaria is pruritic and not painful. By comparison, up to one-third of patients with UV
report burning and tenderness as well as pruritus [39,49].
● The urticarial plaques of UV last longer than those in chronic urticaria, persisting for more than
24 hours in two-thirds of patients, and sometimes for up to 72 hours. The urticarial plaques may
resolve without a trace but may also be associated with residual purpura or hyperpigmentation
in up to 35 percent. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis,
pathogenesis, and natural history", section on 'Clinical manifestations'.)
● When examined with a diascope (a magnifying lens or glass slide applied to the skin over
several drops of contact solution), wheals can have a central dark red or brown macule,
signifying underlying purpura and vasculitis (picture 3) [50].
● UV can present as angioedema when the vasculitis involves the capillary or postcapillary
venules of the deeper layers of the dermis and submucosa [22]. Swelling resembling
angioedema has been reported in approximately 40 percent of UV patients in some series, and
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residual bruising is typical [39]. Edema can develop in areas of focused pressure, causing
confusion in differentiating UV from delayed pressure urticaria. In such cases, skin biopsy would
demonstrate the distinguishing finding of leukocytoclastic vasculitis (LCV) in UV [19]. Patients
with UV can also develop laryngeal edema, although this is uncommon [8].
● Other associated cutaneous disorders include livedo reticularis, erythema multiforme-like

eruptions, and rarely bullous eruptions (table 3) [11,22,51,52]. Raynaud phenomenon may occur
[53].
Systemic symptoms — The many systemic manifestations associated with UV (table 3) are
presented in the following section, categorized by organ system. In a series of 57 patients with
hypocomplementemic UV, extracutaneous manifestations included constitutional symptoms in 56
percent of patients as well as musculoskeletal involvement in 82 percent, ocular involvement in 56
percent, pulmonary involvement in 19 percent, gastrointestinal involvement in 18 percent, and kidney
involvement in 14 percent [49].
Musculoskeletal — Arthralgias and arthritis are the most common systemic manifestation of UV,
with roughly 50 percent of patients reporting arthralgias, usually accompanying cutaneous disease
[38,39]. Joint pain is usually migratory and transient, frequently affecting the hands, elbows, feet,
ankles, and knees. Frank arthritis is seen in up to 50 percent of cases of HUVS.
Jaccoud's arthropathy is seen in hypocomplementemic urticarial vasculitis syndrome (HUVS),

although it is more often associated with systemic lupus erythematosus (SLE) [54-58]. It is
characterized by the typical deformities of rheumatoid arthritis (ulnar deviation, swan neck
deformities, and subluxations) in the absence of radiographic evidence of joint destruction (unlike
true rheumatoid arthritis) [59]. It may be associated with an increased risk of aortic and mitral
valvulopathy, warranting echocardiographic evaluation in these patients [60,61].
The involvement of muscle is not well documented and may be largely subclinical. There are reports
of muscle biopsies showing myositis [15].
Renal — Renal disease is characterized by proteinuria and hematuria, with a number of different
disease entities described histologically. The renal disease of UV may not be distinguishable from
that of other entities. These include proliferative glomerulonephritis, focal necrotizing vasculitis,
crescentic glomerulonephritis, membranoproliferative glomerulonephritis, and tubulointerstitial
nephritis [38,62-64]. In a cohort of patients with HUVS, renal involvement was reported in 14 percent
[49].
Mild nonprogressive renal disease is typical of UV, although there have been occasional reports of
end-stage kidney disease requiring hemodialysis [19,65]. In contrast, HUVS patients typically have
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moderate to heavy proteinuria and mild renal failure.
The renal involvement of UV tends to be more severe in children [66]. Although UV is rare in the
pediatric population, it should be considered when a combination of urticaria, glomerulonephritis,
arthritis or arthralgias, and pulmonary disease coexist [62].
Pulmonary — Pulmonary involvement, a leading cause of morbidity and mortality in UV, may
include cough, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), asthma,
pleuritis, and pleural effusions [14,39,67-70]. Tracheal stenosis has also been reported [9]. In a cohort
of patients with HUVS, pulmonary involvement was reported in 19 percent [49].
The most common pulmonary manifestations are COPD and asthma, seen in up to 20 percent of
patients with HUVS and in 5 percent of patients with normocomplementemic UV [36,39]. Most
patients with COPD and UV are also smokers, although the amount of lung disease present is
typically far greater than would be expected for the level of tobacco exposure, and there have even
been reports of patients with COPD and UV who never smoked [13,39,71,72].
Pulmonary destruction is postulated to occur from vasculitis within the lung tissue, leading to
neutrophilic release of elastase and the development of emphysematous lung disease. Smoking is
thought to accelerate this process by helping to recruit neutrophils [13]. Thus, patients with UV or
HUVS should not smoke and should avoid second-hand smoke.
An interesting speculation is that anti-C1q antibodies may cross-react with pulmonary surfactant
apoproteins, which also contain a C1q collagen-like binding region. This crossreactivity could be a
contributing factor to the pulmonary disease [73].
Gastrointestinal — Gastrointestinal symptoms, seen in up to one-third of patients, include

substernal pain, abdominal pain, nausea, vomiting, and diarrhea. Hepatomegaly and splenomegaly
have been reported. Gastrointestinal bleeding is not associated with UV [33,38,51]. These symptoms
are most likely due to gastrointestinal vasculitis, as cases of biopsy-proven gastrointestinal
vasculitis in patients with HUVS have been described [74].
Other organ systems — Involvement of other organ systems is less frequently observed.
● Ophthalmologic – Ophthalmologic involvement varies, but has been reported in up to 56 percent

of patients with UV in case series [22]. Eye findings can include episcleritis, uveitis, and
conjunctivitis [38,39,75,76]. A rare case of serpiginous choroidopathy with subsequent blindness
was reported, as has optic atrophy. (See "Episcleritis".)
● Cardiovascular – Cardiac disease is rare in UV. Findings have included pericarditis, tamponade,
valvular disease, and pericardial effusion [68,73,77]. Valvular disease has been seen in patients
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with HUVS and Jaccoud's arthropathy.
● Neurologic – Central nervous system (CNS) involvement includes pseudotumor cerebri (the
most common CNS manifestation), aseptic meningitis, cranial nerve palsies, peripheral
neuropathy, and transverse myelitis [68,78-82].
LABORATORY FINDINGS
The most common abnormal laboratory results associated with urticarial vasculitis (UV) include
[20,83]:
● Elevated erythrocyte sedimentation rate (ESR)

● Hypocomplementemia (usually decreased C1q, C3, and C4)
● Circulating immune complexes by the C1q solid phase test and/or anti-C1q antibody assay
● Positive antinuclear antibodies (ANA)
Erythrocyte sedimentation rate — Although commonly elevated, the ESR is not related to the severity
of the disease or to the extent of systemic involvement [20,84]. Data from a small case series
suggest that an elevated ESR may also be detected in patients with typical urticaria without evidence
of vasculitis [33]. Data on the role of C-reactive protein (CRP) in patients with UV are lacking.
Hypocomplementemia — Hypocomplementemia is a sensitive marker for systemic disease and

correlates with severity of illness [36,39,46,63,85]. In patients with UV, decreased C1, C1q, C2, C3,
and/or C4 levels, as well as a reduction in the CH50/100, due to activation of the classical
complement pathway, may be found. C1q, C3, and C4 are probably the most commonly reduced
components. A depressed C1q level and a normal C1 inhibitor level is found in most patients with
hypocomplementemic urticarial vasculitis syndrome [1,5,20,36,49], as discussed above. (See
"Overview and clinical assessment of the complement system".)
Antinuclear antibodies — A large percentage of patients with UV are ANA-positive, some in high
titers. Although UV patients are anti-double-stranded DNA (dsDNA) antibody negative as a rule,
distinguishing some patients with UV from those with systemic lupus erythematosus (SLE) may be
challenging. Many patients with UV meet criteria set forth by the American College of Rheumatology
(ACR) for the diagnosis of SLE [20,86]. (See 'Associated conditions' below.)
Other laboratory tests — Other laboratory findings may include positive hepatitis B or C serologies,
elevated Epstein-Barr virus titers, or positive serologies for Borrelia species. Abnormal laboratory
values suggesting specific organ involvement (particularly renal disease) may be observed. (See
'Laboratory studies' below.)
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ASSOCIATED CONDITIONS
Although most cases are idiopathic, there are a variety of systemic diseases and exposures
associated with urticarial vasculitis (UV). Their causal role has not been established.
Systemic lupus erythematosus — UV and systemic lupus erythematosus (SLE) have overlapping
features and there is speculation that hypocomplementemic urticarial vasculitis syndrome (HUVS) is
within the spectrum of SLE.
Some overlapping features of HUVS and SLE include arthritis, glomerulonephritis, and the presence
of hypocomplementemia and antinuclear antibodies (ANA) [36,87]. Autoantibodies against C1q can
also be found in both HUVS and SLE, particularly in SLE patients with glomerulonephritis. By
contrast, there are some distinguishing features of HUVS which are not typically observed in patients
with SLE. These include angioedema (up to 50 percent), chronic obstructive pulmonary disease
(COPD, up to 50 percent), and uveitis (30 percent) [87].
HUVS can be a presenting feature of SLE, or more commonly, it can develop in patients with
longstanding SLE [88-90]. Patients that have both UV and a "lupus-like" syndrome have also been
described [91].
Sjögren's syndrome — Patients with Sjögren's syndrome may develop UV, and these patients
commonly demonstrate the anti-Ro (SSA) antibody [92].
Medication use — Medications from virtually every drug class have been associated with the
development of UV [93] (see "Overview of cutaneous small vessel vasculitis"); over-the-counter diet
pills have also been associated with UV [94].
Infections — Infections may be associated with the development of UV. These include hepatitis B
[23], hepatitis C [95], Lyme disease [96], and infectious mononucleosis [97].
Serum sickness — Serum sickness is a disease in which non-human proteins form immune
complexes that cause vasculitis and urticarial eruptions. Biopsies of these urticarial lesions
sometimes show signs of dermal venulitis and inflammation leading to the diagnosis of UV [53,98].
However, the term serum sickness is generally applied to a self-limited condition occurring in
temporal association with an identifiable exogenous trigger. (See "Serum sickness and serum
sickness-like reactions".)
Complement disorders — Inherited complement deficiencies of C3 or C4, and secondary C3

deficiency due to the presence of C3 nephritic factor have been associated with UV [99-102]. (See
"Inherited disorders of the complement system".)
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Malignancy — Malignancy has also been implicated in UV, albeit rarely. Specifically, Hodgkin
lymphoma, IgA myeloma, metastatic adenocarcinoma of the colon, metastatic malignant testicular
teratoma, acute nonlymphocytic leukemia, acute myeloid leukemia, agnogenic myelodysplasia,
essential thrombocythemia and myelofibrosis [103], and B-cell non-Hodgkin lymphoma have been
noted in association with UV [104-110].
Miscellaneous — A variety of other miscellaneous conditions have been seen in association with UV.
These include monoclonal IgG gammopathy [111], idiopathic thrombocytopenia purpura [39],
polycythemia vera [112], cryoglobulinemia [113], inflammatory bowel disease [39], striae distensae of
pregnancy [114], IgG4-related disease [115], and rarely cold urticaria [116-118] and solar or local heat
urticaria [20,119]. Cogan's syndrome, a rare inflammatory disorder characterized by interstitial
keratitis and vestibule-auditory dysfunction, has been infrequently seen in patients with UV (see
"Cogan's syndrome"). Muckle-Wells syndrome, an autosomal dominant systemic inflammatory
disorder, is also associated with the development of UV, deafness, and renal amyloidosis [120,121].
(See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Muckle-Wells
syndrome'.)
DIAGNOSTIC APPROACH
The diagnosis of urticarial vasculitis (UV) should be considered in the presence of persistent or
recurrent urticaria with suggestive clinical characteristics (table 1), serologic findings, or evidence of
systemic disease (table 3).
History — The history should address the following:
● Symptoms of systemic disease

● Preceding infections
● Preceding drug ingestion
● Prior associated conditions (see 'Associated conditions' above)
● Behavior and characteristics of the urticarial lesions (table 2)
● Response of the skin lesions to treatment
Physical examination — Physical examination is directed at determining the physical characteristics

of the urticarial lesions and detecting signs of systemic disease. (See 'Dermatologic findings' above
and 'Systemic symptoms' above.)
Skin biopsy — If UV is suspected, skin biopsy of one or more early lesions is obtained in order to
establish the presence of leukocytoclastic vasculitis (LCV). By definition, the diagnosis of UV
requires the presence of both characteristic clinical manifestations and pathologic evidence of LCV.
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Thus, a biopsy should always be performed to establish the diagnosis of UV, even if the clinical
presentation appears typical of UV or hypocomplementemic urticarial vasculitis syndrome (HUVS).
In addition to routine histologic evaluation for LCV, direct immunofluorescence should be performed
[19]. Perivascular and/or basement membrane zone deposits of immunoglobulin or complement
frequently are present in UV. However, these findings are not exclusive to UV and the absence of
immunoreactant deposits does not exclude the diagnosis. (See 'Histology' above.)
The punch biopsy is our preferred procedure for obtaining tissue for routine histologic evaluation and
direct immunofluorescence. We typically obtain two 4 mm punch biopsies from lesional skin. Our
tissue sample for direct immunofluorescence is usually one-half of one of the punch biopsy
specimens (split vertically with a scalpel) as this procedure allows for an additional tissue sample for
routine histologic evaluation. Alternatively, the entire specimen from the second punch biopsy can be
sent for direct immunofluorescence. (See "Skin biopsy techniques", section on 'Punch biopsy'.)
Unlike the tissue for routine hematoxylin and eosin staining, tissue for direct immunofluorescence
should not be preserved in formalin. Formalin interferes with the performance of
immunofluorescence. Options for preserving tissue for direct immunofluorescence include
preservation in Michel's medium or prompt freezing in liquid nitrogen followed by transport to an
appropriate laboratory.
If the results do not demonstrate LCV and clinical suspicion for UV remains high, we suggest repeat
biopsy on a newly developed lesion. Multiple biopsies are sometimes needed to establish the
diagnosis.
Laboratory studies — If LCV is confirmed, then an evaluation for hypocomplementemia and the
presence of systemic disease is required. The following tests should be performed in patients who
meet both the clinical and pathologic criteria for UV and HUVS:
● Complement studies (CH50, C3, C4 and C1q levels)

● Complete blood count with differential
● Urinalysis
● Serum creatinine and blood urea nitrogen
● ESR
● Hepatitis B surface antigen
● Hepatitis C serologies
● Antinuclear antibodies (ANA)
● Anti-double stranded-DNA (ds-DNA)
● Anti-Ro, -La, -Sm, and -RNP antibodies
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● Anti-neutrophil cytoplasmic antibodies (ANCA), particularly enzyme immunoassays for
antibodies to proteinase-3 and myeloperoxidase (PR3- and MPO-ANCA)
● Rheumatoid factor and/or anti-cyclic citrullinated peptides (anti-CCP)
● Immunofixation electrophoresis
● Cryoglobulins and cryofibrinogens
In addition, C1q precipitin (anti C1q antibody) assays have become available in a number of
laboratories. When available, these assays should also be obtained as a decreased C1q level due to
anti C1q antibodies is characteristic of HUVS.
Other investigations should be guided by findings from the history and physical examination [53]. As
an example, chest imaging and pulmonary function tests are appropriate in patients with pulmonary
symptoms. Skeletal radiographs are useful to evaluate patients with arthritis. Echocardiogram to
assess for valvular heart disease should be considered in patients suspected to have Jaccoud's
arthropathy. (See 'Musculoskeletal' above.)
Malignancy is rarely associated with UV, and screening patients for underlying malignancy, beyond
the age-appropriate recommendations, is not reasonable unless a thorough history and physical
exam leads to a strong suspicion of occult cancer [113].
DIAGNOSIS
The diagnosis of urticarial vasculitis (UV) is confirmed by the presence of both:
● Clinical manifestations of urticaria

● Histopathological evidence of leukocytoclastic vasculitis (LCV)
The presence or absence of hypocomplementemia and/or associated conditions can help determine
whether UV can be further delineated into hypocomplementemic urticarial vasculitis syndrome
(HUVS), hypocomplementemic urticarial vasculitis (HUV), or normocomplementemic urticarial
vasculitis (NUV) and/or whether UV is associated with another pathogenic process. (See
'Terminology' above and 'Associated conditions' above.)
Other diseases to consider in the diagnosis of urticarial vasculitis (UV) are described below.
● Common urticaria – Certain clinical features can help distinguish UV wheals from those in
common urticaria, although these are not diagnostic (table 2) (see 'Dermatologic findings'
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above). Histopathologically, acute urticaria has marked dermal edema in the absence of
endothelial cell swelling, leukocytoclasis, or red blood cell extravasation. A sparse leukocytic
perivascular infiltrate may occasionally be seen [4,22]. Complement levels are normal.
Chronic urticaria may have perivascular infiltrates composed of T cells, macrophages, and
eosinophils. In contrast to UV, leukocytoclasis and fibrinoid degeneration are always absent, red
cell extravasation is rarely seen, and immunofluorescence staining of immunoglobulins and
complement is negative [122,123]. Complement levels are normal. (See "Chronic spontaneous
● Erythema multiforme (EM) minor – EM minor is an acute eruption characterized by distinctive

target or iris lesions with a predilection for the extensor surfaces of the extremities, as well as
the palms and soles (picture 4). EM minor can be preceded by infections (typically Herpes virus
or Mycoplasma) and has a benign clinical course. Histology of EM minor shows a perivascular
mononuclear infiltrate. Complement levels are normal. Although the appearance of the lesions
of EM minor can be similar to that of UV, the two can usually be distinguished by the larger
clinical picture and the pathology. In contrast, EM major is a more severe blistering disease
involving the mucous membranes that would not be confused with UV. (See "Erythema
multiforme: Pathogenesis, clinical features, and diagnosis".)
● Acquired angioedema – Angioedema in an adult patient with a depressed C1q level should also
prompt consideration of acquired C1-inhibitor deficiency, a condition that is associated with B-
cell lymphomas in a substantial percentage of patients [124]. Like hypocomplementemic
urticarial vasculitis syndrome (HUVS), there are a number of reports suggesting an association
between acquired angioedema/acquired C1-inhibitor deficiency and systemic lupus
erythematosus (SLE) and lupus-like conditions [125-131]. A difference between HUVS and
acquired C1-inhibitor deficiency is that urticaria is not seen in the latter. (See "Acquired C1
inhibitor deficiency: Management and prognosis".)
● Neutrophilic urticarial dermatosis – Neutrophilic urticarial dermatosis is characterized by an

urticarial eruption with the histopathologic features of a perivascular and interstitial neutrophilic
infiltrate with intense leukocytoclasia without vasculitis or edema. In addition, the urticarial
lesions in this condition generally resolve within 24 hours. Purpura, angioedema, and facial
swelling are generally not seen with neutrophilic urticarial dermatosis. In a report of nine
patients with neutrophilic urticarial dermatosis, seven had associated systemic diseases
including adult-onset Still's disease, SLE, and Schnitzler syndrome, suggesting an association
with systemic inflammatory diseases [132].
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● Other – Although UV may occasionally exist in patients with the following syndromes, the skin
lesions in such patients are generally distinct from UV:
• AHA syndrome – The AHA syndrome consists of arthritis (A), hives (H), and angioedema
(A). Flares may be associated with emotional stress, anxiety, exercise, and excessive
alcohol consumption [133].
• Cryopyrin-associated periodic syndromes – In patients presenting with a persistent history

of recurrent urticarial plaques associated with signs of systemic inflammation including
fevers and elevated inflammatory markers (C-reactive protein [CRP]/serum amyloid A,
leukocytosis, and a negative connective tissue disease workup), the cryopyrin-associated
periodic syndromes (CAPS) should be considered in addition to other autoinflammatory
diseases [134]. (See "Periodic fever syndromes and other autoinflammatory diseases: An
overview", section on 'Cryopyrin-associated periodic syndromes'.)
• Schnitzler syndrome – Schnitzler syndrome, which is often unrecognized, is a form of

chronic urticaria associated with monoclonal gammopathy (most often IgM kappa) and
additional features, which may include bone pain, skeletal hyperostosis, arthralgias,
lymphadenopathy, and intermittent fevers [135-142]. Hematologic malignancy is reported in
between 15 and 45 percent of patients [135,141], and up to 1.5 percent of patients with a
monoclonal IgM gammopathy may have the syndrome [142]. Initial reports of this syndrome
described UV as a feature of this syndrome, but subsequent studies demonstrated that a
neutrophilic urticarial dermatosis is most common. Indeed, a retrospective analysis of 20
patients seen at the Mayo Clinic did not identify leukocytoclastic vasculitis (LCV) in any of
the patients studied [141].
This condition responds very well to inhibition of the interleukin (IL)-1 pathway, with the
most evidence supporting the use of anakinra as the first line of therapy. The role of IL-1
signaling in disease pathogenesis is highlighted by treatment response to anakinra
[140,143-146] (an IL-1 receptor antagonist), rilonacept (an IL-1 binding and neutralizing
fusion protein), and canakinumab (a monoclonal antibody against IL-1 beta) [147,148].
The largest study to demonstrate the long-term effectiveness of IL-1 inhibition in patients
with Schnitzler syndrome included 29 patients treated with anakinra, all of whom were
found to have a sustained improvement in disease activity [146]. After a median follow-up
period of 36 months of anakinra administration, 24 patients were in complete remission and
five patients were in partial remission. Severe infections were observed in six patients, but
no lymphoproliferative diseases occurred during treatment with anakinra.
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Three patients unresponsive to IL-1 inhibition have been described who responded to IL-6
pathway inhibition with tocilizumab [149], the anti-IL-6 receptor antibody, suggesting the
possibility of an alternative disease mechanism in some patients. Symptomatic
improvement occurs in some patients with treatment using pefloxacin [150].
TREATMENT
The treatment of urticarial vasculitis (UV) is often challenging and therapy is not standardized.
Management is guided by the clinical presentation, and agents are chosen based upon the severity
of the disease and presence of systemic involvement. Systemic glucocorticoids are considered the
mainstay of therapy for UV, and additional agents described below are typically added when
necessary. The approach outlined here is based upon case and series reports of successful
therapies. Randomized and controlled trials have not been performed.
Mild disease — Patients with mild disease are usually treated symptomatically. Common symptoms
associated with UV include urticaria and arthralgias or arthritis.
● Antihistamines – If urticaria is a prominent feature of the disease, then antihistamines may be

helpful to manage pruritus. These drugs do not impact the course of the disease, and one
preparation has not been shown to be superior to another for this condition [21,22,38,63]. We
start with a nonsedating agent, such as loratadine (10 mg once daily), fexofenadine (60 mg once
or twice daily), or cetirizine (10 mg once daily). The doses of these nonsedating agents may be
increased above the standard doses. Our approach to increasing the dose of some of these
agents is discussed in detail separately. (See "Chronic spontaneous urticaria: Standard
management and patient education", section on 'Up-dosing of second-generation agents'.)
If the patient is still having unmanageable pruritus, the sedating antihistamines are added, in
addition to the less-sedating agents above. Diphenhydramine and chlorpheniramine are over-
the-counter options. Prescription agents include doxepin, hydroxyzine, or promethazine. The
patient should be informed about side effects (drowsiness, headache, dry mouth, constipation,
dizziness, and confusion) (see "Chronic spontaneous urticaria: Standard management and
patient education"). However, additional therapies are often needed to clear the skin lesions and
prevent additional lesions from appearing.
● Nonsteroidal antiinflammatory drugs (NSAIDs) – NSAIDs are commonly used to treat the
arthralgias and arthritis of UV, with good results in up to 50 percent of patients [39,46]. We begin
with ibuprofen up to 800 three or four times daily or naproxen 500 mg twice a day. Indomethacin,
25 mg three times daily, increasing as needed to a maximum dose of 50 mg four times daily, is
another option, although this medication can cause gastrointestinal irritation and headaches.
2202
Moderate disease — Glucocorticoids with or without dapsone are typically used as initial therapy for
patients with mild to moderate disease (no organ- or life-threatening disease manifestations such as
renal failure) who have not responded to antihistamines and NSAIDs. Some prefer initial combination
therapy in patients who are anticipated to require a glucocorticoid for more than two to three
months. Among patients in whom dapsone is contraindicated, we initiate therapy with either the
combination of glucocorticoids plus colchicine, or colchicine alone. Another alternative is
hydroxychloroquine.
● Glucocorticoids – Systemic glucocorticoids are used to gain control of the disease in patients
with significant illness or systemic involvement. Most patients with hypocomplementemia
require this therapy to achieve control of the illness [33,39] The dosing of glucocorticoids varies
and is usually dictated by the severity of systemic illness. We begin treatment at doses between
0.5 and 1.0 mg/kg per day. Benefits from glucocorticoids are usually noticeable within a day or
two of initiation. We typically give these medications for at least a week before making an
assessment about clinical response. Rarely, a patient may require glucocorticoid doses of 1.5
mg/kg per day.
Typically, once control of disease is established, the dose of glucocorticoids is gradually

reduced week by week to the lowest dose that will control the disease. Some patients can be
tapered off glucocorticoid therapy over time, although many cannot and require protracted use.
Because of the long-term sequelae of glucocorticoids, glucocorticoid-sparing therapies should
be considered in such patients and efforts made to find adjunctive treatments that might allow
for lowering of the chronic glucocorticoid dose.
● Dapsone – Dapsone can be initiated alone or in combination with glucocorticoids, or it can be

reserved for patients who develop disease recurrence with attempts to taper glucocorticoid
therapy. It has been used successfully in a limited number of case reports to treat skin
involvement of UV and hypocomplementemic urticarial vasculitis syndrome (HUVS). Dapsone is
relatively inexpensive, usually well tolerated (with certain important exceptions noted below),
although patients require close monitoring initially [46,72,84,151-155].
We start with a dose of 50 mg once daily and increase to 100 mg once daily if needed.
Pentoxifylline acts synergistically with dapsone and can be added as adjunctive therapy,
although we generally use dapsone as a single agent initially [156].
Because dapsone is a sulfone, patients with glucose-6-phosphate dehydrogenase (G6PD)

deficiency may experience severe hemolysis when exposed to this drug, and G6PD levels should
be checked prior to initiating therapy with this agent [22]. Other side effects of therapy with
dapsone include headaches, nonhemolytic anemia, and agranulocytosis, requiring intermittent
2203
complete blood counts (CBCs) for monitoring. Practices for monitoring patients while on
dapsone vary. Our approach is to check a CBC usually weekly for the first month, then monthly
for six months, and then semiannually thereafter [157]. For additional information on monitoring,
refer to the Lexicomp drug information monograph included within UpToDate. Although rare,
dapsone hypersensitivity syndrome is a potentially fatal complication [158] characterized by
fever, hemolytic anemia, lymphocytosis, and transaminitis. Finally, methemoglobinemia can
occur with dapsone [159].
● Colchicine – Colchicine has been used effectively to treat cutaneous manifestations of UV, and it
is used as an alternative to dapsone. Complete blood cell counts should be ordered after
initiation of treatment to screen for cytopenias associated with this drug [22]. We use colchicine
for UV at starting doses of 0.5 to 0.6 mg orally per day. This drug may also be administered
twice daily (ie, 0.25 to 0.3 mg twice daily). If minimal to no response is noted after a few weeks,
the dose of colchicine may be increased to 1.5 to 1.8 mg per day (or 0.75 to 0.9 mg twice daily).
(See "Treatment of gout flares", section on 'Safety of colchicine'.)
● Hydroxychloroquine – Hydroxychloroquine may be a beneficial therapy for patients with UV and

limited skin involvement [63,160]. It is given at a dose of 400 mg per day for patients weighing
more than 70 kg and 200 mg once daily for patients weighing less than 70 kg.
Hydroxychloroquine can be used alone or in combination with glucocorticoids. There have been
case reports in the literature showing complete clearing of cutaneous disease and normalization
of renal function when hydroxychloroquine is used with low-dose prednisone [161]. Monitoring
of patients receiving hydroxychloroquine is discussed separately (See "Antimalarial drugs in the
treatment of rheumatic disease".)
Severe systemic disease — For patients with refractory symptoms or those with organ-threatening or
life-threatening disease manifestations, we use other agents in combination with glucocorticoids.
The assistance of a rheumatologist with experience in the management of vasculitides is suggested
for patients with evidence of significant systemic disease. Based on limited data from case reports
and small case series, along with our own experience, we generally use the following agents listed in
order of preference: mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine. We rarely
use cyclophosphamide given the potential toxicity and limited benefit. Finally, as more evidence
becomes available for the use of rituximab, anakinra, canakinumab, and omalizumab, these may
become preferred. These treatments, along with a few others that have been used, are described
below.
● Mycophenolate mofetil – Mycophenolate mofetil was reported as effective maintenance therapy

in one case of HUVS after symptoms were controlled with glucocorticoids and
2204
cyclophosphamide [162]. Doses of 0.5 – 1 g twice daily are suggested. (See "Mycophenolate:
Overview of use and adverse effects in the treatment of rheumatic diseases".)
● Methotrexate – Methotrexate can be used as a steroid-sparing agent [163]. While methotrexate

is often effective, there is a case report describing an exacerbation of UV with methotrexate use
[164].
● Azathioprine – Azathioprine has been associated with beneficial results in the setting of UV
[22,53,165]. When used in combination with prednisone, azathioprine is associated with marked
beneficial improvement in renal disease [13,33,116,166] and cutaneous involvement of HUVS
[167].
The starting dose is 1 mg/kg daily. This may be increased by 0.5 mg/kg daily if no effect is
apparent after a few weeks. The maximum recommended dose is 2.5 mg/kg daily. Testing for
deficiency of one or both alleles for thiopurine methyltransferase (TPMT), the enzyme required
to metabolize azathioprine, prior to the initiation of therapy is discussed separately. (See
"Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
● Cyclosporine A – Cyclosporine A has been used effectively in HUVS, particularly for renal and
pulmonary disease [5,168,169]. Cyclosporine A has also been a useful agent to use when
attempting to taper glucocorticoid therapy [66]. Initial dosing is 2 to 2.5 mg/kg daily. If no
response is noted after a few weeks, this dosing can be increased to 5 mg/kg daily. Details
regarding side effects of cyclosporine A, including nephrotoxicity and hypertension, are
presented separately. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side
effects'.)
● Rituximab – Rituximab has been used in several patients with recalcitrant UV with a variable
degree of success [170,171].
● Anakinra – A dramatic response to anakinra has been described in patients with Schnitzler
syndrome and UV unresponsive to other therapies [30,143,144]. (See 'Differential diagnosis'
above.)
● Canakinumab – An open-label pilot study of 10 patients with UV reported significant

improvements across several outcome measures including a mean reduction in UV activity
score, an improvement in patient and clinician global assessment of disease activity scales, a
decrease in inflammatory markers, and a decrease in serum cytokine levels of the 1L-1 pathway.
There were no serious adverse events [31].
● Omalizumab – A few case reports describe the successful use of omalizumab in a dose of 150
to 300 mg subcutaneously every four weeks for patients with urticarial vasculitis refractory to
2205
antihistamines, glucocorticoids, and other immunosuppressive treatments including
azathioprine and cyclosporine [172,173].
Other therapies — Interferon alfa has been used in UV associated with hepatitis C or A infection,
either alone or in combination with ribavirin [5,106,174-176]. Other therapies reported in the literature
include cyclophosphamide, intravenous immunoglobulin, reserpine, anti-B-cell therapy, and
monoclonal antibody therapy. However, these are limited to single case reports and further
evaluation is needed before they can be recommended [19,22,170,177-181]. Therapies that most
likely offer little benefit and are not recommended include calcium channel blockers, pentoxifylline as
a single agent, and dietary manipulations [5,182].
PROGNOSIS
Urticarial vasculitis (UV) is a complicated disease with an unpredictable outcome. It is usually

benign, with no permanent sequelae, in the majority of patients with normal complement levels. The
average duration of disease is three to four years, although individual cases extending beyond 20
years have been reported [38,39]. In the largest series studied, patients with UV had no other disease
manifestations over a 12-year span [51].
Patients with hypocomplementemia have more severe disease and may experience significant
morbidity and mortality [19]. However, they rarely die as a direct result of the disease, even in the
setting of multisystem involvement [38].
Pulmonary involvement is a leading cause of morbidity and mortality, due largely to complications of
chronic obstructive pulmonary disease (COPD) [51]. There have been rare reports of fatal episodes of
laryngeal edema [8].
the world are provided separately. (See "Society guideline links: Urticarial vasculitis" and "Society
guideline links: Vasculitis".)
Presentation and diagnosis
2206
● Urticarial vasculitis (UV) is a clinicopathologic entity consisting of urticaria and evidence of
leukocytoclastic vasculitis on skin biopsy. UV predominantly involves the skin but may affect
other organs, particularly the lungs, kidney, and gastrointestinal tract. Hypocomplementemia,
when present, may be associated with extensive vasculitis and systemic features. (See
● Hypocomplementemic urticarial vasculitis syndrome (HUVS) is recognized as a specific

autoimmune disorder involving six or more months of urticaria, with hypocomplementemia, in
the presence of various systemic findings (table 1). (See 'Terminology' above.)
● The pathophysiology of UV is believed to involve the deposition of immune complexes in vessel

walls, complement activation, and mast cell degranulation due to C3a and C5a with resultant
urticaria. (See 'Pathophysiology' above.)
● Leukocytoclasis, or fragmentation of leukocytes with nuclear debris, and fibrinoid deposits are
important histopathologic findings that represent direct signs of vessel damage.
Immunofluorescence reveals deposits of immunoglobulins, complement, or fibrin around blood
vessels in most patients. (See 'Histology' above.)
● The urticarial lesions of UV can be found anywhere on the body (picture 2A-B and picture 2C and
picture 2D and picture 2E). Certain features can help distinguish UV wheals from those in
common urticaria (table 2), although none is diagnostic. Systemic findings (table 3) most often
involve the musculoskeletal, renal, and pulmonary systems. (See 'Clinical presentation' above.)
● UV is most commonly idiopathic, although it can occur in association with autoimmune

diseases, drug reactions, infections, or malignancy. (See 'Associated conditions' above.)
● The diagnosis of UV requires the presence of urticaria with leukocytoclastic vasculitis (LCV) on
skin biopsy. If LCV is present, then further testing is indicated to define the presence and extent
of systemic disease and evaluate for associated conditions. (See 'Diagnosis' above and 'Skin
biopsy' above and 'Laboratory findings' above and 'Differential diagnosis' above.)
● UV is a benign and self-limited disease for the majority of patients, although symptoms can last
for decades in some individuals. (See 'Prognosis' above.)
Treatment recommendations — UV is often difficult to treat, and therapy is based upon case reports
and small series. Management is guided by the clinical presentation, and agents are chosen based
upon the severity of the disease and presence of systemic involvement. Systemic glucocorticoids
are considered the mainstay of therapy for UV, and additional agents are typically added.
Mild disease
2207
● Antihistamines are used to manage pruritus if urticaria is a prominent feature of the disease.
These drugs do not impact the course of the disease, and one preparation has not been shown
to be superior to another for this condition. We start with a nonsedating agent such as
loratadine (10 mg once daily), fexofenadine (60 mg once or twice daily), or cetirizine (10 mg
once daily). (See 'Mild disease' above.)
● Nonsteroidal antiinflammatory drugs (NSAIDs) may be used to treat the arthralgias and arthritis
associated with UV. (See 'Mild disease' above.)
Moderate disease — Glucocorticoids in combination with either dapsone, colchicine, or

hydroxychloroquine are typically used as initial therapy for patients with mild to moderate disease,
although there is more experience with glucocorticoids and dapsone. This approach is typically
reserved for patients who do NOT have organ- or life-threatening manifestations of the disease (eg,
renal failure) and who have not responded to antihistamines and NSAIDs. (See 'Moderate disease'
above.)
Severe systemic disease — For patients with refractory symptoms or those with organ- or life-
threatening disease manifestations, we use other agents in combination with glucocorticoids. The
assistance of a rheumatologist with experience in the management of vasculitides is suggested for
patients with evidence of significant systemic disease. (See 'Severe systemic disease' above.)
● Based on limited data from case reports and small case series, along with our own experience,
we generally use the following agents listed in order of preference: mycophenolate mofetil,
methotrexate, azathioprine, and cyclosporine. We rarely use cyclophosphamide, given the
potential toxicity and limited benefit. (See 'Severe systemic disease' above.)
● As more evidence becomes available for the use of rituximab, anakinra, canakinumab, and
omalizumab, these agents may become preferred. (See 'Severe systemic disease' above.)
2208
GRAPHICS
Diagnostic criteria of hypocomplementemic urticarial vasculitis syndrome
Criteria Specifics Needed for the diagnosis
Major Urticaria for more than six months The patient must have both major criteria.
criteria
Hypocomplementemia
Minor Venulitis of the dermis (established via biopsy) The patient must have at least two of the
criteria minor criteria.
Arthralgia or arthritis
Mild glomerulonephritis
Uveitis or episcleritis
Recurrent abdominal pain
Positive C1q precipitin test by immunodiffusion with an associated

suppressed C1q level
2209
Immunofluorescence findings in urticarial vasculitis
Direct immunofluorescence of a biopsy specimen from a patient with urticarial vasculitis,

demonstrating IgM deposits along the dermal-epidermal junction as well as involving blood
vessel walls in the dermis.
2210
Immunofluorescence findings in urticarial vasculitis
Direct immunofluorescence of a biopsy specimen from a patient with urticarial vasculitis,

demonstrating IgM deposits along the dermal-epidermal junction as well as involving blood
vessel walls in the dermis.
2211
2212
2213
2214
Urticarial patches with central ecchymosis.
2215
Urticarial patches with annular, semiannular, and occasionally concentric formation. Note
scattered associated ecchymoses.
2216
Cutaneous features of urticarial vasculitis versus common urticaria
Urticarial vasculitis Common urticaria
Description Painful, tender, burning, and/or pruritic Mainly pruritic
Persistence Between 24 and 72 hours Between 8 and 24 hours
Residual effects Purpura or hyperpigmentation None
Predilection Anywhere Anywhere
2217
Diascopy of urticarial vasculitis skin lesion
(A) Lesion of urticarial vasculitis on the neck.

(B) Diascopy causes erythematous halo to disappear, revealing clinically inapparent purpura.
Reproduced with permission from: Dahl MV. Clinical pearl: diascopy helps diagnose urticarial vasculitis. J Am
Acad Dermatol 1994; 30:481. Copyright © 1994 American Academy of Dermatology.
2218
Clinical features of urticarial vasculitis
Cutaneous features Systemic features
Common Erythematous urticarial papules and plaques Musculoskeletal: arthralgia, arthritis

(wheals), angioedema, dermographism,
annular erythema
Less Urticarial lesions with residual Respiratory: cough, dyspnea, hemoptysis, COPD, asthma, pleural effusion
common hyperpigmentation and/or purpura
Renal disease: proteinuria, hematuria, glomerulonephritis
Gastrointestinal: substernal pain, abdominal pain, nausea, vomiting, diarrhea
Rare Erythema multiforme-like lesions, livedo Cardiac: pericarditis, pericardial effusion, cardiac tamponade
reticularis, Raynaud's phenomenon,
Ophthalmologic: conjunctivitis, episcleritis, uveitis, geographic serpiginous
laryngeal edema
choroidopathy, visual loss
Other: fever, splenomegaly, lymphadenopathy, cold sensitivity, reversible

tracheal stenosis
Very rare CNS: pseudotumor cerebri, cranial nerve palsies, aseptic meningitis
Miscellaneous: transverse myelitis, cardiac valve disease, optic atrophy,

Jaccoud's arthropathy (chronic non-erosive, deforming arthropathy),
peripheral neuropathy, pleuritis
2219
Erythema multiforme
Target lesions are present on the palm of this patient with erythema multiforme.
2220
Pathogenesis, clinical manifestations, and diagnosis of
pemphigus
uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus/print
INTRODUCTION Pemphigus is defined as a group of life-threatening

blistering disorders characterized by acantholysis (loss of keratinocyte to keratinocyte adhesion)
that results in the formation of intraepithelial blisters in mucous membranes and skin [1]. The
process of acantholysis is induced by the binding of circulating immunoglobulin G (IgG)
autoantibodies to intercellular adhesion molecules [1-3]. Patients with pemphigus develop mucosal
erosions and/or flaccid bullae, erosions, or pustules on skin.
The four major entities of the pemphigus group include pemphigus vulgaris, pemphigus foliaceus,
immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus. The different forms of
pemphigus are distinguished by their clinical features, associated autoantigens, and laboratory
findings [4,5].
The pathogenesis, clinical features, and diagnosis of pemphigus will be discussed here. The
management of pemphigus and greater detail on paraneoplastic pemphigus are reviewed
separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and
2221
"Management of refractory pemphigus vulgaris and pemphigus foliaceus" and "Paraneoplastic
pemphigus".)
CLASSIFICATION Common features of the major types of pemphigus

are reviewed briefly below. A broader summary of the clinical and laboratory features of pemphigus
is provided in the table (table 1).
●Pemphigus vulgaris
•Key features –Mucosal or mucosal and cutaneous involvement, suprabasal acantholytic blisters,
autoantibodies against desmoglein 3 or both desmoglein 1 and desmoglein 3
•Clinical variants – Pemphigus vegetans, pemphigus herpetiformis
●Pemphigus foliaceus
•Key features –Cutaneous involvement only, subcorneal acantholytic blisters, autoantibodies

against desmoglein 1
•Clinical variants – Endemic pemphigus foliaceus (fogo selvagem), pemphigus erythematosus

(Senear-Usher syndrome), pemphigus herpetiformis
●Immunoglobulin A (IgA) pemphigus
•Subtypes – Subcorneal pustular dermatosis-type IgA pemphigus (distinct from classic subcorneal
pustular dermatosis [Sneddon-Wilkinson disease]), intraepidermal neutrophilic IgA dermatosis
•Key features – Grouped vesicles or pustules and erythematous plaques with crusts, subcorneal or
intraepidermal acantholytic blisters, autoantibodies against desmocollin 1 in subcorneal pustular
dermatosis-type IgA pemphigus [6]
●Paraneoplastic pemphigus
•Key features –Extensive, intractable stomatitis and variable cutaneous findings with multiform
exanthems, associated neoplastic disease, suprabasal acantholytic blisters, autoantibodies against
desmoplakins or other desmosomal antigens (see "Paraneoplastic pemphigus")
EPIDEMIOLOGY Pemphigus vulgaris, which represents the most common

form of pemphigus, is a rare disease. Although pemphigus vulgaris occurs worldwide, the frequency
is influenced by geographic location and ethnicity. Incidence rates between 0.1 and 0.5 per 100,000
people per year have been reported most frequently; however, higher rates have been documented in
certain populations [7]. Individuals with Jewish ancestry (particularly Ashkenazi Jews) and
inhabitants of India, Southeast Europe, and the Middle East have the greatest risk for pemphigus
vulgaris [8].
2222
In most geographic locations, pemphigus vulgaris is more common than pemphigus foliaceus.
However, in certain locations, such as North Africa, Turkey, and South America, the prevalence of
pemphigus foliaceus exceeds pemphigus vulgaris [9]. Endemic pemphigus foliaceus (fogo
selvagem) contributes to the higher rate of pemphigus foliaceus in some of these countries. In an
endemic region in the state of Mato Grosso do Sul in Brazil, the prevalence of pemphigus foliaceus
during the mid-1990s was around 3 percent [10]. An endemic form of pemphigus vulgaris also has
been reported in a small number of patients residing in an endemic region of pemphigus foliaceus in
Brazil [11].
Pemphigus usually occurs in adults, with an average age of onset of 40 to 60 years for pemphigus
vulgaris and nonendemic pemphigus foliaceus [12,13]. Pemphigus is rare in children, with the
exception of endemic pemphigus foliaceus, which frequently affects children and young adults in
endemic areas [14]. Neonatal pemphigus is a rare transient form of pemphigus that occurs as a
consequence of placental transmission of autoantibodies to the fetus from a mother with the
disease. (See 'Neonatal pemphigus' below.)
Overall, the sex ratio for pemphigus vulgaris and pemphigus foliaceus appears to be equivalent or
close to equivalent [15]. However, a few studies have found large imbalances in the sex distribution,
such as a study that found a 4:1 ratio of females to males with pemphigus foliaceus in Tunisia [16]
and a study that found a 19:1 ratio of males to females in an endemic location in Colombia [17].
Epidemiologic information on immunoglobulin A (IgA) pemphigus is sparse. The disorder may occur
at any age and may be slightly more common in females [6]. Paraneoplastic pemphigus is rare. The
disorder is most commonly seen in middle-aged adults, but may also occur in children. (See
"Paraneoplastic pemphigus", section on 'Epidemiology'.)
PATHOGENESIS
Overview — Intensive investigations to elucidate the pathogenesis of pemphigus have led
to wide acceptance of the theory that acantholysis induced by the binding of autoantibodies to
epithelial cell surface antigens leads to the clinical manifestations of pemphigus [2,18,19]. This
theory is supported by the consistent detection of intercellular autoantibodies in perilesional tissue
from patients with pemphigus (picture 1A-B) (see 'Diagnosis' below). Experimental findings that offer
further support include the following:
●In vitro studies have demonstrated that immunoglobulin G (IgG) autoantibodies from patients with
pemphigus vulgaris, pemphigus foliaceus, and immunoglobulin A (IgA) pemphigus are capable of
inducing loss of epidermal cohesion [20-23].
●In vivo studies have shown that the passive transfer of IgG autoantibodies from patients with
pemphigus vulgaris into neonatal mice induces blistering and erosions with histologic,
ultrastructural, and immunofluorescence features consistent with pemphigus [24,25]. The blister-
2223
inducing potential of IgG autoantibodies in pemphigus foliaceus and paraneoplastic pemphigus has
been demonstrated in similar in vivo mouse studies [26-28].
●Removal of pemphigus autoantibodies from serum from patients with pemphigus vulgaris or
pemphigus foliaceus via antigen-specific immunoadsorption prior to injection into neonatal mice
prevents blistering [29,30].
The molecular mechanisms through which binding of autoantibodies to epithelial cells leads to
acantholysis are still intensively debated. Several mechanisms for antibody-mediated acantholysis
have been proposed, including the induction of signal transduction events that trigger cell separation
and the inhibition of adhesive molecule function through steric hindrance [2,31,32]. In particular, the
theory of apoptolysis suggests that acantholysis results from autoantibody-mediated induction of
cellular signals that trigger enzymatic cascades that lead to structural collapse of cells and cellular
shrinkage [33].
Target antigens — Autoantibodies against a variety of epithelial cell surface

antigens, intracellular and transmembranous components of desmosomes, have been identified in
patients with pemphigus.
Pemphigus vulgaris and pemphigus

foliaceus — Desmogleins, which are transmembrane glycoproteins of the cadherin (calcium-
dependent cell adhesion molecule) family, are the antigens that have been most extensively studied
in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes,
integral structures for cell-to-cell adhesion (figure 1).
IgG autoantibodies to desmogleins are consistently detected via enzyme-linked immunosorbent

assay (ELISA) in patients with pemphigus, and the expression of these autoantibodies often
correlates with the type of disease [34,35]. IgG autoantibodies against desmoglein 3 are
characteristic of mucosal pemphigus vulgaris, autoantibodies against desmoglein 1 have been
linked to pemphigus foliaceus, and autoantibodies to desmoglein 1 and desmoglein 3 have been
linked to mucocutaneous pemphigus vulgaris. The amino-terminal portions of desmogleins appear
to be the important epitopes for pathogenicity as evidenced by studies that demonstrate that IgG
directed against an amino-terminal recombinant fraction of desmoglein 3 (EC1-2), but not the
carboxy-terminal portion, induce epithelial blistering when injected into neonatal mice or exposed to
cultured human skin [36,37]. IgG autoantibodies considered to be pathogenic are of the IgG4
subclass [25,37-39].
In the 1990s, the desmoglein compensation theory was proposed as an explanation for the observed
correlation between the clinical features and autoantibody profiles of pemphigus vulgaris and
pemphigus foliaceus [40]. Although the theory is still widely cited, subsequent data has raised
questions about whether this concept sufficiently explains the pathogenic mechanism of these
diseases [41].
2224
According to the desmoglein compensation theory, the correlation between clinical findings and
ELISA results reflects innate differences in desmoglein expression in the skin and mucous
membranes [40]. In the skin, desmoglein 1 is expressed most intensely in the upper portions of the
epidermis, whereas desmoglein 3 is more strongly expressed in the basal and parabasal layers. In
the mucous membranes, desmoglein 3 is present in abundance throughout the epithelium. In
contrast, the expression of desmoglein 1 is much lower throughout the mucosal epithelium (figure
2).
The interpretation of this theory as it relates to the clinical findings in pemphigus is as follows:
●Patients with only autoantibodies against desmoglein 3 should have mucosal dominant
pemphigus vulgaris because in skin, desmoglein 1 compensates for the loss of desmoglein 3. In the
mucous membranes, the expression of desmoglein 1 is insufficient for compensation.
●Patients with only autoantibodies against desmoglein 1 should have pemphigus foliaceus
(superficial skin blistering and no mucous membrane involvement) because autoantibodies against
desmoglein 1 result in separation of cells in the superficial epithelium, but not in the deeper
epithelium, where desmoglein 3 compensates well for desmoglein 1 dysfunction. The mucous
membranes are spared due to the high levels of desmoglein 3 and the relatively low levels of
desmoglein 1 expressed in mucosa.
●Patients with both autoantibodies against desmoglein 1 and 3 should have mucocutaneous
pemphigus vulgaris because dysfunction of both desmoglein 1 and 3 prevents the ability of these
glycoproteins to compensate for one another, resulting in a loss of cell-cell adhesion in both skin and
mucous membranes.
However, it is likely that the pathogenesis of pemphigus is more complex than this model predicts.
Discordance between the clinical and serologic profiles (eg, patients with pemphigus foliaceus who
have autoantibodies against desmoglein 3, patients with pure mucosal pemphigus vulgaris who
have autoantibodies against desmoglein 1, and patients with pemphigus who have neither
autoantibodies against desmoglein 1 nor autoantibodies against desmoglein 3) may occur in about
one-third of cases [41,42]. This observation and the knowledge that the presence of autoantibodies
to both desmoglein 1 and desmoglein 3 does not result in complete dissolution of the epithelium
suggest that other factors contribute to the development of these diseases.
Autoantibodies against desmocollin 3 may contribute to pemphigus in some patients. Like

desmogleins, desmocollins are transmembrane glycoproteins found within desmosomes (figure 1).
Desmocollin 3-specific autoantibodies from patients with pemphigus have induced loss of
keratinocyte adhesion ex vivo and in experimental animals [43,44]. Moreover, a subset of patients
with clinical features most consistent with pemphigus herpetiformis or pemphigus vegetans and
direct immunofluorescence findings consistent with pemphigus who have autoantibodies against
desmocollin but no autoantibodies against desmoglein has been identified [45,46].
2225
Additional autoantibodies detected in serum from patients with pemphigus include autoantibodies
against desmoglein 4, the acetylcholine receptor, pemphaxin, and others [33,47-51]. Whether
autoantibodies with any of these molecular specificities are pathogenic in pemphigus vulgaris or
pemphigus foliaceus remains to be determined.
IgA pemphigus — Unlike the other forms of pemphigus, which are characterized by IgG
autoantibodies targeting epithelial cell surface antigens, IgA pemphigus is characterized by
antikeratinocyte cell surface autoantibodies of the IgA class [52]. The target antigen in the
subcorneal pustular dermatosis type of IgA pemphigus is desmocollin 1, a transmembrane
glycoprotein within desmosomes [53-55].
In contrast, the targeted antigens in the intraepidermal neutrophilic dermatosis variant of IgA
pemphigus appear to be more heterogeneous. While autoantibodies against desmogleins 1 and 3
have been reported in several patients [54,56-58], immunoelectron microscopy studies suggest that
IgA autoantibodies in these patients recognize an unidentified non-desmosomal transmembranous
protein [59]. Thus, a common autoantigen remains elusive and the mechanism of blister formation in
IgA pemphigus is not fully understood [23].
Paraneoplastic pemphigus — Multiple autoantibodies have been detected in

patients with paraneoplastic pemphigus. The target antigens for this variant are reviewed separately.
(See "Paraneoplastic pemphigus", section on 'Humoral immunity'.)
Contributing factors — As with many other autoimmune diseases, the

precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental
factors may influence the development of pemphigus [9].
Genetics — Multiple studies have evaluated the relationship between pemphigus vulgaris
and pemphigus foliaceus with human leukocyte antigen (HLA) class II alleles. Pemphigus vulgaris is
associated with DR4 and DR14, though the susceptibility gene differs dependent upon ethnic origin.
HLA-DRB1 0402 is associated with the disease in Ashkenazi Jews [60,61], and DRB1 1401/04 and
DQB1 0503 are associated pemphigus vulgaris in non-Jewish patients of European or Asian descent
[62-67]. Sporadic and endemic pemphigus foliaceus are also associated with DR4, DR14, and DR1
alleles [9].
In contrast to pemphigus vulgaris, the association with HLA alleles in pemphigus foliaceus is less
restricted. DRB1 0402, 0403, 0404, 0406, 1401, 1402, 1406, and 0102 subtypes have been detected
at increased frequency in patients with pemphigus foliaceus, while DRB1 0301, 0701, 0801, 1101,
1104, and 1402 are negatively associated with this disease [68-71].
The involvement of genetic factors in susceptibility to pemphigus is further strengthened by

detection of low titers of desmoglein 3-specific autoantibodies in asymptomatic relatives of patients
with both pemphigus vulgaris and foliaceus [11,72]. In addition, a case-control study found that
compared with relatives of healthy controls, first-degree family members of patients with pemphigus
2226
had an increased prevalence of autoimmune diseases [60]. The findings of one study suggest that
pemphigus vulgaris clusters with autoimmune thyroid disease, rheumatoid arthritis, and type 1
diabetes in patients and their families [73].
Environment — While most cases of pemphigus foliaceus are idiopathic, environmental

factors appear to contribute in the development of endemic pemphigus foliaceus (fogo selvagem)
[47,74]. A black fly (Simulium nigrimanum) or other insects may serve as a vector for the endemic
form of this disease [75].
Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and
pemphigus vulgaris [76-79], and pemphigus has been reported to develop following burns or
cutaneous electrical injury [80]. Viral infections, certain food compounds, ionizing radiation, and
pesticides have been suggested as additional stimuli for this disease [81-86].
Drug exposure — Pemphigus vulgaris and pemphigus foliaceus may be precipitated by

drugs. Thiol drugs, including penicillamine and captopril, are the most common inciting agents [87].
In one series of 104 patients treated with penicillamine for at least six months, 7 percent developed
pemphigus foliaceus [88]. Examples of additional drugs that have been associated with pemphigus
vulgaris or pemphigus foliaceus include penicillins, cephalosporins, enalapril, rifampin, and
nonsteroidal anti-inflammatory agents (table 2) [87,89,90].
Drug-induced biochemical and/or immunologic reactions may contribute to the development of

acantholysis in drug-induced pemphigus. Potential mechanisms include effects on enzymes that
mediate keratinocyte aggregation, direct interference through binding to molecules involved in cell
adhesion, and stimulation of neoantigen formation [89].
Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies are negative in
some patients with drug-induced pemphigus. In a series of six patients with this disorder, DIF was
negative in one patient and IIF was negative in two patients [90]. ELISA was positive for desmoglein
1 or desmoglein 3 in all patients in this series.
Diet — Dietary factors including garlic, leek, onion, black pepper, red chili pepper, red wine, and
tea have been implicated as inducers of pemphigus vulgaris and pemphigus foliaceus based on
concise case reports. However, the existing evidence does not support a strong link between diet as
an environmental factor and pemphigus [85].
CLINICAL FEATURES
Pemphigus vulgaris — Almost all patients with pemphigus vulgaris develop
mucosal involvement. The oral cavity is the most common site of mucosal lesions and often
represents the initial site of disease [91]. Mucous membranes at other sites are also often affected,
2227
including the conjunctiva, nose, esophagus, vulva, vagina, cervix, and anus [92-94]. In women with
cervical involvement, the histologic findings of pemphigus vulgaris may be mistaken for cervical
dysplasia in Papanicolaou (Pap) smears [95].
Since mucosal blisters erode quickly, erosions are often the only clinical findings (picture 2A-C). The
buccal mucosa and palatine mucosa are the most common sites for lesion development in the oral
cavity [96].
The pain associated with mucosal involvement of pemphigus vulgaris can be severe. Oral pain is
often augmented by chewing and swallowing, which may result in poor alimentation, weight loss,
and malnutrition.
Most patients also develop cutaneous involvement manifesting as flaccid blisters on normal-
appearing or erythematous skin (picture 3A-B). The blisters rupture easily, resulting in painful
erosions that bleed easily (picture 3B-D). Pruritus usually is absent. Although any cutaneous site
may be affected, the palms and soles are usually spared. The Nikolsky sign (induction of blistering
via mechanical pressure at the edge of a blister or on normal skin) often can be elicited [97]. (See
"Approach to the patient with cutaneous blisters", section on 'Nikolsky sign'.)
Rarely, mucous membrane involvement is not observed despite the presence of circulating
autoantibodies to both desmoglein 1 and desmoglein 3 [98-100]. The term "cutaneous-type
pemphigus vulgaris" is used to refer to this presentation of the disease. (See 'Target antigens'
above.)
Other uncommon clinical presentations of pemphigus vulgaris include:
●Pemphigus vegetans – Patients with pemphigus vegetans present with vegetating plaques
composed of excessive granulation tissue and crusting (picture 4). The intertriginous areas, scalp,
and face are the most common sites for these lesions. Two clinical presentations of pemphigus
vegetans have been described [101]. In pemphigus vegetans of Neumann, vegetating plaques evolve
from typical pemphigus vulgaris lesions. Pemphigus vegetans of Hallopeau is a milder form of
pemphigus vegetans in which the vegetating plaques are not preceded by bullae. Lesions of
pemphigus vegetans of Hallopeau usually are found in intertriginous areas.
●Pemphigus herpetiformis –Pemphigus herpetiformis (also known as herpetiform pemphigus) is a

term that describes pemphigus vulgaris or pemphigus foliaceus that manifests with urticarial
plaques and cutaneous vesicles arranged in a herpetiform or annular pattern (picture 5) [1,102-105].
Pruritus is frequently present. Mucosal involvement is uncommon.
The clinical features of drug-induced pemphigus vulgaris are similar to idiopathic disease.
Pemphigus foliaceus — Pemphigus foliaceus is a superficial variant of

pemphigus that presents with cutaneous lesions. The mucous membranes are typically spared [1].
2228
Pemphigus foliaceus usually develops in a seborrheic distribution. The scalp, face, and trunk are
common sites of involvement. The skin lesions usually consist of small, scattered superficial blisters
that rapidly evolve into scaly, crusted erosions (picture 6A-C). The Nikolsky sign often is present [13].
The skin lesions may remain localized or may coalesce to cover large areas of skin. Occasionally,
pemphigus foliaceus progresses to involve the entire skin surface as an exfoliative erythroderma
[12].
Pain or burning sensations frequently accompany the cutaneous lesions. Systemic symptoms are
usually absent.
Clinical variants of pemphigus foliaceus include:
●Endemic pemphigus foliaceus (fogo selvagem) –Endemic pemphigus foliaceus presents with
clinical features that are similar to the idiopathic form of the disease [13]. An environmental trigger is
believed to account for this variant of the disease. (See 'Epidemiology' above.)
●Pemphigus erythematosus (Senear-Usher syndrome) – This term pemphigus erythematosus is

used to describe pemphigus foliaceus localized to the malar region of the face (picture 7) [12].
Historically, the term was used to refer to patients who exhibited immunofluorescence findings
consistent with pemphigus as well as laboratory features of systemic lupus erythematosus.
However, the term is no longer used in this manner.
The clinical manifestations of drug-induced pemphigus foliaceus are similar to idiopathic disease.
IgA pemphigus — Both the subcorneal pustular dermatosis and intraepidermal

neutrophilic immunoglobulin A (IgA) dermatosis types of IgA pemphigus are characterized by the
subacute development of vesicles that evolve into pustules [6]. The vesicles and pustules are
usually, but not always, accompanied by erythematous plaques. A herpetiform, annular, or circinate
pattern may be present [6,55,96].
The trunk and proximal extremities are common sites for involvement. The scalp, postauricular skin,
and intertriginous areas are less common sites for lesion development [6,55,106]. Pruritus may or
may not be present. Mucous membranes are usually spared.
The subcorneal pustular dermatosis type of IgA pemphigus is clinically similar to classic subcorneal
pustular dermatosis (Sneddon-Wilkinson disease). Immunofluorescence studies are necessary to
distinguish these diseases. (See "Neutrophilic dermatoses", section on 'Subcorneal pustular
dermatosis' and 'IgA pemphigus' below.)
Paraneoplastic pemphigus — Paraneoplastic pemphigus (also

known as paraneoplastic autoimmune multiorgan syndrome) is an autoimmune multi-organ
syndrome associated with neoplastic disease [27]. Typically, patients suffer from severe and acute
mucosal involvement with extensive, intractable stomatitis (picture 8A-C). The cutaneous
manifestations are variable, and include blisters, erosions, and lichenoid lesions that may resemble
2229
other autoimmune blistering diseases, erythema multiforme, graft versus host disease, or lichen
planus (picture 9A-B). Life-threatening pulmonary involvement consistent with bronchiolitis
obliterans also may be seen [107]. (See "Paraneoplastic pemphigus", section on 'Clinical
manifestations'.)
Neonatal pemphigus — Neonatal pemphigus is a rare transient condition in

which neonates develop blisters due to placental transmission of autoantibodies from a mother with
pemphigus. Neonatal pemphigus vulgaris occurs more frequently than neonatal pemphigus
foliaceus [108,109]. The clinical, histologic, and direct immunofluorescence findings of neonatal
pemphigus are consistent with pemphigus. Indirect immunofluorescence has been positive in the
majority of reported cases [108]. The disease manifestations usually resolve within three weeks.
COMORBIDITIES Cross-sectional studies have found increased

prevalence rates for other disorders in patients with pemphigus, including hematologic
malignancies, solid malignancies (esophageal and laryngeal cancer), other autoimmune diseases
(Sjögren syndrome, systemic lupus erythematosus, and alopecia areata), psoriasis, and neurologic
diseases (dementia, Parkinson disease, and epilepsy) [110-113]. Further studies are necessary to
firmly establish the clinical relevance of these findings.
Although an increased prevalence of malignancy in patients with pemphigus has been reported,
malignancy is uncommon overall [110,114]. A cross-sectional study of 1985 patients with
pemphigus vulgaris or pemphigus foliaceus and 9874 matched controls found modest increases in
the prevalence rates of chronic leukemia (0.9 versus 0.4 percent, odds ratio [OR] 2.1, 95% CI 1.2-3.6),
multiple myeloma (0.8 versus 0.4 percent, OR 2.2, 95% CI 1.2-3.9), and non-Hodgkin lymphoma (1.8
versus 1.2 percent, OR 1.5, 95% CI 1.0-2.2) among pemphigus patients [114]. Paraneoplastic
pemphigus, a very rare obligate paraneoplastic disease, is a distinct subtype of pemphigus that
occurs only in association with malignancy and is reviewed separately. (See "Paraneoplastic
pemphigus".)
DIAGNOSIS The diagnosis of pemphigus is made through the assessment of

clinical, histologic, immunopathologic, and serologic findings (table 1). Even in cases in which the
clinical findings strongly suggest pemphigus, laboratory investigations to confirm the diagnosis are
indicated since other disorders may present with similar clinical findings. (See 'Differential diagnosis'
below.)
Pemphigus vulgaris and pemphigus

foliaceus — In addition to a complete examination of cutaneous and mucosal surfaces,
the clinical assessment should include a review of the patient's medications since clinical and
laboratory studies cannot reliably distinguish between idiopathic pemphigus and drug-induced
pemphigus. In addition, patients who may have pemphigus vulgaris should be questioned about
2230
ocular symptoms, hoarseness, dysphagia, dysuria, and dyspareunia to evaluate for symptoms
suggestive of extraoral mucus membrane involvement. (See 'Drug exposure' above and 'Clinical
features' above.)
Our standard laboratory work-up for patients with clinical findings suggestive of pemphigus vulgaris
or foliaceus includes:
●A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining
●A perilesional skin or mucosal biopsy for direct immunofluorescence (DIF)
●Serum collection for enzyme-linked immunosorbent assay (ELISA) and indirect

immunofluorescence (IIF)
Histopathology — The biopsy for routine histologic examination should be taken from
an early lesion. The biopsy should be placed at the edge of a blister or erosion. A 4 mm punch
biopsy is usually sufficient. (See "Approach to the patient with cutaneous blisters", section on 'Skin
biopsy'.)
The characteristic findings in pemphigus vulgaris include (picture 10):
●Intraepithelial cleavage with acantholysis (detached keratinocytes) primarily localized to the

suprabasal region
●Retention of basal keratinocytes along the basement membrane zone, resulting in an appearance
that resembles a "row of tombstones"
●Sparse inflammatory infiltrate in the dermis with eosinophils
In the pemphigus vegetans variant of pemphigus vulgaris, the suprabasal cleavage is accompanied
by hyperkeratosis, papillomatosis, and prominent acanthosis with downward proliferation of the rete
ridges [115]. Eosinophils may be present within the areas of cleavage.
The characteristic findings of pemphigus foliaceus include (picture 11) [115]:
●Intraepithelial cleavage with acantholysis beneath the stratum corneum or within the granular
layer; neutrophils within the blister cavity are occasionally seen
●Mixed inflammatory infiltrate in the superficial dermis with eosinophils and neutrophils; eosinophils
may be more prevalent in drug-induced pemphigus foliaceus
Direct immunofluorescence — Unlike the biopsy for routine histologic

examination, the biopsy for DIF should be taken from normal-appearing perilesional skin or mucosa.
The biopsy should not be placed in formalin. (See "Approach to the patient with cutaneous blisters",
section on 'Direct immunofluorescence'.)
2231
Both pemphigus vulgaris and pemphigus foliaceus demonstrate intercellular deposition of
immunoglobulin G (IgG) on DIF (picture 1A-B). Although some cases of pemphigus foliaceus
demonstrate deposition of IgG that is primarily distributed in upper levels of the epidermis (picture
1B), DIF cannot be used to reliably distinguish between these diseases.
Essentially all patients with idiopathic pemphigus vulgaris or pemphigus foliaceus have positive DIF
results. Thus, if DIF is negative, the diagnosis should be questioned. In contrast, negative DIF studies
may occur in patients with drug-induced pemphigus (see 'Drug exposure' above) [87,90].
Occasionally, intercellular deposition of antibodies occurs in other diseases (eg, spongiotic
dermatitis, burns, toxic epidermal necrolysis, systemic lupus erythematosus, or lichen planus) [96].
Serology — IIF and ELISA are serologic studies that can detect circulating autoantibodies
that bind epithelial cell surface antigens. In patients with positive DIF results, these tests are used to
further support the diagnosis of pemphigus.
Indirect immunofluorescence — More than 80 percent of patients with pemphigus

vulgaris or pemphigus foliaceus have circulating antibodies detectable by IIF [101]. The substrate
used influences the test sensitivity [101]. Monkey esophagus is the preferred substrate for the
diagnosis of pemphigus vulgaris. In contrast, normal human skin and guinea pig esophagus are the
most sensitive substrates for the diagnosis of pemphigus foliaceus. In both disorders, IgG deposits
are found intercellularly (picture 12). IIF cannot be used to distinguish between these diseases. (See
"Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)
Enzyme-linked immunosorbent assay — ELISA for IgG antibodies to

desmoglein 1 and desmoglein 3 is commercially available. ELISA is more sensitive and specific than
IIF for the diagnosis of pemphigus vulgaris and pemphigus foliaceus [101]. The sensitivity of ELISA
exceeds 90 percent [12].
In addition, since desmoglein antibody levels often fall in the setting of clinical improvement, ELISA
may aid with monitoring disease activity and the response to treatment [116-118]. In a retrospective
study that assessed the predictive values of pemphigus autoantibodies in patients with pemphigus
vulgaris and pemphigus foliaceus, desmoglein 1 autoantibodies were more closely correlated with
the disease course than desmoglein 3 autoantibodies [117]. Desmoglein 3 antibody levels remained
high during disease remissions in some patients with mucosal pemphigus vulgaris. In patients with
pemphigus vulgaris, levels of IgE antibodies to desmoglein 3 may also correlate with disease activity
[119]. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and "Management
of refractory pemphigus vulgaris and pemphigus foliaceus".)
Other — Additional serologic tests that may be used for the diagnosis of pemphigus vulgaris and
pemphigus foliaceus include immunoblotting and immunoprecipitation. However, these tests are
more difficult to perform than IIF and ELISA. Thus, they are infrequently used in the clinical setting.
2232
Aside from the detection of pemphigus antibodies in serum, pemphigus is not associated with
specific laboratory abnormalities. Other laboratory abnormalities may occur related to complications
of the disease or its treatment.
IgA pemphigus — Similar to other forms of pemphigus, the diagnosis of

immunoglobulin A (IgA) pemphigus is based upon the combined assessment of clinical and
laboratory findings. The standard laboratory workup consists of histologic examination, DIF, and IIF.
Typical histologic findings of IgA pemphigus include [6,115]:
●Intraepidermal clefts and pustules located in a subcorneal location (subcorneal pustular

dermatosis-type IgA pemphigus) or in the entire or mid-epidermis (intraepithelial neutrophilic
dermatosis)
●Slight or absent acantholysis
●Mixed inflammatory infiltrate in the dermis
DIF microscopy of perilesional skin reveals intercellular IgA deposition within the epidermis that is
occasionally more pronounced in the upper epidermis. Weaker intercellular deposits of IgG and/or
C3 may also be present [6,55]. IIF on monkey esophagus demonstrating intercellular deposits of IgA
offers further support for the diagnosis. However, IIF on monkey esophagus is positive in less than
or equal to 50 percent of patients [6,55]. IIF on human skin may demonstrate intercellular antibody
deposition more frequently; in one series of patients with IgA pemphigus, IIF of normal human skin
showed intercellular deposition of IgA in 31 of 48 patients (65 percent) [55].
Other studies that have been utilized to identify circulating IgA pemphigus desmocollin
autoantibodies include immunoblotting [120], ELISA using recombinant desmocollin [55,106], and
immunofluorescence molecular assay using desmocollin-transfected COS-7 cells [53,55]. The
availability of these studies is limited to specialized centers and research settings.
Although autoantibodies against desmocollin 1 appear to be strongly associated with the

subcorneal pustular dermatosis type of IgA pemphigus, autoantibodies to desmogleins may be
present in other patients with IgA pemphigus [54,55]. In one series of 22 patients with IgA
pemphigus, ELISA tests for IgA autoantibodies against desmoglein 1 or desmoglein 3 were positive
in three patients and one patient, respectively [54]. The patients with desmoglein autoantibodies had
either the intraepidermal neutrophilic type of IgA pemphigus or a presentation that had clinical and
pathologic features of pemphigus foliaceus. None of the 10 patients with subcorneal pustular
dermatosis-type IgA pemphigus had autoantibodies against these desmogleins, but all 10 had
serum samples that reacted with desmocollin 1 expressing COS-7 cells.
Paraneoplastic pemphigus — Similar to other forms of pemphigus,

the diagnosis of paraneoplastic pemphigus involves review of clinical, histologic, immunopathologic,
and serologic findings. The diagnosis of paraneoplastic pemphigus vulgaris is reviewed separately.
2233
(See "Paraneoplastic pemphigus", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS Multiple mucocutaneous

blistering diseases share clinical features with the different forms of pemphigus (table 3). In all
forms of pemphigus, laboratory investigations, particularly immunopathologic tests, usually easily
distinguish pemphigus from other diseases.
●Pemphigus vulgaris – Cutaneous involvement in pemphigus vulgaris must be distinguished from

other autoimmune blistering diseases. The morphology of cutaneous blisters in pemphigus vulgaris
can be helpful for narrowing the differential diagnosis. The flaccid blisters often seen in pemphigus
vulgaris contrast with the tense blisters that are frequently seen in association with subepithelial
blistering diseases, such as bullous pemphigoid, linear immunoglobulin A (IgA) bullous dermatosis,
and epidermolysis bullosa acquisita (picture 13A-C and algorithm 1). (See "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Bullous
pemphigoid' and "Linear IgA bullous dermatosis", section on 'Clinical manifestations' and
"Epidermolysis bullosa acquisita", section on 'Clinical manifestations'.)
Mucosal lesions pemphigus vulgaris can resemble other blistering or erosive disorders of the
mucous membranes. As examples, the possibility of other pemphigus variants, mucous membrane
pemphigoid, mucosal linear IgA bullous dermatosis or epidermolysis bullosa acquisita, erythema
multiforme, and Stevens-Johnson syndrome should be considered. (See "Approach to the patient
with cutaneous blisters", section on 'Mucous membrane involvement'.)
●Pemphigus foliaceus – The lesions of pemphigus foliaceus may resemble other inflammatory
disorders, such as seborrheic dermatitis (picture 14), impetigo, subacute cutaneous lupus
erythematosus (picture 15A-B), IgA pemphigus, and the non-IgA pemphigus form of subcorneal
pustular dermatosis (picture 16A-B). (See "Neutrophilic dermatoses", section on 'Subcorneal pustular
dermatosis'.)
●IgA pemphigus – The differential diagnosis of IgA pemphigus overlaps with pemphigus foliaceus.
In addition, disorders that may present with grouped vesicular lesions or pustules, such as
dermatitis herpetiformis (picture 17), bullous impetigo, linear IgA bullous dermatosis (picture 13B),
and pustular psoriasis (picture 18A-B) should be considered.
●Paraneoplastic pemphigus – The differential diagnosis of paraneoplastic pemphigus is reviewed

separately. (See "Paraneoplastic pemphigus", section on 'Differential diagnosis'.)
SUMMARY AND
RECOMMENDATIONS
2234
●Pemphigus comprises a group of autoimmune blistering diseases that are characterized by
histologic acantholysis (loss of cell-to-cell adhesion) and mucosal and/or cutaneous blistering. The
four major types of pemphigus are pemphigus vulgaris, pemphigus foliaceus, immunoglobulin A
(IgA) pemphigus, and paraneoplastic pemphigus (table 1). (See 'Classification' above.)
●Pemphigus is rare. Pemphigus vulgaris is the most common form of pemphigus. However, in
certain areas, particularly in locations where an endemic form of pemphigus foliaceus occurs,
pemphigus foliaceus is more prevalent. (See 'Epidemiology' above.)
●The intraepidermal blistering observed in pemphigus occurs due to an immune response that
results in the deposition of autoantibodies against epidermal cell surface antigens within the
epithelium of mucous membranes or skin. The mechanism through which acantholysis occurs is
not fully understood. (See 'Pathogenesis' above.)
●Pemphigus vulgaris generally is a more severe disease than pemphigus foliaceus. Patients with
pemphigus vulgaris usually present with widespread mucocutaneous blisters and erosions (picture
2A-B, 3A-D). Cutaneous blistering in pemphigus foliaceus tends to occur in a seborrheic distribution
(picture 6A-C). Compared with pemphigus vulgaris, blistering in pemphigus foliaceus is more
superficial. (See 'Clinical features' above.)
●Vesicles, pustules, and crusts on skin are common features of IgA pemphigus. The skin lesions
may appear in an annular, circinate, or herpetiform distribution. (See 'IgA pemphigus' above.)
●The diagnosis of pemphigus is based upon the recognition of consistent clinical, histologic, and
direct immunofluorescence (DIF) findings, as well as the detection of circulating immunoglobulin G
(IgG) and IgA autoantibodies against cell surface antigens in serum (table 1). Laboratory studies are
useful for distinguishing pemphigus from other blistering and erosive diseases. Our standard
laboratory work-up for patients with clinical findings suggestive of pemphigus vulgaris or foliaceus
includes (see 'Diagnosis' above):
•A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining
•A perilesional skin or mucosal biopsy for DIF
•Serum collection for detection of autoantibodies by enzyme-linked immunosorbent assay (ELISA)

and indirect immunofluorescence (IIF)
2235
Paraneoplastic pemphigus - UpToDate
uptodate.com/contents/paraneoplastic-pemphigus/print
INTRODUCTION Paraneoplastic pemphigus (PNP) is an often fatal

paraneoplastic mucocutaneous blistering disease that is most commonly induced by
lymphoproliferative disorders [1]. Paraneoplastic autoimmune multiorgan syndrome (PAMS) is an
alternative term used to refer to PNP. This latter term reflects the inclusion of the nonbullous
cutaneous eruptions and pulmonary involvement that may develop in the setting of PNP [2].
The pathogenesis, clinical features, and treatment of PNP will be discussed here. Pemphigus
vulgaris and pemphigus foliaceus are reviewed separately. (See "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus" and "Fogo selvagem (Brazilian endemic pemphigus
foliaceus)".)
EPIDEMIOLOGY Although it is well-accepted that PNP is a rare disorder,

the incidence and prevalence of PNP are unknown. The rarity of the disorder is supported by a
review of 100,000 adverse events reports to the US Food and Drug Administration from patients with
non-Hodgkin lymphoma and chronic lymphocytic leukemia [3]. The review identified only 12 patients
who likely had the disease.
2236
Adults between the ages of 45 and 70 years constitute the most common demographic affected by
PNP [4]. However, the disorder may also occur in children [5-7]. Both males and females may be
affected. Clear racial, ethnic, or geographic differences in the risk for PNP have not been established.
ETIOLOGY PNP occurs in association with a variety of neoplastic disorders [8,9]. In

a review of 163 cases of PNP reported between 1990 and 2003, the frequency of associated
conditions was as follows [8]:
●Non-Hodgkin lymphoma (39 percent)
●Chronic lymphocytic leukemia (18 percent)
●Castleman's disease (18 percent)
●Carcinoma (9 percent)
●Thymoma (6 percent)
●Sarcoma (6 percent)
●Waldenström's macroglobulinemia (1 percent)
●Hodgkin lymphoma, monoclonal gammopathy, and melanoma (each <1 percent)
As illustrated in this study, lymphoproliferative diseases account for the vast majority of disorders
associated with PNP. The sarcomas detected in patients with PNP include liposarcoma,
leiomyosarcoma, reticulum cell sarcoma, and malignant nerve sheath tumors [8]. Rare patients have
tumors that are too poorly differentiated to define; these tumors are usually retroperitoneal and often
have the characteristics of follicular dendritic cell sarcomas [10].
The distribution of PNP-associated neoplastic disorders may differ between children and the general
population of patients with PNP. Castleman's disease is likely the most common associated disease
in children. In a series of 14 children and adolescents with PNP, Castleman's disease was present in
12 patients (86 percent) [5].
The time course for the development of PNP in relation to the underlying neoplastic disorder varies.
In two-thirds of patients, the discovery of the neoplastic disorder precedes PNP [11]. In our
experience, the peak time for the development of PNP in patients with non-Hodgkin lymphoma is two
to three years after diagnosis of the lymphoma. Although as many as 40 years have elapsed
between Castleman's disease and the subsequent development of PNP, an interval of this length is
highly unusual [8]. Occasionally, the underlying neoplastic disorder is not identified prior to the death
of the patient. In a series of 104 patients with clinical and immunologic findings consistent with PNP,
12 patients had no detectable tumor [9].
2237
PATHOGENESIS Several theories on the connection between neoplasms
and PNP have been proposed. In general, it appears that the neoplastic process induces an
autoimmune disorder in which both humoral and cell-mediated immune responses play significant
roles [2,12]. In an individual patient, the degree to which each type of immune response contributes
to PNP may influence the clinical presentation of the disease.
Humoral immunity — Antibodies against multiple epithelial antigens have

been detected in PNP. The primary antigenic targets are desmoplakins, intracellular proteins that
play an integral role in the anchoring of intermediate filaments to desmosomal plaques and in
epidermal cell adhesion [13]. The detection of antibodies against two desmoplakins (periplakin and
envoplakin) are the most specific laboratory findings in PNP [14,15]. (See 'Other studies' below.)
Serum from affected patients can also contain antibodies against desmoplakin I, desmoplakin II,
epiplakin, bullous pemphigoid antigen 1, plectin, and the protease inhibitor alpha-2-macroglobulin-
like-1 (A2ML1) [16,17]. Antibodies against desmoglein 3, a desmosomal protein targeted in
pemphigus vulgaris, have also been identified in patients with PNP [18]. In addition, rare cases of
PNP in which antibodies against laminin 332 were detected in patients with follicular dendritic cell
sarcoma have been reported [19,20]. (See "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus", section on 'Pathogenesis'.)
Antibody production — The pathways that lead to the production and deposition
of antibodies in the skin and mucous membranes in PNP are not well understood. Proposed
mechanisms include the stimulation of antibody production by tumor-induced immune
dysregulation as well as the occurrence of cross-reactivity between antibodies directed against
tumor cells and epithelial antigens [12]. Epitope spreading, a phenomenon in which tissue injury
leads to the exposure of antigens normally hidden from the immune system, may also play a role
[12]. In such cases, a cutaneous cytotoxic or inflammatory reaction induced by the tumor could
result in the immune detection of intracellular antigens in desmosomes and hemidesmosomes
[12,21].
Although some authors have proposed that in certain lymphoproliferative disorders, antibody
production by B lymphocytes may contribute to the development of PNP [22,23], the relatively long
period required for PNP resolution after the resection of Castleman's tumors (5 to 10 months) and
the association of PNP with other malignancies, such as retroperitoneal sarcomas, reduce support
for this concept as a major pathogenic mechanism. Moreover, in PNP related to Waldenström's
macroglobulinemia, an IgM myeloma, the autoantibodies detected are polyclonal antibodies of the
IgG class. This finding suggests an alternative source for antibody production [24].
Pathogenicity — Several studies have sought to clarify which antibodies, if any, are truly
pathogenic in PNP. Although antibody deposition could stimulate the local recruitment of
inflammatory cells and antibody-dependent cellular cytotoxicity, antibodies against epidermal
2238
components could also form as a secondary event following epidermal injury. A pathogenic role for
antienvoplakin, antiperiplakin, and antidesmoglein 3 antibodies is suggested by the following
observations:
●Antienvoplakin and antiperiplakin antibodies can induce dissociation of cultured human epidermal
keratinocytes in vitro [25].
●Levels of antienvoplakin and antiperiplakin antibodies decreased as clinical improvement occurred

following surgical removal of Castleman's tumors or thymoma in one small study [25].
●Removal of antidesmoglein 3 antibodies from serum taken from PNP patients prior to the injection
of the serum into neonatal mice prevented the development of blisters in mice [18].
However, the contribution of these and other antibodies to the development of PNP remains
uncertain. In particular, antidesmoglein 3 antibodies have not been essential for the induction of
PNP in other animal models [2], and normally, desmoglein 3 is not expressed by pulmonary
epithelium, which can be affected in PNP [26]. However, in one mouse model of PNP, lung
inflammation produced ectopic expression of desmoglein 3 in the pulmonary epithelium [27].
Cell-mediated immunity — The presence of cellular infiltrates and

features consistent with interface or lichenoid dermatitis in tissue specimens taken from patients
with PNP suggests that cellular immunity contributes to this disorder. In support of this concept,
CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages
have been detected at the epidermal-dermal junction in affected patients [2]. In addition, high levels
of interleukin-6 (IL-6), a cytokine that promotes lymphocyte maturation, cytotoxic T cell activation,
and antibody production, have been detected in patients with PNP [28]. Increased local production of
the proinflammatory cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha has
also been reported in these patients [29].
Additional support for a role for cell-mediated immunity stems from the observation that cell-
mediated cytotoxic reactions are seen in other skin diseases that clinically and histopathologically
resemble PNP. Cutaneous graft-versus-host disease, lichen planus, and erythema multiforme can be
difficult to distinguish clinically from PNP [12]. (See 'Clinical manifestations' below.)
A cell-mediated immune reaction in the skin and mucous membranes may contribute to the
stimulation of the humoral immune system. Inflammation-induced damage to the basal layer of the
epithelium could result in the immune recognition of normally hidden epithelial antigens through
epitope spreading. (See 'Antibody production' above.)
CLINICAL MANIFESTATIONS Clinically, PNP is

characterized by the following mucocutaneous and systemic features:
●Severe erosive stomatitis
2239
●Polymorphous skin lesions
●Lymphoreticular or other malignancies
●Pulmonary involvement with features of bronchiolitis obliterans (may or may not be present)
Mucosal lesions — Erosive, painful mucositis is uniformly present in patients

with PNP, and in its absence, the diagnosis should not be considered. Oral involvement is most
common [9,15], and patients develop a painful, erosive stomatitis that characteristically includes
involvement of the tongue (picture 1A-C) [15]. Oral erosions are the initial disease manifestation in
almost one-half of patients [12].
Other potential sites of mucosal involvement include the nasopharynx, conjunctiva, and anogenital
area. Occasionally, lesions develop on the mucosal surfaces of the esophagus, stomach, duodenum,
or colon [30,31].
Mucosal involvement may lead to significant side effects. The pain associated with oral mucosal
disease often inhibits oral intake, contributing to malnutrition. Conjunctival involvement may lead to
cicatrizing conjunctivitis, damage to the cornea, and visual impairment [32-34].
Cutaneous lesions — Cutaneous lesions typically develop after the onset of

mucosal lesions. The morphology of the cutaneous eruption is highly variable. Patients may present
with bullae resembling the flaccid bullae of pemphigus vulgaris or the tense bullae of bullous
pemphigoid, inflammatory violaceous papules or plaques resembling lichen planus or graft-versus-
host disease, targetoid lesions similar to those of erythema multiforme or Stevens-Johnson
syndrome, or extensive cutaneous desquamation resembling toxic epidermal necrolysis (picture 2A-
C) [9,11,15,35]. The cutaneous lesions of patients who develop PNP following treatment with
rituximab may lack blistering and have more of a lichenoid or erythema multiforme-like appearance
[36].
More than one lesion type may occur simultaneously in individual patients. Less common
cutaneous manifestations include psoriasiform, pustular, and vegetative lesions, as well as the
development of alopecia or palmoplantar or periungual involvement [6,12,37].
Pulmonary disease — Patients with PNP may develop a life-threatening

restrictive bronchiolitis consistent with bronchiolitis obliterans. The frequency with which pulmonary
involvement occurs is not well-defined. In one retrospective study of 17 patients with PNP, restrictive
bronchiolitis was detected in three patients (18 percent) [38]. In contrast, in a series of 28 patients
with PNP related to Castleman's disease, pulmonary involvement was detected in 26 of 28 patients
(93 percent) [39].
2240
Bronchiolitis obliterans usually occurs late in the course of the disease, and is heralded by the
development of shortness of breath that is out of proportion to changes visualized on chest imaging.
An obstructive pattern is evident on pulmonary function tests, and CT scans may demonstrate
patchy or diffuse air trapping [38]. (See "Overview of bronchiolar disorders in adults" and "Overview
of pulmonary function testing in adults" and "Overview of pulmonary function testing in children".)
The mechanism through which pulmonary damage occurs is not definitively known. Acantholysis,
mixed inflammatory infiltrates, and antibody deposition have been detected in pulmonary epithelium
in PNP [26]. It has been suggested that pulmonary involvement results from the immune targeting of
plakin proteins in the bronchial epithelium, resulting in detachment of cells and the occlusion of the
distal alveolar sacs by cellular debris [2]. CD8+ T lymphocytes may play an important role in
pulmonary injury; a panmural infiltrate composed of CD8+ T lymphocytes was detected in a post-
mortem examination of pulmonary tissue from a patient with PNP [40].
Antibodies against epiplakin may be markers for pulmonary involvement in PNP. In a series of 48
patients with PNP in Japan, antibodies against epiplakin were more prevalent in patients with
associated bronchiolitis obliterans than patients without this condition [17]. The finding that passive
transfer of antiepiplakin antibodies into mice produces inflammatory changes in small airway
epithelia suggests a possible pathogenic role for antiepiplakin antibodies [17].
Other organs — Antibody deposition was detected in muscle, bladder, and renal
glomeruli in a study of three patients with PNP [2]. However, evidence for organ dysfunction related
to these findings was not identified in these patients.
DIAGNOSIS
Diagnostic approach — Due to the variability in the clinical findings of PNP
and the similarities between PNP and other disorders, the combined assessment of clinical and
laboratory findings is necessary to establish the diagnosis. The key clinical findings that suggest
PNP are the development of a painful erosive mucositis and polymorphous skin eruption in the
setting of neoplastic disease. The laboratory studies used to support the diagnosis include light
microscopy, direct immunofluorescence microscopy (DIF), and serologic studies that detect
antibodies against epidermal proteins. (See "Approach to the patient with cutaneous blisters",
section on 'Diagnostic tests'.)
Our standard laboratory work-up for patients with suggestive clinical findings is as follows:
●A lesional skin or mucosal biopsy for light microscopy (typically a 4 mm punch biopsy)
●A perilesional punch biopsy specimen from skin or mucosa for DIF (specimen must not be placed
in formalin)
2241
●Serum for indirect immunofluorescence (IIF) studies on monkey esophagus and rat bladder
epithelium
●Serum for enzyme-linked immunosorbent assay (ELISA) for antienvoplakin and antiperiplakin
antibodies
Immunoprecipitation and immunoblotting are additional serologic tests that have been utilized for
the diagnosis of PNP. However, the availability of these tests is limited and these studies are not
typically utilized in the clinical setting.
Careful correlation of the clinical and laboratory findings is necessary for an accurate diagnosis of
PNP because the histologic findings of PNP are not pathognomonic, and immunofluorescence
studies and ELISA testing are sometimes negative. In particular, in patients who develop PNP after
treatment with rituximab, an anti-CD20 monoclonal antibody, autoantibodies may not be detectable
in the epidermis or serum [36].
The laboratory studies used for the diagnosis of PNP are reviewed below.
Histopathology — The most common histopathologic findings in PNP are suprabasal

acantholysis (picture 3), keratinocyte necrosis, and a lichenoid interface dermatitis [12,41]. However,
the histopathologic findings vary, often resembling other disorders that have similar clinical features
(see 'Cutaneous lesions' above) [42]. For example, while acantholysis is typically a prominent feature
in lesions that resemble pemphigus vulgaris, specimens taken from patients with tense bullae that
resemble bullous pemphigoid may exhibit subepidermal clefting. Epidermal dyskeratosis,
vacuolization of basal keratinocytes, and a lichenoid lymphocytic infiltrate are often found in
cutaneous lesions that resemble lichen planus, erythema multiforme, or graft-versus-host disease
[12].
Since the histologic findings overlap with multiple other disorders, correlation with the clinical
scenario and other laboratory tests is important for diagnosis. The technique used to perform skin
biopsies in blistering disorders is reviewed separately. (See "Approach to the patient with cutaneous
blisters", section on 'Skin biopsy'.)
Direct immunofluorescence — IgG or C3 can be detected intercellularly

and/or at the basement membrane zone on DIF microscopy in many cases of PNP (picture 4).
However, negative DIF studies are not uncommon [15,43]. In a study of 115 patients with PNP,
pemphigus vulgaris, or pemphigus foliaceus, the sensitivity of DIF for PNP was only 41 percent [15].
The specificity of the test was higher; when compared with patients with pemphigus vulgaris or
pemphigus foliaceus who had (n = 12) or did not have (n = 81) a concurrent malignancy, the
specificity of DIF was 83 and 93 percent, respectively. (See "Approach to the patient with cutaneous
blisters", section on 'Direct immunofluorescence'.)
2242
The DIF findings of PNP can be similar to the findings of pemphigus vulgaris and pemphigus
erythematosus. Pemphigus vulgaris is characterized by the presence of epithelial cell surface IgG
and C3, and pemphigus erythematosus sometimes presents with both epithelial cell surface and
basement membrane zone deposition of IgG and C3.
Indirect immunofluorescence — IIF performed on rat bladder epithelium is

particularly useful for differentiating PNP from pemphigus vulgaris. While both PNP and pemphigus
vulgaris demonstrate epithelial cell surface deposits of IgG on monkey esophagus epithelium
(picture 5), only PNP demonstrates this finding on rat bladder epithelium. This feature results from
the absence of desmogleins (the target of antibodies in pemphigus vulgaris) in rat bladder
epithelium.
The transitional epithelium of murine (eg, rat) bladder is the preferred substrate for IIF studies in
patients with PNP (picture 6) [12]. When performed on rat bladder epithelium, estimates for the
sensitivity and specificity of this test have ranged from 74 to 86 percent and 83 to 100 percent,
respectively [15,43,44]. (See "Approach to the patient with cutaneous blisters", section on 'Indirect
immunofluorescence'.)
Enzyme-linked immunosorbent assay — Enzyme-linked

immunosorbent assays (ELISA) for antibodies against envoplakin and periplakin have been utilized
in studies of patients with PNP [14,45]. In one series of 16 patients with PNP, ELISA utilizing
recombinant proteins derived from human kidney cells detected antibodies against envoplakin and
periplakin in all patients [14]. ELISA for desmoglein 3 was positive in 11 patients. In a separate study
that evaluated serum from 31 patients with PNP and 80 controls, an ELISA based on the N-terminal
fragment of envoplakin had a sensitivity and specificity for PNP of 81 and 99 percent, respectively;
the ELISA for periplakin had a sensitivity and specificity of 74 and 96 percent [45].
Other studies — Immunoprecipitation and immunoblotting are additional serologic tests

that have been utilized for the diagnosis of PNP. However, the availability of these labor-intensive
tests is limited to research laboratories and specialized centers. Thus, in clinical practice,
immunoprecipitation and immunoblotting are not typically utilized for diagnosis.
●Immunoprecipitation – The immunoprecipitation assay is considered to be more sensitive and

specific than indirect immunofluorescence for diagnosis [46]. The use of immunoprecipitation
assays for the diagnosis of PNP involves the incubation of patient serum with radiolabeled
keratinocyte proteins extracted from keratinocyte cultures [39]. The antibody-antigen complexes that
result are precipitated and analyzed via gel electrophoresis.
A variety of immunoprecipitation bands have been detected in PNP, including plectin (>400 kDa),
desmoplakin I (250 kDa), bullous pemphigoid antigen 1 (230 kDa), envoplakin and desmoplakin II (a
210 kDa double band), periplakin (190 kDa), and alpha-2-macroglobulin-like-1 (A2ML1, 170 kDa)
[2,47]. The detection of periplakin and envoplakin or A2ML1 by immunoprecipitation is considered a
highly specific laboratory finding of PNP [44]. (See 'Diagnostic approach' above.)
2243
The high sensitivity of immunoprecipitation for the diagnosis of PNP was demonstrated in a study of
19 patients with PNP (defined by consistent mucocutaneous findings, plakin autoantibodies, and an
underlying neoplasm) and 40 controls that found sensitivities of antienvoplakin ELISA, rat bladder
IIF, immunoblotting, radioactive immunoprecipitation, and a novel nonradioactive
immunoprecipitation procedure of 63, 74, 89, 95, and 100 percent respectively [44]. Specificities for
these tests were 98, 100, 100, 100, and 86 percent, respectively.
●Immunoblotting – In addition to immunoprecipitation, immunoblotting is another highly sensitive

and specific method that has been used to detect autoantibodies in PNP [15,44]. In a study of 115
patients with PNP, pemphigus vulgaris, and pemphigus foliaceus, the sensitivity of immunoblotting
for envoplakin and/or periplakin for the diagnosis of PNP was 82 percent [15]. The specificity of the
immunoblot technique was 100 percent. Similar to immunoprecipitation, the availability of
immunoblotting is limited.
Associated laboratory findings — Aside from the characteristic

autoantibodies, no serologic tests are useful for the diagnosis of PNP. Autoimmune cytopenias
including thrombocytopenia, neutropenia, and autoimmune hemolytic anemia may be present as
associated features. PNP patients may also develop clinical and serologic evidence of myasthenia
gravis [48].
Evaluation for the underlying disorder — The selection

of studies for the evaluation for an underlying cause in patients with PNP is based upon the
spectrum of associated neoplasms. As examples, laboratory evaluation may identify hematologic
disorders such as chronic lymphocytic leukemia or Waldenström's macroglobulinemia, while
radiologic imaging can aid in the diagnosis of Castleman's disease and lymphomas.
We typically perform the following evaluation [12]:
●Thorough patient history and physical examination for signs suggestive of malignancy or
lymphoproliferative disease
●Complete blood count
●Serum protein electrophoresis
●CT scan of the chest, abdomen, and pelvis
As noted above, the vast majority of cases in children and adolescents are associated with
Castleman's disease [5]. (See 'Etiology' above.)
Evaluation for pulmonary involvement — Because

pulmonary involvement in PNP is typically accompanied by dyspnea, an evaluation for pulmonary
involvement can be reserved for symptomatic patients. At the initial signs of shortness of breath or
2244
dyspnea on exertion, we refer patients to a pulmonologist for further evaluation. (See 'Pulmonary
disease' above.)
DIFFERENTIAL DIAGNOSIS Due to the wide variety of

clinical findings that occur in PNP, the differential diagnosis is broad. Oral mucosal lesions must be
differentiated from chemotherapy-associated mucositis and the multiple other blistering disorders
that may affect mucosal surfaces (see "Approach to the patient with cutaneous blisters", section on
'Mucous membrane involvement'). In patients with widespread blisters and erosions, the possibility
of pemphigus vulgaris and subepidermal autoimmune blistering disorders should be considered
(see "Approach to the patient with cutaneous blisters", section on 'Generalized distribution'). Papular
lesions of PNP can resemble lichenoid drug eruptions and lichen planus. (See "Lichenoid drug
eruption (drug-induced lichen planus)" and "Lichen planus".)
In addition to correlation of the mucocutaneous lesions with pathologic and serologic studies,
knowledge of the chronic, progressive course of PNP is useful for diagnosis. Although similar
mucocutaneous lesions may occur in erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis, the acute nature of these disorders (improvement usually attained within three
to five weeks) distinguishes them from PNP. (See 'Prognosis' below and "Erythema multiforme:
Pathogenesis, clinical features, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal
TREATMENT The treatment of patients with PNP consists of the suppression

of the disease manifestations and the management of patient symptoms. Treatment of the
underlying malignancy is beneficial in some cases.
Treatment of the underlying neoplasm — In PNP

associated with Castleman's disease or thymoma, resection of the tumor often results in disease
remission. In one series of five adults with Castleman's disease and PNP, significant improvement in
mucosal lesions and resolution of skin lesions occurred in all four patients who returned for a follow-
up visit six months after surgery [49]. However, remission may take up to one to two years to occur,
and the disease persists after resection in some cases [39,50].
In PNP associated with other neoplastic disorders, the response of PNP to treatment of the
underlying neoplasm appears to be less favorable. Once initiated, PNP often progresses
independent of the status of the underlying neoplastic disease [46].
Suppression of disease — Due to the rarity of PNP, no randomized

therapeutic trials have been performed and efficacy data are primarily limited to case reports. The
response to treatment is highly variable. Refractory PNP, particularly refractory stomatitis, is
common [50].
2245
Conventional immunosuppressants — Systemic glucocorticoids are
often the initial treatments attempted in patients with PNP [11,43,50]. High-dose regimens, usually
beginning with 1 mg/kg per day of prednisone followed by a slow taper as tolerated are used [11].
We typically taper patients to a maintenance dose of 10 to 15 mg of prednisone per day over the
course of six months. The cutaneous manifestations are more likely to respond to systemic
glucocorticoids than the oral mucosal lesions; the latter are often refractory to therapy [50].
Other immunosuppressive agents are often combined with systemic glucocorticoids in attempts to
attain further clinical improvement or to take advantage of their glucocorticoid-sparing effects.
Cyclophosphamide [51,52], mycophenolate mofetil [53], azathioprine [54,55], and cyclosporine [56]
have been reported to be beneficial in individual patients [50].
Rituximab — Multiple case reports have described the use of rituximab, a chimeric antibody
that targets CD20 on B lymphocytes, in patients with PNP associated with various neoplastic
disorders [57]. Patients have been treated with various regimens, including 375 mg/m2 of rituximab
administered on a weekly basis for four weeks with or without subsequent less frequent doses [57].
The response to rituximab therapy is highly variable. A review of 13 reported cases of PNP that were
treated with rituximab found complete responses in three patients, all of whom had non-Hodgkin
lymphoma [57]. The limited efficacy of rituximab may reflect the fact that the drug reduces
autoantibody levels but has a lesser effect on regulation of cell-mediated immunity. In one patient,
rituximab improved the blistering mucocutaneous lesions but failed to prevent the progression of
fatal bronchiolitis obliterans [58]. Further study is necessary to definitively determine the role
rituximab should play in PNP.
Other therapies — In individual patients, plasmapheresis [59], myeloablation with

cyclophosphamide [60], intravenous immunoglobulin (IVIG) [22,61], alemtuzumab [62,63], and
daclizumab [36] have been reported to be effective in combination with other therapeutic
interventions. Topical tacrolimus in a 0.03% suspension used to rinse the mouth three times daily for
six weeks was associated with improvement in a relapse of oral involvement in a patient with PNP
due to non-Hodgkin lymphoma [64].
Our approach — Definitive guidelines for the management of PNP have not been
established. We have found the following approach most useful:
●Define and treat the underlying neoplasm (particularly useful in Castleman's disease).
●First-line therapy: Administer prednisone (1 mg/kg) in an attempt to provide acute improvement in

mucocutaneous manifestations; initiate rituximab as soon as feasible (375 mg/m2 weekly for four
weeks and repeat this course every three to six months); taper prednisone slowly as tolerated.
2246
●For patients who improve only partially with the regimen above or who develop disease flares
during prednisone tapering, we typically add an immunosuppressive agent, either mycophenolate
mofetil (1000 mg twice daily) or azathioprine (up to 3 mg/kg per day; dose adjustments may be
made according to thiopurine methyltransferase [TPMT] activity). We generally avoid
cyclophosphamide or cyclosporine due to concerns regarding the consequences of profound
immunosuppression.
●IVIG (2 g/kg given as 0.67 g/kg per day for three days and repeated monthly as needed) can be
added to the therapeutic regimen to provide an additional immunomodulatory effect without
increasing the level of overall immunosuppression.
We have observed positive responses to the non-depleting anti-CD25 monoclonal antibody

daclizumab in patients who have failed to improve with the above measures, particularly in patients
with progressive pulmonary involvement. However, daclizumab is no longer commercially available.
We do not have experience with basiliximab, an agent with a similar mechanism of action.
Of note, the decision to initiate immunomodulatory therapy in the setting of PNP should be made in
conjunction with the patient's oncologist.
Adjunctive measures — Due to the fact that PNP may be difficult to treat,
management of patient symptoms is also an important component of patient management.
Anesthetic mouthwashes can be attempted for oral pain, but often do not help significantly, and
narcotic pain medications may be necessary. Vaseline gauze can be applied to cutaneous erosions.
For patients with extensive cutaneous erosions, such as patients with a toxic epidermal necrolysis-
like presentation, admission to a burn unit facilitates patient management and wound care.
Given the extent of immunosuppressive therapy often required for the management of PNP, the need
for prophylaxis against Pneumocystis pneumonia should be evaluated. (See "Treatment and
prevention of Pneumocystis pneumonia in HIV-uninfected patients", section on 'Prophylaxis'.)
PROGNOSIS PNP has traditionally been thought to have a very poor prognosis
with most patients dying within two years and mortality rates between 75 and 90 percent [26,43].
Affected patients usually succumb to sepsis, respiratory failure due to pulmonary involvement, or
the underlying malignancy [9,10,43]. However, a French multicenter retrospective study of 53
patients with PNP who received a variety of therapies suggested that the prognosis of PNP may be
better [43]. The respective one, three, and five-year overall survival rates were 49, 41, and 38 percent.
Patients with erythema multiforme-like skin lesions, particularly in the context of severe skin or
mucosal involvement appeared to have the worst prognosis.
Pulmonary disease often fails to improve despite successful treatment of the malignancy and the
resolution of mucocutaneous lesions [4,38]. Lung transplantation was used for the management of
an adolescent with pulmonary involvement related to Castleman's disease [65].
2247
SUMMARY AND
RECOMMENDATIONS
●Paraneoplastic pemphigus (PNP) is a rare autoimmune blistering disorder that may occur in the
setting of lymphoproliferative disorders and malignancies. Although adults are most commonly
affected, PNP may also occur in children. (See 'Epidemiology' above.)
●Multiple malignant and lymphoproliferative disorders are associated with PNP. The disorders most
frequently linked to PNP are non-Hodgkin lymphoma, chronic lymphocytic leukemia, and
Castleman's disease. (See 'Etiology' above.)
●The pathophysiology of PNP is not well understood. It is likely that both the humoral and cellular
immune system contribute significantly to this disease. (See 'Pathogenesis' above.)
●Antibodies against periplakin and envoplakin are strongly associated with PNP. A pathogenic role
for these and the multiple other antibodies detected in patients with PNP remains uncertain. (See
●The clinical manifestations of PNP vary widely. Mucosal involvement occurs in all patients, with
oral involvement being the most common site for involvement (picture 1A-C). The most common
cutaneous manifestations are flaccid or tense bullae, lichenoid papules or plaques, targetoid lesions,
and erosions (picture 2A-B). (See 'Clinical manifestations' above.)
●A restrictive bronchiolitis consistent with bronchiolitis obliterans occurs in a minority of patients

with PNP. Pulmonary involvement can be life-threatening. (See 'Pulmonary disease' above.)
●PNP shares clinical and pathologic features with multiple other disorders. Confirmation of a
diagnosis of PNP requires the correlation of clinical, pathologic, and immunologic studies. (See
'Diagnosis' above and 'Differential diagnosis' above.)
●Data are limited on therapies for PNP. Surgical removal of the underlying tumor can be beneficial in
patients with Castleman's disease or thymoma, but is much less likely to be of value for other
malignancies. (See 'Treatment' above.)
●For patients with PNP, we suggest the use of prednisone and rituximab as first-line therapy (Grade
2C). If this is not effective, additional therapies such as mycophenolate mofetil, azathioprine, and
intravenous immunoglobulin can be added as adjunctive therapy. (See 'Our approach' above.)
2248
Initial management of pemphigus vulgaris and pemphigus
foliaceus
uptodate.com/contents/initial-management-of-pemphigus-vulgaris-and-pemphigus-foliaceus/print
INTRODUCTION The term "pemphigus" describes a group of autoimmune

mucocutaneous blistering disorders characterized by acantholysis (loss of keratinocyte to
keratinocyte adhesion) in the epithelium of mucous membranes or skin. Pemphigus vulgaris and
pemphigus foliaceus are the two most common forms of pemphigus. Significant morbidity and
mortality can occur as a result of complications of these diseases and their treatments.
Systemic glucocorticoids and rituximab are the mainstays of therapy for pemphigus vulgaris and
pemphigus foliaceus, and are usually highly effective for obtaining control of disease. Nonsteroidal
immunomodulatory agents such as azathioprine, mycophenolate mofetil, and dapsone commonly
are prescribed in conjunction with systemic glucocorticoids in an attempt to minimize the risk for
adverse effects of long-term, high-dose glucocorticoid therapy. Other interventions, including
intravenous immune globulin (IVIG), immunoadsorption, and cyclophosphamide, are typically
reserved for patients with refractory disease. (See "Management of refractory pemphigus vulgaris
and pemphigus foliaceus".)
The initial management of pemphigus vulgaris and pemphigus foliaceus will be reviewed here. The
management of refractory pemphigus vulgaris and pemphigus foliaceus, the pathogenesis and
diagnosis of pemphigus, and the diagnosis and management of paraneoplastic pemphigus are
reviewed separately. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus"
and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Paraneoplastic
pemphigus".)
2249
INDICATIONS FOR THERAPY Although pemphigus
vulgaris typically presents as a more severe disorder than pemphigus foliaceus due to the common
presence of both mucosal and cutaneous involvement (picture 1A-B), both disorders can lead to
significant morbidity. Oral mucosal involvement, which occurs in almost all patients with pemphigus
vulgaris, usually is accompanied by severe pain, and may lead to poor alimentation resulting in
weight loss and malnutrition (picture 2A-C). In addition, the widespread loss of the epidermal barrier
that occurs in pemphigus vulgaris and pemphigus foliaceus may lead to protein loss, fluid loss,
electrolyte imbalances, dietary insufficiencies, increased catabolism, and increased risk for local and
systemic infections (picture 3A-D). (See "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus", section on 'Clinical features'.)
The complications of pemphigus vulgaris can be life-threatening; it is estimated that prior to the use
of systemic immunosuppressants, more than 70 percent to nearly 100 percent of patients died
within one to five years [1-3]. Pemphigus foliaceus, which is characterized by shallow blisters and
involvement limited to the skin, is considered to have a better prognosis than pemphigus vulgaris
(picture 4A-C) [3]; however, progression of pemphigus foliaceus may lead to extensive involvement
and similar complications.
Given the potential for severe morbidity and mortality from pemphigus vulgaris and pemphigus
foliaceus, treatment is always indicated at the time of disease onset, even for patients who initially
present with only mild disease. However, treatment must be approached carefully because the
therapeutic regimens utilized for pemphigus are not benign; most of the currently estimated 5 to 10
percent mortality rate from pemphigus vulgaris is considered to result from complications from
treatment [4-7]. Infections ranging from minor skin infections to life-threatening opportunistic
infections are common complications of the immunosuppressive regimens typically used for
pemphigus therapy [8,9].
APPROACH TO TREATMENT The goal of treatment

in pemphigus is to induce complete remission while minimizing treatment-related adverse effects.
The paucity of large, high-quality prospective trials that compare the therapeutic options for this
disease as well as the variability in study protocols, outcome measures, and results have made
definitive conclusions on the best approach to treatment difficult [10]. Adherence to the definitions
for patient assessment outlined by a 2008 consensus of experts may facilitate systematic
interpretation of published literature in the future [11].
The approach to treatment of pemphigus vulgaris and pemphigus foliaceus is similar. Many studies
that have evaluated therapies for pemphigus have combined patients with these disorders [12].
The first priority for patient management is to attain rapid disease control. This is typically achieved
through the administration of systemic glucocorticoids [13]. The response to systemic
glucocorticoid therapy often is fast; clinically significant improvement is usually evident within two
weeks. (See 'First-line therapy' below.)
2250
Although systemic glucocorticoid therapy is highly effective, the high doses and long treatment
periods that are needed to maintain the clinical response may lead to serious or life-threatening side
effects [4]. For this reason, a nonsteroidal systemic immunomodulatory medication is often used as
an adjunct to systemic glucocorticoid therapy in an attempt to minimize glucocorticoid
consumption. (See "Major side effects of systemic glucocorticoids" and 'Rituximab and prednisone'
below and 'Nonsteroidal adjuvant therapies' below.)
The addition of rituximab, an agent traditionally reserved for refractory pemphigus, to a systemic
glucocorticoid appears to allow for use of lower cumulative doses of the systemic glucocorticoid
and improve treatment efficacy and safety in patients with newly diagnosed pemphigus, although
additional data are necessary to clarify best practices for the use of rituximab as an initial therapy.
An international consensus of experts supports use of the drug as initial therapy [14].
Other drugs commonly used in conjunction with glucocorticoids include azathioprine,

mycophenolate mofetil, and cyclophosphamide. Among these three agents, many clinicians
consider azathioprine the preferred immunosuppressant drug due to the relatively long history of
use of this drug for this indication and a randomized trial that supported a glucocorticoid-sparing
effect superior to mycophenolate mofetil [10,15-18]. Cyclophosphamide is typically reserved for
severe and refractory cases due to its less favorable side effect profile. (See "General toxicity of
cyclophosphamide in rheumatic diseases" and "Management of refractory pemphigus vulgaris and
pemphigus foliaceus", section on 'Cyclophosphamide'.)
The approach to the initiation of nonsteroidal adjuvant agents, such as azathioprine and
mycophenolate mofetil, varies. Some clinicians routinely prescribe a nonsteroidal agent at the start
of treatment with a systemic glucocorticoid or shortly after the start of glucocorticoid therapy. Other
clinicians primarily begin use of these agents when disease flares occur during glucocorticoid
tapering or when the response to systemic glucocorticoid monotherapy remains unsatisfactory after
several weeks. Definitive conclusions on the best approach are complicated by limited and
conflicting data on the glucocorticoid-sparing effects and prognostic impact of these agents. (See
'Nonsteroidal adjuvant therapies' below.)
Disease activity is considered under control after a period of a few weeks during which no new
lesions form, the Nikolsky sign (induction of skin blistering with manual pressure (picture 5)) is
absent, and most lesions are healed. At this point, therapy should be reduced slowly to the lowest
dose that is necessary to prevent the appearance of new lesions. We taper the systemic
glucocorticoid first, and then gradually reduce the dose of the adjuvant nonsteroidal agent. (See
'Administration' below.)
Long-term remission after the discontinuation of therapy is the ultimate goal for patient
management, though it may take some time to achieve. A French retrospective study of 134 patients
with pemphigus (80 with pemphigus vulgaris, 47 with pemphigus foliaceus, and 7 with
paraneoplastic pemphigus) treated with various regimens and followed for a mean of 77±64 months
found that 59 percent of patients with pemphigus vulgaris and 45 percent of patients with
pemphigus foliaceus achieved complete remission off therapy (defined as the absence of new
and/or established lesions while the patient was off all systemic therapy for at least two months)
2251
[19]. The mean duration of treatment prior to reaching this endpoint was 36±39 months. Surprisingly,
disease severity did not appear to influence the likelihood of complete remission off therapy in this
study. Mucosal involvement and younger age (<61 years) were associated with an increased chance
of complete remission off treatment. Additional studies will be useful for clarifying the relevant
prognostic factors for pemphigus.
Measures aimed at managing oral pain and cutaneous wounds are additional important aspects of
the management of pemphigus [1]. Such measures may help to improve patient quality of life and
prevent and manage secondary infection. (See 'Additional measures' below.)
The management of refractory pemphigus is reviewed separately. (See "Management of refractory

pemphigus vulgaris and pemphigus foliaceus".)
FIRST-LINE THERAPY Systemic glucocorticoids play a central

role in the treatment of pemphigus due the high efficacy of these agents for achieving rapid control
of the disease [13,20]. Combination therapy with rituximab and prednisone (or prednisolone) is an
alternative initial approach for moderate to severe pemphigus that may lead to improved outcomes
compared with systemic glucocorticoid monotherapy [14]. (See 'Alternative first-line therapy' below.)
Systemic glucocorticoids
Efficacy — Support for the use of systemic glucocorticoids as the primary treatment for
pemphigus stems from randomized trials and other studies that have documented improvement in
pemphigus with glucocorticoid monotherapy in the majority of patients, and extensive clinical
experience with this treatment [18,21-23]. As an example, in a randomized open-label trial in which
30 patients with pemphigus vulgaris were treated with prednisolone alone (2 mg/kg per day), 23 of
these patients (77 percent) responded to treatment and the average time to cessation of blistering
was 18 days [18]. The dramatic fall in mortality from pemphigus observed after the introduction of
systemic glucocorticoid therapy also supports the value of systemic glucocorticoid therapy for this
indication. (See 'Indications for therapy' above.)
Administration — Despite the well-accepted status of systemic glucocorticoids as the

primary treatment for pemphigus, the optimum treatment regimen is not established. Oral therapy
with prednisone, prednisolone, or methylprednisolone is the most common mode of glucocorticoid
administration for patients with pemphigus.
Multiple regimens have been utilized for glucocorticoid therapy. The most common approach
consists of treatment with around 1 to 1.5 mg/kg per day of prednisone or prednisolone [17].
Alternatively, higher doses of prednisone or prednisolone (1.5 to 2.5 mg/kg per day) have been given
as initial treatment.
2252
Direct comparisons of the efficacy and safety of these approaches are limited to a small randomized
trial (n = 22) that compared high doses of prednisone (120 to 150 mg per day) with lower doses of
prednisone (45 to 60 mg per day) in patients with newly diagnosed pemphigus vulgaris (n = 19) or
pemphigus foliaceus (n = 3) [24]. A statistically significant difference in the time to achieve initial
disease control was not detected between patients treated with the higher and lower doses; the
mean times to initial disease control were 20 (range 5 to 42 days) and 24 days (range 7 to 42 days),
respectively. A significant difference in the rate of adverse effects also was not detected.
Given the lack of evidence that treatment with higher doses or prednisone leads to better patient
outcomes, most clinicians, including ourselves, initiate therapy with doses ranging from 1 to 1.5
mg/kg per day. If the clinical response is insufficient, we consider a rapid increase in dose up to a
maximum of 2 mg/kg per day.
In most patients treated with systemic glucocorticoid therapy, cessation of blistering takes place
within two to three weeks and full disease control is achieved within six to eight weeks [25]. Once the
disease activity is under control, glucocorticoid tapering should begin, with the goal of reaching the
lowest dose needed to keep the disease under control. The ultimate goal is to withdraw all
treatment.
The optimal method of tapering glucocorticoids in patients with pemphigus has not been
determined. Thus, approaches to glucocorticoid tapering vary. Our approach for a 70 kg adult is as
follows:
●Once no new lesions have formed for seven days, we reduce prednisone from 1 mg/kg per day to
0.75 mg/kg per day.
●If at least seven days have elapsed since the first dose reduction and no new lesions have formed,
we reduce the dose of prednisone to 0.5 mg/kg per day.
●If at least 14 days have elapsed since the reduction to 0.5 mg/kg per day and no new lesions have
formed for at least one week, we reduce the dose of prednisone to 30 mg per day.
●Thereafter, we continue dose reductions in a stepwise manner with at least 14 days between each
reduction and continue the requirement that no new lesions form within seven days prior to the next
reduction. Our dose reduction series is as follows: 30, 25, 20, 15, 10, 7.5, 5, 2.5, and 0 mg per day.
●We continue adjuvant therapy with azathioprine or mycophenolate until prednisone has been
completely discontinued, and eight weeks after successful discontinuation of prednisone, we begin
to reduce the dose of the adjuvant medication. We reduce azathioprine by 50 mg every eight weeks,
mycophenolate mofetil by 500 mg every eight weeks, or mycophenolate sodium by 360 mg every
eight weeks until treatment cessation.
Pulsed glucocorticoids — Intravenous or oral pulsed glucocorticoids have been

utilized for the treatment of pemphigus vulgaris. Treatment regimens have varied widely, and data
comparing regimens that incorporate pulsed glucocorticoids with regimens that do not include
2253
pulsed glucocorticoids are limited to a few small studies that have [26,27] or have not [28]
demonstrated benefits over various nonpulsed regimens.
Adverse effects — Adverse effects, such as hypertension, hyperlipidemia, diabetes

mellitus, osteoporosis, increased susceptibility to infections, gastrointestinal ulcers, and aseptic
bone necrosis, may cause significant morbidity and mortality among patients who receive prolonged
systemic glucocorticoid therapy. Hence, frequent patient follow-up and the implementation of
appropriate preventive and therapeutic measures for glucocorticoid side effects are essential. (See
"Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-
induced osteoporosis".)
Alternative first-line therapy

Rituximab and prednisone — Historically, the anti-CD20 antibody rituximab
has been primarily used for pemphigus refractory to other treatments and for pemphigus in patients
for whom severe adverse effects or contraindications prevent the use of conventional
immunosuppressive therapies. However, combination therapy with rituximab and prednisone can be
an effective initial treatment for pemphigus that permits use of reduced doses of prednisone and is
associated with lower rates of serious side effects compared with higher-dose, longer-term
prednisone monotherapy [29]. This approach may be particularly useful for patients with moderate
to severe disease or who are less favorable candidates for high-dose, long-term prednisone therapy.
The high cost of rituximab can be a limiting factor for use of this regimen. (See "Management of
refractory pemphigus vulgaris and pemphigus foliaceus", section on 'Rituximab'.)
Efficacy — The most robust data regarding use of rituximab as an initial treatment for
pemphigus comes from a prospective open-label randomized trial in which 90 patients with newly
diagnosed pemphigus vulgaris or pemphigus foliaceus were randomly assigned to either
intravenous rituximab (1000 mg on days 1 and 14, then 500 mg at months 12 and 18) plus oral
prednisone (0.5 mg/kg per day for moderate disease and 1 mg/kg per day for severe disease)
tapered over three to six months or prednisone alone (1 mg/kg per day for moderate disease and 1.5
mg/kg per day for severe disease) tapered over 12 to 18 months [29]. At month 24, 41 of 46 patients
(89 percent) in the rituximab plus prednisone group were in complete remission off therapy
compared with 15 of 44 patients (34 percent) in the prednisone only group. In addition, the rituximab
plus prednisone group had a shorter median delay to achieve complete remission off therapy (277
versus 677 days) and less frequent severe adverse events compared with the prednisone only group.
In addition, successful use of rituximab as a first-line therapy for pemphigus as a single initial agent,
in combination with systemic glucocorticoids as a first-line glucocorticoid-sparing treatment, or
along with intravenous immune globulin has been described in case reports and retrospective case
series [30-34]. Additional support for early rituximab therapy comes from a retrospective study of 24
patients with pemphigus vulgaris and 7 patients with pemphigus foliaceus given rituximab as an
2254
adjuvant therapy; patients achieving complete remission taking no or minimal therapy had a shorter
duration of disease prior to rituximab treatment than patients who did not achieve this status (19
versus 86 months) [35].
Administration — Additional data are needed to clarify optimal dosing for initial treatment
with rituximab and best practices for use of rituximab in combination with systemic glucocorticoids
and other immunosuppressive therapies. The suggested dosing is two 1000 mg intravenous
infusions separated by two weeks given in combination with a tapering course of systemic
glucocorticoids [36]. Maintenance therapy may consist of 500 mg given at month 12 and every 6
months thereafter or based on clinical evaluation. Relapses may be treated with a 1000 mg dose,
and based upon the clinical evaluation, the systemic glucocorticoid may be resumed (if
discontinued) or the glucocorticoid dose increased. Intravenous methylprednisolone (100 mg) or an
equivalent glucocorticoid should be given 30 minutes prior to each rituximab infusion.
Adverse effects — Risks of rituximab therapy include infusion reactions and infections.
The adverse effects of rituximab are reviewed in greater detail separately. (See "Management of
refractory pemphigus vulgaris and pemphigus foliaceus", section on 'Adverse effects'.)
NONSTEROIDAL ADJUVANT
THERAPIES Although systemic glucocorticoids are the mainstay of pemphigus
treatment, concern for the serious adverse effects associated with prolonged, high-dose systemic
glucocorticoid therapy have led to the use of nonsteroidal immunomodulatory agents as adjuvant
therapies [4,13,20]. Azathioprine and mycophenolate mofetil are the most common adjuvant agents
utilized in the initial management of patients with pemphigus. Based upon the available evidence,
the major benefit of adjuvant therapy appears to be a glucocorticoid-sparing effect rather than a
direct disease-modifying effect [37].
Additional trials evaluating adjuvant therapies will be useful for clarifying the impact of adjuvant
therapy. A systematic review and meta-analysis of randomized trials comparing treatment with
systemic glucocorticoids and an adjuvant therapy (azathioprine, mycophenolate mofetil,
cyclophosphamide, cyclosporine, intravenous immune globulin, plasma exchange, or infliximab) to
treatment with systemic glucocorticoids alone or with a placebo found support for a collective
benefit of adjuvant therapy for reducing risk for relapse (relative risk 0.71, 95% CI 0.53-0.95), but did
not find an overall benefit of adjuvant therapy for increasing rates of remission [38]. Major
limitations of the meta-analysis were the pooling of data from trials evaluating different adjuvant
therapies and trials with varying treatment populations and treatment regimens.
Azathioprine — Azathioprine is the most common nonsteroidal immunomodulatory

drug given to patients with pemphigus. Azathioprine has been used for this indication for decades.
2255
Efficacy — Randomized trials that have evaluated the use of azathioprine as an adjuvant to
systemic glucocorticoids for patients with pemphigus include trials that have compared
combination therapy with a systemic glucocorticoid and azathioprine, with treatment with a
systemic glucocorticoid alone, or treatment with a systemic glucocorticoid plus another
nonsteroidal immunosuppressive agent. Two randomized trials that evaluated the glucocorticoid-
sparing effects of azathioprine have found conflicting results, and a beneficial effect of adjuvant
therapy with azathioprine on patient outcomes remains to be proven:
●A randomized open-label trial of 120 patients with pemphigus vulgaris that compared four
treatment regimens in which prednisolone (2 mg/kg per day up to a maximum of 120 mg per day
followed by a taper) was given alone or in conjunction with another immunosuppressive agent
supported the glucocorticoid-sparing effects of azathioprine (2.5 mg/kg per day for two months then
50 mg per day) [18]. After one year, patients who received combination therapy with prednisolone
and azathioprine had a significantly lower mean total dose of prednisolone than patients treated with
prednisolone alone (7712 mg versus 11,631 mg). However, clinical outcomes were similar in the two
groups. After one year, complete remission was attained by 77 percent of patients in the
prednisolone only group and 80 percent of patients who received combination therapy.
●In a 12-month randomized trial in which 56 patients with a new diagnosis of pemphigus vulgaris
were treated with prednisolone (2 mg/kg per day up to 120 mg per day followed by a taper) plus
azathioprine (2.5 mg/kg per day) or prednisolone in a similar regimen plus a placebo pill, patients in
both groups achieved statistically significant clinical improvement. A nonsignificant trend towards a
lower mean disease activity score was detected in the combination therapy group at each monthly
assessment during the last six months of the trial [21]. This difference achieved statistical
significance when data from the last three months of therapy were jointly assessed. In contrast to
the trial above, a significant difference in the mean total dose of prednisolone was not detected.
The glucocorticoid-sparing effect of azathioprine was compared with other nonsteroidal

immunosuppressants in a 2011 systematic review and meta-analysis of randomized trials published
prior to 2009 [10]. The glucocorticoid-sparing effect of azathioprine appeared to be superior to the
glucocorticoid-sparing effects of mycophenolate mofetil based upon the meta-analysis of two
randomized trials that compared these agents [5,18]. Of note, the independent analysis of one of the
included trials did not yield a significant difference in the glucocorticoid-sparing effect [5].
Additional trials would be useful for clarifying the efficacy of azathioprine as a glucocorticoid-
sparing agent and for comparing this drug with other therapies. Multiple uncontrolled studies have
documented successful use of azathioprine in combination with systemic glucocorticoid therapy
[16,39,40].
Administration — Dosing of azathioprine is influenced by the level of activity thiopurine

methyltransferase (TPMT), an enzyme involved in the degradation of azathioprine to inactive
metabolites. Reduced TPMT activity is associated with an increased risk for azathioprine-induced
myelosuppression [41,42]. (See "6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing
in patients with inflammatory bowel disease", section on 'Introduction'.)
2256
Recommendations for azathioprine dosing based upon TPMT activity vary [43,44]. In general, adults
with pemphigus and high TPMT activity can be treated with normal doses of azathioprine (up to 2.5
mg/kg [ideal body weight] per day), patients with intermediate or low TPMT activity should receive a
lower maintenance dose (up to 0.5 to 1.5 mg/kg per day depending on level of enzyme activity), and
patients with absent TPMT activity should not be treated with azathioprine [44]. TPMT activity may
be assessed through testing for the level of enzyme activity or genotyping. (See "6-mercaptopurine
(6-MP) metabolite monitoring and TPMT testing in patients with inflammatory bowel disease",
section on 'TPMT enzyme determination'.)
In patients with high TPMT activity, we typically begin treatment with 1 mg/kg (ideal body weight)
per day of azathioprine. We increase the dose by increments of 0.5 mg/kg to reach a maintenance
dose of 2.5 mg/kg per day within two to three weeks, provided serious toxicity is not detected.
Adverse effects — Due to the risk for myelosuppression, close laboratory monitoring is
necessary for patients treated with azathioprine. We typically monitor a complete blood count with
differential, renal function tests and liver function tests at baseline, every two weeks for the first
three months, and periodically (every two to three months) thereafter.
In additionto myelosuppression, malignancy, gastrointestinal disorders, and infections are potential

adverse effects of azathioprine therapy. (See "Pharmacology and side effects of azathioprine when
used in rheumatic diseases", section on 'Adverse effects'.)
Mycophenolate mofetil — Mycophenolate mofetil is an

immunosuppressive agent that may be useful for pemphigus [45-49]. The relatively favorable side
effect profile of mycophenolate mofetil is an advantage of this agent. (See "Mycophenolate:
Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse
effects'.)
Efficacy — A few randomized trials have evaluated the effects of adjuvant treatment with
mycophenolate mofetil on glucocorticoid requirements and patient outcomes. Although two
randomized trials found a statistically significant reduction in glucocorticoid consumption in
patients who received adjuvant mycophenolate mofetil compared with patients treated with a
glucocorticoid alone [18,22], another randomized trial failed to find a significant glucocorticoid-
sparing effect [23]. In addition, a meta-analysis of two randomized trials that compared the
glucocorticoid-sparing effects of azathioprine and mycophenolate mofetil found that mycophenolate
mofetil appeared to have inferior glucocorticoid-sparing effects [10].
A beneficial effect of adjuvant mycophenolate mofetil on the likelihood that patients will respond to
glucocorticoid treatment has not been demonstrated in the available randomized trials [18,22,23].
However, one trial found that adjuvant mycophenolate mofetil was associated with a longer duration
of clinical remission [22].
Randomized trials of mycophenolate mofetil in pemphigus are described in greater detail below:
2257
●A randomized open-label trial of 120 patients with pemphigus vulgaris that compared four
treatment regimens found that patients treated with prednisolone (2 mg/kg per day up to a
maximum of 120 mg per day followed by a taper) and mycophenolate mofetil (2 g per day) had lower
mean total doses of prednisolone than patients treated with prednisolone alone after one year (9798
versus 11,631 mg, respectively) [18]. A statistically significant difference in the rate of complete
remission was not detected between the two groups. Complete remission occurred in 70 versus 77
percent of patients, respectively.
●A randomized trial of 94 patients with pemphigus vulgaris that compared treatment with oral
prednisone (initial dose 1 to 2 mg/kg per day followed by a taper) plus mycophenolate mofetil (2 or 3
g per day), with oral prednisone given plus a placebo pill failed to find a significant difference in the
proportion of responders; 40 of 58 patients in the mycophenolate mofetil group (69 percent) and 23
of 36 patients in the placebo group (64 percent) responded to treatment [22]. Patients treated with
mycophenolate mofetil had significantly lower total prednisone ingestion over the course of one year
than patients in the placebo group (3220 versus 4450 mg, respectively). In addition, relapse was
significantly more delayed in the mycophenolate group; 22 percent of mycophenolate-treated
patients versus 45 percent of placebo-treated patients relapsed by 24 weeks after an initial
response. A borderline statistically significant trend for faster response also was observed in the
mycophenolate mofetil group (24 versus 31 weeks to initial response).
●A randomized trial of 47 patients with newly diagnosed pemphigus (36 with pemphigus vulgaris
and 11 with pemphigus foliaceus) that compared treatment with methylprednisolone alone (initial
dose equivalent to 1 mg/kg of prednisone then increased and tapered per clinical response) and in
combination with mycophenolate mofetil (initial dose 3 g per day then reduced to 2 g per day) found
no difference in the glucocorticoid-sparing effects, the rate of response, or remission rates [23].
Administration — Doses of 2 g per day (taken as 1 g twice daily) are typically used
when mycophenolate mofetil is added to systemic glucocorticoid therapy for the treatment of
pemphigus in adults. Enteric-coated mycophenolate sodium is an alternative form of mycophenolate
that is given to adults in a dose of 720 mg twice daily.
Adverse effects — The most common side effects of mycophenolate mofetil are
gastrointestinal complaints. Enteric-coated mycophenolate sodium may have some benefit for
patient tolerance while maintaining the immunosuppressive effects [50]. Pancytopenia is another
important side effect of mycophenolate. A complete blood count with differential can be obtained at
baseline and every two weeks during the first two to three months of therapy, then once monthly
within the first year, and every three months thereafter [51]. Renal function tests and liver function
tests can be obtained at baseline, after one month, and periodically thereafter. Side effects of
mycophenolate mofetil are reviewed in greater detail separately. (See "Mycophenolate: Overview of
use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)
2258
Dapsone — Data on dapsone therapy for pemphigus are more limited than data for
azathioprine and mycophenolate mofetil, and dapsone is less commonly utilized for this indication.
However, based upon reports of efficacy in some patients and the favorable status of dapsone as a
nonimmunosuppressive therapy [52-59], some clinicians choose to use dapsone as a first-line
adjuvant therapy in patients with pemphigus, particularly for patients with pemphigus foliaceus or
IgA pemphigus.
Efficacy — A 2009 review of case reports and case series identified 37 patients with
pemphigus vulgaris and 18 patients with pemphigus foliaceus who were treated with dapsone (50 to
300 mg per day) with or without prednisone or other immunosuppressive therapies [52]. Responses
to dapsone were documented in 86 percent of the patients with pemphigus vulgaris and 78 percent
of the patients with pemphigus foliaceus. The responders included 6 of 6 patients with pemphigus
vulgaris and 9 of 14 patients with pemphigus foliaceus who received dapsone as monotherapy.
A subsequent multicenter randomized trial that evaluated the efficacy of adjuvant dapsone (150 to
200 mg per day) for facilitating the tapering of systemic glucocorticoids in patients with pemphigus
vulgaris that was well-controlled with a systemic glucocorticoid (with or without an adjuvant
immunosuppressant), but refractory to glucocorticoid-tapering, failed to find a statistically
significant effect [53]. A reduction in the dose of prednisone to less than 7.5 mg per day was
achieved within one year in 5 of 9 patients treated with adjuvant dapsone (56 percent) and 3 of 10
patients (30 percent) who received a placebo pill instead of dapsone as adjuvant therapy.
Monotherapy with relatively high doses of dapsone (200 to 300 mg per day) appeared to be effective
as an initial treatment for pemphigus foliaceus in a small series [54]. Five of the nine patients had at
least 50 percent reduction in the extent of the disease within 15 days. However, four patients failed
to respond to dapsone treatment, and three patients required discontinuation of therapy; one ceased
treatment due to toxic hepatitis and hemolytic anemia, and two ceased treatment due to
methemoglobinemia. Additional studies are necessary to determine the role of dapsone in the
treatment of pemphigus.
Administration — Target doses for dapsone for pemphigus range from 50 to 200 mg
per day. Treatment is usually initiated at a low dose (eg, 25 or 50 mg per day in adults) and titrated
upward as tolerated.
Adverse effects — Hemolysis is an expected side effect of dapsone that occurs to

some degree in all treated patients. Patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency have an elevated risk for severe hemolytic anemia related to dapsone therapy. Thus, we
evaluate patients for G6PD deficiency prior to the initiation of dapsone. (See "Diagnosis and
management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
2259
Additional adverse effects of dapsone include methemoglobinemia, agranulocytosis,
hypersensitivity, and motor neuropathy. Close hematologic monitoring for hemolysis and
agranulocytosis is essential during treatment.
Other agents — Other drugs that have been used as adjuvants to systemic
glucocorticoids for the treatment of pemphigus are methotrexate (10 to 25 mg per week),
cyclosporine (2.5 to 5 mg/kg per day), and combination therapy with a tetracycline derivative and
nicotinamide:
●Methotrexate– No randomized trials have evaluated the efficacy of methotrexate as an adjuvant

therapy. Support for this drug is derived from uncontrolled studies and case series [60-62]. In a
retrospective study of 23 patients with pemphigus vulgaris for whom methotrexate (up to 15 to 25
mg per week) was added to systemic glucocorticoid therapy, 21 patients (91 percent) had
improvement in blistering after the addition of methotrexate and 16 patients (70 percent) eventually
were able to discontinue prednisone completely (mean time to discontinuation of prednisone
therapy 18 months) [62]. In a separate case series, six of nine patients treated with adjuvant
methotrexate (10 to 17.5 mg per week) for pemphigus vulgaris were able to discontinue prednisone
within six months [63]. These observations suggest benefit of methotrexate as a glucocorticoid-
sparing therapy.
●Cyclosporine– Although efficacy of cyclosporine was reported in case series of patients with
pemphigus [64,65], two randomized trials did not demonstrate an advantage of cyclosporine therapy
[66,67].
●Tetracyclines and nicotinamide– Limited data from retrospective studies suggest that combination
therapy with a tetracycline derivative (eg, tetracycline, doxycycline, or minocycline) and nicotinamide
(also known as niacinamide), a well-tolerated regimen often used for bullous pemphigoid, may be a
useful adjuvant to systemic glucocorticoid therapy for pemphigus [68,69]. The typical adult dose for
tetracycline is 500 mg four times daily; doxycycline and minocycline are given as 100 mg twice daily
and nicotinamide is usually given as 500 mg three times per day. Of note, a small uncontrolled
prospective study found poor treatment results when tetracycline and nicotinamide were given as
the primary therapeutic regimen for pemphigus rather than as a glucocorticoid-sparing therapy [70].
Successful treatment of pemphigus vegetans (a rare variant of pemphigus vulgaris) with only
minocycline and nicotinamide is documented in a case report [71].
REFRACTORY DISEASE The management of pemphigus

vulgaris and pemphigus foliaceus that is refractory to initial therapy is reviewed separately. (See
"Management of refractory pemphigus vulgaris and pemphigus foliaceus".)
2260
ASSESSING THE RESPONSE TO
THERAPY Patients with pemphigus should be followed closely to evaluate disease
activity and the response to treatment, as well as to assess for adverse effects of therapy. Because
pemphigus is a dynamic disease, management often requires frequent adjustments of therapy [1].
The response to treatment primarily is assessed through clinical observation. Cessation of new
blister formation, an absent Nikolsky sign (picture 5), and healing of old lesions with re-epithelization
indicate that disease activity is under control. Enzyme-linked immunosorbent assay titers for
desmoglein 1 and desmoglein 3 autoantibodies may be helpful as an adjunct to clinical assessment
since titers may correlate with disease activity [72-76]. However, the correlation is not perfect, and
ELISA results must be interpreted carefully. (See "Pathogenesis, clinical manifestations, and
diagnosis of pemphigus", section on 'Enzyme-linked immunosorbent assay'.)
ADDITIONAL MEASURES
Skin care — Local skin care measures may help to improve patient comfort and reduce
the risk for infection. Clinicians or patients should puncture and drain large blisters in a sterile
manner. The epithelial roof of the blister should be left intact after draining to serve as wound
covering and to reduce the risk for infection.
In our experience, twice daily application of a high potency topical corticosteroid (eg, clobetasol
propionate ointment or gel) directly to erosions can be a useful adjunct to systemic therapy for
persistent, active, hard-to-treat pemphigus lesions [1]. Intralesional injection of triamcinolone
acetonide (20 mg/mL) may also help to heal persistent lesions [1].
Wound areas should be kept clean to reduce the risk for infection. Erosions may be covered with
antibiotic ointment or a bland emollient (eg, petrolatum), with or without a nonadhesive wound
dressing. Patients should be informed about the warning signs of infection to facilitate prompt
diagnosis and early treatment.
Of note, the possibility of secondary infection (particularly herpes simplex virus infection) should be
considered for lesions that fail to respond as expected to therapy, and infection should be treated
appropriately if detected [1,77,78]. Due to the inhibitory effects of herpes simplex virus infection on
healing of skin lesions in patients with pemphigus, we often initiate prophylactic antiviral therapy
after an episode of pemphigus complicated by herpes simplex infection. (See "Epidemiology, clinical
manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis'.)
Management of oral symptoms — Oral mucosal involvement in

pemphigus vulgaris causes discomfort, which may be severe. In addition to treatment of the disease
process with systemic therapy, we have found the following measures useful for reducing
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symptoms during active disease:
●Avoidance of spicy, sharp, abrasive, or very hot foods
●Application of topical anesthetics as needed (eg, viscous lidocaine 2% solution, lidocaine 2% gel)
●Oral hygiene (teeth should be brushed twice daily with a soft-bristle brush with a bland toothpaste
and flossed daily; additionally, professional dental cleanings may be of use)
In our experience, topical corticosteroids help to improve oral symptoms of pemphigus in some
patients. We often utilize a medium or high potency topical corticosteroid (eg, triamcinolone 0.1% in
dental paste or fluocinonide 0.05% gel applied with gauze occlusion) or a corticosteroid mouthwash
(eg, 5 mL of dexamethasone 0.5 mg/5 mL solution as a mouth rinse) two to three times per day. We
have also found topical tacrolimus 0.1% ointment useful. Patients may find topical anesthetics (eg,
viscous lidocaine) helpful for managing symptoms.
Candida infection is a common occurrence in patients with mucosal pemphigus vulgaris who are
treated with systemic glucocorticoids. We prescribe oral nystatin swish and swallow (or swish and
spit) or clotrimazole lozenges as prophylaxis for patients receiving systemic glucocorticoids, or
monitor patients closely for the development of oropharyngeal candidal infection and treat if
infection develops. (See "Treatment of oropharyngeal and esophageal candidiasis".)
SUMMARY AND
RECOMMENDATIONS
●Pemphigus is a potentially life-threatening disorder for which treatment is always indicated. The
approach to the treatment of pemphigus vulgaris and pemphigus foliaceus is similar. (See
'Indications for therapy' above and 'Approach to treatment' above.)
●Data on the treatment of pemphigus vulgaris and pemphigus foliaceus are limited; few high quality
randomized trials of therapies of this disorder have been performed, resulting in uncertainty about
the efficacy of some therapies. Thus, the approach to treatment has been largely guided by limited
data and the clinical experience of expert dermatologists. (See 'Approach to treatment' above.)
●Systemic glucocorticoids are very effective for the treatment of pemphigus. For patients with
pemphigus, we recommend initiating treatment with an oral glucocorticoid (Grade 1A). Most centers
initiate treatment at a dose between 1 to 2 mg/kg of oral prednisone per day. We begin treatment
with 1 to 1.5 mg/kg of oral prednisone per day. Alternatively, patients with moderate to severe
disease may be treated with rituximab and a reduced dose of oral prednisone (0.5 to 1 mg/kg per
day). Combination therapy with rituximab and prednisone has been associated with reduced rates of
severe adverse events compared with prednisone monotherapy. The high cost of rituximab may limit
the use of this regimen in some settings. (See 'First-line therapy' above and 'Alternative first-line
therapy' above.)
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●Prolonged treatment with high doses of a systemic glucocorticoid is not desired due to the
potential for serious adverse effects. Nonsteroidal agents such as azathioprine or mycophenolate
mofetil are frequently used in an attempt to reduce dependence on systemic glucocorticoids. Data
are limited on the efficacy of dapsone as an adjuvant treatment for pemphigus. (See 'Nonsteroidal
adjuvant therapies' above.)
●Cutaneous and mucosal involvement in pemphigus may result in significant pain and functional
impairment. Local measures may help to improve patient symptoms. (See 'Additional measures'
above.)
●The possibility of secondary infection (eg, herpes simplex virus infection) should be considered
when lesions fail to respond to therapy. (See 'Skin care' above.)
●Additional therapeutic options are available for refractory cases. (See "Management of refractory
pemphigus vulgaris and pemphigus foliaceus".)
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Management of refractory pemphigus vulgaris and pemphigus
foliaceus
uptodate.com/contents/management-of-refractory-pemphigus-vulgaris-and-pemphigus-foliaceus/print
INTRODUCTION Pemphigus vulgaris and pemphigus foliaceus are

autoimmune blistering diseases that may result in significant morbidity and death. Traditional first-
line treatment for pemphigus consists of systemic immunosuppression with systemic
glucocorticoids with or without adjuvant immunosuppressive medications [1-3]. (See "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus" and "Initial management of pemphigus
vulgaris and pemphigus foliaceus".)
Patients who do not respond to traditional first-line therapies may benefit from additional
interventions. Treatment regimens that include rituximab, intravenous immune globulin (IVIG),
immunoadsorption, plasmapheresis, and cyclophosphamide may lead to clinical improvement in
these patients.
The treatment of pemphigus vulgaris and pemphigus foliaceus refractory to initial therapies will be
reviewed here. The initial management of pemphigus vulgaris and pemphigus foliaceus, and the
management of paraneoplastic pemphigus are reviewed separately. (See "Initial management of
pemphigus vulgaris and pemphigus foliaceus" and "Paraneoplastic pemphigus", section on
'Treatment'.)
DEFINITION The traditional initial approach to the treatment of pemphigus

vulgaris and pemphigus foliaceus consists of systemic glucocorticoid therapy, which is often given
in conjunction with an adjuvant nonsteroidal immunosuppressant, such as azathioprine or
mycophenolate mofetil. The term refractory pemphigus is generally used to refer to pemphigus that
fails to respond sufficiently to optimal administration of these agents. The initial management of
pemphigus is reviewed in detail separately. (See "Initial management of pemphigus vulgaris and
pemphigus foliaceus".)
Various definitions for refractory pemphigus have been utilized in the medical literature. In 2008, a
panel of experts proposed standardized definitions for the assessment of therapeutic responses in
pemphigus for use in clinical studies, including definitions of treatment failure from certain therapies
[4]. The consistent use of these guidelines in clinical studies may facilitate systematic interpretation
of the literature in the future and may provide further clarification on therapeutic efficacy.
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OVERVIEW Pemphigus is a chronic disorder that usually requires treatment for a
period of years. A retrospective study of 40 patients with pemphigus vulgaris who were seen in an
academic medical center between 1983 and 1993 and followed for an average of 7.7 years found
that long-lasting complete remission (ie, complete clinical remission off systemic therapy for at least
six months) was achieved in 25 percent after 2 years, 50 percent after 5 years, and 75 percent after
10 years [5].
Although the majority of patients with pemphigus vulgaris or pemphigus foliaceus (around 60 to 80
percent) can achieve at least initial improvement with traditional first-line therapies [6-8], other
patients fail to respond or experience frequent relapses while on these therapies. Our first steps for
patients who fail initial therapy are to optimize the dose of the systemic glucocorticoid (up to a
maximum of an equivalent of 1.5 to 2 mg/kg per day of prednisone) and adjuvant agent, or to
change the adjuvant therapy to a different first-line agent (eg, change from azathioprine to
mycophenolate mofetil or vice versa). If an adequate response still cannot be obtained, we proceed
with the initiation of other therapies.
The major therapeutic options for refractory disease include interventions that directly target the
antibody-mediated pathogenesis of pemphigus (rituximab, intravenous immune globulin [IVIG],
immunoadsorption, and plasmapheresis) and cyclophosphamide, a drug that may be used as an
alternative adjuvant immunosuppressant. Concern for the high cost of rituximab, IVIG,
immunoadsorption, and plasmapheresis and the unfavorable adverse effect profile of
cyclophosphamide (eg, sterility, cytopenia, hemorrhagic cystitis) contribute to the preferred use of
these agents for refractory pemphigus, rather than for new-onset disease.
In addition to patients who fail to respond to first-line regimens, other patients with pemphigus may
benefit from the therapies utilized for refractory disease. Patients with contraindications to initial
therapies or who are unable to tolerate initial treatments may also benefit from treatments used for
refractory disease.
TREATMENT OPTIONS
Treatment selection — The paucity of high-quality studies on the treatment of
refractory pemphigus impedes both conclusions on the relative efficacies of interventions as well as
the formation of definitive guidelines on the best approach to the treatment [9]. Thus, therapeutic
choice remains heavily influenced by consideration of patient tolerability for specific treatments and
treatment availability. In particular, treatment-specific contraindications should be considered.
Examples of clinical scenarios that have influenced the choice of therapy for our patients include:
●Preference to avoid cyclophosphamide in a patient of child-bearing potential due to the risk of

cyclophosphamide-induced premature gonadal failure
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●Preference to avoid extracorporeal therapies such as immunoadsorption and plasmapheresis in
older patients with severe heart disease
●Preference for use of a rapid-acting therapy (eg, immunoadsorption) in patients with severe
manifestations of the disease
Treatment availability is a major factor in treatment selection that is based on both the ability to
obtain a treatment and access to appropriate equipment and expertise to administer it safely. For
example, although the use of cyclophosphamide for refractory pemphigus has decreased in clinical
settings where patients have access to other less toxic treatment options, the relatively higher cost
and more limited availability of rituximab, intravenous immune globulin (IVIG), immunoadsorption,
and plasmapheresis contributes to the continued use of cyclophosphamide in certain clinical
settings. Whenever possible, the therapies utilized for refractory pemphigus should be administered
by clinicians experienced in the use and adverse effects of these treatments. Referral to specialized
treatment centers can be useful for additional access to treatments.
We manage most patients with refractory pemphigus with the addition of one of the therapeutic
options for refractory pemphigus to baseline immunosuppressive regimen that consists of systemic
glucocorticoids with or without a first-line adjuvant medication. Although combination therapy with
immunoadsorption and rituximab has been utilized by ourselves and other clinicians for patients
with severe, refractory disease (extensive involvement or involvement of mucosal sites that may
result in significant morbidity [conjunctiva, pharynx, larynx, or esophagus]), additional studies are
necessary to confirm whether this approach is ideal. (See 'Combination therapy' below.)
Rituximab — Based upon the rationale that pemphigus is primarily an autoantibody-

driven autoimmune disorder, therapies that deplete autoreactive B cell clones have been investigated
for the treatment of pemphigus [10,11]. Rituximab, a monoclonal antibody directed against the CD20
antigen on B lymphocytes, has demonstrated efficacy for pemphigus vulgaris and pemphigus
foliaceus [12-15]. The immunologic effects of rituximab that contribute to its benefit in pemphigus
may be complex; long-lasting B cell depletion following rituximab treatment may be one significant
factor [16-18]. Additional findings during rituximab therapy that may be involved in the treatment
effect include a preferential decline in autoantibodies compared with pathogen-specific antibodies
(potentially due to a different effect of rituximab on autoreactive and pathogen-specific plasma cells)
and a decline in autoreactive CD4+ T cells (a possible indirect effect of B cell depletion) [16,17].
Efficacy and administration — In accordance with the emergence of

rituximab therapy for pemphigus from patients with lymphoma [19,20], dosing for rituximab in
pemphigus initially reflected a regimen commonly used for lymphoma (375 mg/m2 once weekly for
four weeks) [21]. Since then, other dose regimens for rituximab have been evaluated in clinical
studies [22-25]. Most often, a dose regimen similar to that used in the treatment of rheumatologic
disease (two 1000 mg infusions separated by two weeks) is given. Lower dose regimens (eg, two
500 mg doses of rituximab separated by two weeks) may be associated with reduced duration of
remission. (See 'Standard dosing' below and 'Lymphoma dosing' below and 'Other protocols' below.)
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Standard dosing — Rituximab appears to be effective for refractory pemphigus when
administered in a regimen similar to the regimen used for rheumatoid arthritis (two 1000 mg
infusions separated by two weeks) [22-24,26]. Advantages of this dose over lymphoma dosing
include the requirement for fewer infusion sessions and the often lower total dose of rituximab
required for treatment.
The suggested dosing is two 1000 mg intravenous infusions separated by two weeks given in
combination with a tapering course of systemic glucocorticoids [27]. Maintenance therapy may
consist of 500 mg given at month 12 and every 6 months thereafter or based on clinical evaluation.
Relapses may be treated with a 1000 mg dose, and based upon the clinical evaluation, the systemic
glucocorticoid may be resumed (if discontinued) or the glucocorticoid dose increased. Intravenous
methylprednisolone (100 mg) or an equivalent glucocorticoid should be given 30 minutes prior to
each rituximab infusion.
Rituximab has also demonstrated efficacy for the initial treatment for pemphigus when given in
combination with prednisone [15]. Use of rituximab in newly diagnosed pemphigus is reviewed
separately [15]. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section
on 'Alternative first-line therapy'.)
One of the largest prospective studies to evaluate the treatment of refractory pemphigus with this
protocol is a study of 42 patients with severe refractory pemphigus vulgaris (n = 37) or pemphigus
foliaceus (n = 5) in which patients were treated with rituximab and prednisone (0.5 mg/kg per day
followed by a taper to discontinuation) [28]. After six months, complete remission (defined as an
absence of new or established lesions) occurred in 36 patients (86 percent), including 29 patients
who had complete remissions for at least two months after treatment was stopped and seven
patients who required minimal therapy (≤10 mg per day of prednisone for at least two months).
The median time to complete remission was 70 days (range 30 to 150 days). The seven patients who
required minimal therapy were able to discontinue treatment within three additional months. An
additional 500 mg dose of rituximab led to complete remissions in the six patients who had partial
remissions and to reinstitution of complete remission in 20 patients who relapsed. The median time
to relapse was 16 months (range 6 to 41 months). Additional doses of rituximab also appeared to be
of benefit for patients who relapsed or failed to achieve remission after a single cycle of rituximab in
a retrospective study of 92 patients with pemphigus vulgaris or pemphigus foliaceus [26].
Lymphoma dosing — Uncontrolled studies and case series support a beneficial effect of
rituximab given in a dose of 375 mg/m2 in various regimens [11]. The benefit of a single cycle of
rituximab (375 mg/m2 once weekly for four weeks) was illustrated in an open, multicenter study of
14 patients with pemphigus and 7 patients with pemphigus foliaceus. The patients had disease that
was refractory to systemic glucocorticoids, had experienced multiple relapses during glucocorticoid
tapering, or were unable to receive systemic glucocorticoids due to contraindications to
glucocorticoid therapy [29]. The treatment protocol consisted of rituximab and a systemic
glucocorticoid that was tapered as tolerated. Five patients did not receive a systemic glucocorticoid
due to contraindications for glucocorticoid therapy.
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Of the 21 patients, 18 (86 percent) achieved complete remission (defined as epithelialization of all
lesions) within three months. The median time to complete remission for cutaneous pemphigus
vulgaris, mucosal pemphigus vulgaris, and pemphigus foliaceus were 30, 90, and 60 days,
respectively. Two additional patients achieved complete remission within six months and one year.
Although nine of the patients who achieved complete remission relapsed during the course of the
study within a mean of 19 months, seven of these patients were successfully managed with topical
or systemic glucocorticoids, and the remaining two responded to a second course of rituximab.
The number of treatments administered with this dose of rituximab may influence patient outcomes.
A retrospective analysis of 27 patients found that three or more infusions of rituximab (375 mg/m2
once weekly) was associated with better patient outcomes than fewer treatments [30].
Additional doses of rituximab after completion of an initial treatment cycle are typically reserved for
patients who relapse or do not respond adequately to therapy. The findings of a nonrandomized
prospective study of 17 patients treated for pemphigus with 375 mg/m2 of rituximab once weekly for
four weeks suggest that a prophylactic infusion of rituximab six months after treatment may not be
of benefit [31].
Other protocols — Rituximab administered in a lower dose than described above may be
effective for pemphigus [25,32] though further study is necessary to clarify whether long-term
outcomes are less favorable when compared with outcomes from higher dose regimens [25,32,33].
The comparative efficacy of low-dose rituximab (two 500 mg doses of rituximab separated by two
weeks) and standard rheumatologic dosing of rituximab (two 1000 mg infusions separated by two
weeks) was evaluated in a 48-week randomized trial with 22 patients with pemphigus vulgaris or
pemphigus foliaceus [32]. The study population included both patients who had failed other
therapies and patients who received rituximab as initial treatment. Most patients received systemic
glucocorticoids in addition to rituximab and adjuvant immunosuppressants (primarily azathioprine)
were added for patients with incomplete responses to treatment.
All 11 patients in the low-dose rituximab group and 10 of 11 patients in the standard rheumatologic
dosing group achieved complete remission. Although the trial did not find statistically significant
differences in the primary endpoints (time to disease control, time to end of consolidation phase,
time to partial remission, or time to complete remission) between the two groups, there was a
nonstatistically significant trend towards greater risk for relapse among patients treated with low-
dose rituximab than among patients given the rheumatologic dose regimen (64 versus 36 percent
relapsed, respectively). In addition, patients in the low-dose rituximab group had a significantly
higher cumulative dose of azathioprine, and a statistically significant decline in enzyme-linked
immunosorbent assay (ELISA) indices of desmoglein 1 and desmoglein 3 was evident only in the
rheumatologic dose group.
Limited data suggest that intralesional injection of rituximab may be an effective treatment modality
for oral pemphigus. In an open study, all of three patients given intralesional rituximab (5 mg/cm2 on
days 1 and 15) for refractory oral pemphigus vulgaris had marked improvement [34]. One patient
achieved clinical remission of oral lesions at week 12 and the remaining two patients achieved
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clinical remission at week 16. Adverse effects were limited to pain from injection in one patient. Of
note, marked reductions in peripheral blood CD19+ B cell counts were noted in all patients two weeks
after the initial treatment session. Patients were followed for up to six months; one patient relapsed
five months after the start of therapy. Further study is necessary to confirm the efficacy of this
therapy.
Children — Pemphigus is rare in children and data on rituximab therapy for pemphigus in this
population are limited [35,36]. The findings of a retrospective study of 10 children (<18 years of age)
who had severe or resistant pemphigus or who were unable to tolerate other treatments support a
beneficial effect of rituximab in children. The study evaluated outcomes after treatment with
rituximab (either two 500 mg doses of rituximab separated by 15 days or two 375 mg/m2 doses of
rituximab separated by 15 days) [35]. All 10 children improved after rituximab therapy, including 7
children who achieved complete remission off all therapy after a single infusion cycle. The mean
time to complete remission was 21 weeks. Six children experienced relapses, with a mean time to
relapse of 13 months. Two of the children who relapsed were subsequently given rituximab and both
achieved good results. Further study is needed to confirm the safety and efficacy of rituximab for
pemphigus in children.
Combination therapy — Rituximab has been combined with IVIG or immunoadsorption

in attempts to take advantage of the fast onset of action of these therapies [37-41]. Although rapid
and long-lasting remissions have been reported in uncontrolled studies of patients with refractory
pemphigus who were treated with combination therapy [37-41], the efficacy of rituximab given with
and without these therapies has not been directly compared. Examples of studies that have
evaluated combination therapy are provided:
●In an uncontrolled study of 11 patients with refractory pemphigus vulgaris, combination therapy
with rituximab and IVIG was associated with rapid resolution of lesions and sustained clinical
remissions in nine patients [37]. The remaining two patients relapsed after initial therapy, but
achieved sustained remissions following one or two additional courses of rituximab. Among the 10
patients available for a 10-year follow-up study (follow-up range of 111 to 136 months), all remained
in remission without recurrence of disease. [41]. Pemphigus IgG autoantibodies remained
undetectable in serum during the 10-year follow-up period.
●In a series of 23 patients with severe pemphigus treated with immunoadsorption, rituximab, pulsed
dexamethasone, and azathioprine or mycophenolate mofetil, improvement in pemphigus was noted
within a few weeks and 19 patients (83 percent) achieved long-term complete remissions [38].
●In a retrospective study of 10 patients with refractory pemphigus vulgaris, eight patients achieved
complete remission within six months after the addition of immunoadsorption and rituximab to
systemic glucocorticoids and/or glucocorticoid sparing agents [39].
●In an uncontrolled study of seven patients with severe or refractory pemphigus treated with
immunoadsorption, rituximab, and conventional immunosuppressants with or without IVIG, all
patients had improvement in clinical manifestations within four weeks and three patients achieved
2269
long-term remissions [40].
Adverse effects — Although serious infections have been reported in patients treated
with rituximab for pemphigus, the effect of rituximab on risk for infections is unclear because of the
concomitant use of other immunosuppressive drugs [11]. A 2009 review of 136 patients treated with
rituximab for pemphigus found that severe infections were reported in about 10 percent of patients
and fatal infectious events occurred in 3 percent of patients [11]. Of note, progressive multifocal
leukoencephalopathy has been reported in patients treated with rituximab for other indications
[42,43]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on
'Hypogammaglobulinemia and infection'.)
Infusion reactions are a common side effect of rituximab therapy. Deep venous thrombosis,
pulmonary embolism, long-term hypogammaglobulinemia, and neutropenia have also been reported
in patients treated with rituximab for pemphigus [11]. (See "Rituximab: Principles of use and adverse
effects in rheumatoid arthritis", section on 'Other adverse effects'.)
Intravenous immune globulin (IVIG) — Intravenous

immune globulin (IVIG) appears to be effective for refractory pemphigus. However, the mechanism
through which IVIG improves pemphigus is not fully understood. Some authors have proposed that
the infusion of IVIG may contribute to a reduction in circulating pemphigus autoantibodies by
stimulating an increase in catabolism of immunoglobulins [44].
Efficacy and administration — The highest quality evidence for a beneficial

therapeutic effect of IVIG in pemphigus is provided by an 85-day multicenter, randomized trial in 61
adults with glucocorticoid-resistant pemphigus (defined as a failure to respond to the equivalent of
20 mg per day or more of prednisolone) [45]. Patients in the trial were treated with 400 mg/kg of IVIG
per day for five days, 200 mg/kg of IVIG per day for five days, or a placebo infusion for five days. The
primary endpoint in the trial was the duration of time that patients could be maintained on the
treatment protocol before symptoms required additional treatment (ie, time to escape protocol).
The trial found that the time to escape protocol was significantly longer for patients in the 400 mg
IVIG group compared with the patients in the placebo group [45], supporting a beneficial effect of the
400 mg dose of IVIG. The difference in the time to escape protocol for the 200 mg IVIG group and
the placebo group was not statistically significant. Furthermore, a significant decrease in a
pemphigus activity score was detected at all study observation points for patients in the 400 mg
IVIG group and at all study observation points after day 15 in the 200 mg IVIG group. The pemphigus
activity score did not decrease significantly at any time point in the placebo group.
Several uncontrolled studies and case series provide additional support for the use of IVIG for
refractory pemphigus [44,46-50]. In most of the series, patients received IVIG at a dose of 2
g/kg/cycle consisting of two to four consecutive treatment days, and IVIG cycles were repeated in
four-week to six-week intervals. In some studies, clinical improvement following IVIG has been found
to correlate with decreasing titers of desmoglein-specific IgG autoantibodies [44,50]. Additionally, a
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glucocorticoid-sparing effect of adjuvant IVIG was suggested by a small retrospective study that
found significant reductions in glucocorticoid requirements following treatment with adjuvant IVIG.
[49].
Adverse effects — In general, IVIG therapy is well tolerated. Side effects are usually
mild to moderate adverse events such as headache, back pain, increased blood pressure, and
abdominal discomfort [45]. Aseptic meningitis is a serious side effect of IVIG therapy that requires
immediate termination of treatment. Anaphylaxis is a potential risk of IVIG treatment in patients with
IgA deficiency. (See "Intravenous immune globulin: Adverse effects".)
Immunoadsorption — Immunoadsorption is a therapeutic option for

pemphigus that functions through the removal of circulating autoantibodies. In contrast to
plasmapheresis, which nonselectively removes plasma proteins from circulation, immunoadsorption
removes circulating IgG with a very high specificity [51]. The high cost of immunoadsorption limits
use of this therapy. In addition, immunoadsorption for pemphigus is not available in some countries,
including the United States.
Efficacy and administration — Several apheresis systems for

immunoadsorption have been successfully applied in pemphigus. The most effective columns
include regenerative adsorber such as protein A or synthetic ligands (eg, PGAM146, Globaffin) that
have a high affinity to the Fc-portion of human IgG [52-55].
The efficacy of immunoadsorption for removing pemphigus autoantibodies is influenced by the

adsorber utilized and treatment protocol. In one study in which protein A adsorber was utilized,
levels of antibodies against desmogleins 1 and 3 were reduced by an average of 76 percent one
month after the start of immunoadsorption treatment [52]. Immunoadsorption is typically
administered as an adjuvant to immunosuppressive therapies in short three to four day cycles that
are repeated every three to four weeks [52-54,56].
Data on the clinical efficacy of immunoadsorption in pemphigus are primarily limited to small
uncontrolled studies and case series [52-55]. The initial response to treatment can be rapid,
occurring within a few weeks. Long-term improvement after immunoadsorption has been reported in
several case series [52,54]. In our experience, patients with extensive skin involvement seem to
benefit most from the addition of adjuvant immunoabsorption to immunosuppressive therapy.
Adverse effects — Most patients appear to tolerate immunoadsorption well.

Infrequently reported adverse effects that may be directly related to immunoadsorption therapy
include hypotension, bradycardia, anaphylaxis, and sepsis from a central catheter [56].
Plasmapheresis — Compared with immunoadsorption, which specifically

removes circulating IgG, plasmapheresis (also known as plasma exchange) nonselectively removes
plasma proteins from circulation. Plasmapheresis is a more widely available therapy.
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Data are limited on the efficacy of plasmapheresis in pemphigus. Although small uncontrolled
studies and case reports have associated improvement in pemphigus with plasmapheresis [57-62], a
randomized trial of 40 patients in which treatment with prednisolone alone was compared with
prednisolone plus plasmapheresis found no significant difference in efficacy [63].
Cyclophosphamide — Treatment regimens that include cyclophosphamide

may be useful for inducing remission in pemphigus and reducing dependence on systemic
glucocorticoids [6]. The beneficial effect of cyclophosphamide in pemphigus is likely related to the
drug's suppressive effect on B lymphocytes and the ensuing reduction in autoantibody production
[64]. The adverse effect profile of cyclophosphamide contributes to restriction of its use primarily for
refractory disease [65]. (See 'Adverse effects' below.)
Efficacy and administration — Similar to azathioprine and mycophenolate

mofetil, cyclophosphamide is usually prescribed as an adjuvant to systemic glucocorticoid therapy.
Treatment regimens utilized for cyclophosphamide have varied. Several series have documented
high rates of successful treatment of pemphigus with a pulsed regimen of dexamethasone and
cyclophosphamide (monthly infusion of dexamethasone [100 mg for three days] and
cyclophosphamide [500 mg for one day] plus daily 50 mg doses of oral cyclophosphamide in
between pulsed therapy) [66-68]. However, less consistently favorable results with this regimen have
also been reported [69].
A glucocorticoid-sparing effect of adjuvant cyclophosphamide given in a different regimen was

demonstrated in a one-year randomized trial (n = 120) that compared the efficacy of four different
regimens for newly diagnosed pemphigus [6]. Although the rate of clinical response was similar
among patients treated with both prednisolone (2 mg/kg per day followed by a taper) and
cyclophosphamide (one 1000 mg intravenous dose per month for six months and every other month
thereafter) and patients treated with prednisolone alone (73 and 77 percent, respectively), the
cyclophosphamide group had a lower mean total dose of prednisolone (8276 mg versus 11,631 mg).
Further, the glucocorticoid-sparing effects of cyclophosphamide were similar to the glucocorticoid-
sparing effects of adjuvant azathioprine and mycophenolate mofetil.
The effects of treatment regimens with cyclophosphamide specifically on patients with refractory
pemphigus have been evaluated in uncontrolled studies that have demonstrated favorable results in
some patients [65,70]. Examples include:
●In a prospective uncontrolled study, 23 patients with pemphigus (20 pemphigus vulgaris, 3
pemphigus foliaceus) who had disease refractory to prednisone plus azathioprine and/or
mycophenolate mofetil, who could not tolerate other therapies, or who had rapidly progressive
extensive disease were treated with oral cyclophosphamide (2 to 2.5 mg/kg of ideal body weight per
day) and prednisone (1 mg/kg of ideal body weight per day followed by a taper after two to three
months) [70]. Of note, nine patients with severe disease also received plasma exchange during the
first two weeks of treatment.
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Complete remission (defined as the absence of lesions for at least four weeks while on treatment
with cyclophosphamide and less than 0.15 mg/kg per day of prednisone) was achieved by 17 of 20
patients with pemphigus vulgaris (85 percent) and two of three patients with pemphigus foliaceus.
Three patients with pemphigus vulgaris failed to respond to treatment and one patient with
pemphigus foliaceus had a partial response. The median time to remission was 8.5 months for
patients who did not receive plasma exchange and 8 months for those who received the additional
treatment. Six of 12 patients who achieved complete remissions and subsequently discontinued
treatment with cyclophosphamide relapsed within a median time of six months.
●In a retrospective study, 21 patients with pemphigus refractory to prednisolone plus azathioprine or
methotrexate (18 pemphigus vulgaris, 2 pemphigus foliaceus, 1 paraneoplastic pemphigus) were
treated with 4 to 22 pulses of intravenous methylprednisolone (1 g per day for three consecutive
days) together with 500 mg of intravenous cyclophosphamide on the second day of treatment [65].
Between the monthly pulse treatments, patients were given oral cyclophosphamide (50 mg per day)
and prednisolone. Continuation of adjuvant therapy with other immunosuppressives
(mycophenolate mofetil and/or methotrexate) was allowed.
The study found a statistically significant reduction in skin and oral disease scores after treatment.
Seven patients (33 percent) achieved an excellent response (defined as quiescent disease), and a
lesser degree of response was observed in an additional 13 patients. The median number of pulses
given to patients who achieved an excellent response was 12 (range 6 to 19). In addition, four
patients with excellent responses achieved clinical remissions (defined as complete resolution of
blisters and erosions for at least six months) that lasted for six months to six years. One of these
patients was able to completely discontinue treatment while the other three remained on
mycophenolate mofetil and low-dose prednisolone.
A few case reports have documented the successful use of immunoablative high-dose
cyclophosphamide for severe, refractory pemphigus [71,72]. However, treatment is not uniformly
effective, and a disease flare within weeks after treatment has been reported in a patient [71].
Adverse effects — Adverse effects of this cytotoxic drug include myelosuppression,

systemic infections, urine bladder toxicity, increased malignancies, and premature gonadal failure.
Patients receiving cyclophosphamide should be closely monitored for adverse effects of treatment.
(See "General toxicity of cyclophosphamide in rheumatic diseases" and "General principles of the
use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.)
OTHER THERAPIES FOR

PEMPHIGUS In addition to the major therapeutic options for the initial
treatment of pemphigus vulgaris and pemphigus foliaceus and the management of refractory
disease, multiple other interventions have been reported to be of benefit in small numbers of
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patients. Examples include topical pimecrolimus [73], topical tacrolimus [74], sulfasalazine with
pentoxifylline, gold [75], tetracyclines with or without nicotinamide [76], chlorambucil, mizoribine [77],
and subcutaneous veltuzumab [78].
Although case reports have suggested benefit of the biologic TNF-alpha inhibitors infliximab and
etanercept in the treatment of pemphigus [79-83], a small randomized trial that compared
combination therapy with infliximab and prednisone to treatment with prednisone alone in 20
patients with pemphigus vulgaris found only nonstatistically significant trends towards better results
with the addition of infliximab therapy [84]. The small size of the trial was a limiting factor; larger
trials might clarify the effects of infliximab therapy.
SUMMARY AND
RECOMMENDATIONS
●Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening disorders. Traditional
first-line treatment for these diseases consists of a systemic glucocorticoid with or without an
adjuvant immunosuppressant, such as azathioprine or mycophenolate mofetil. (See 'Overview'
above and "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
●Patients who do not respond sufficiently to traditional first-line treatment may benefit from other
interventions, such as rituximab, intravenous immune globulin (IVIG), immunoadsorption,
plasmapheresis, or cyclophosphamide. Rituximab can also be beneficial as an initial treatment. (See
'Treatment options' above and "Initial management of pemphigus vulgaris and pemphigus foliaceus",
section on 'Alternative first-line therapy'.)
●Due to a lack of high-quality comparative trials, data are insufficient for definitive conclusions on
the relative efficacies of therapies for refractory pemphigus. Factors such as patient tolerance for
specific treatments and treatment availability influence treatment selection. (See 'Treatment options'
above.)
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Fogo selvagem (Brazilian endemic pemphigus foliaceus)
uptodate.com/contents/fogo-selvagem-brazilian-endemic-pemphigus-foliaceus/print
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INTRODUCTION Endemic pemphigus foliaceus is a variant of
pemphigus, a group of autoimmune intraepithelial blistering skin diseases characterized by
keratinocyte detachment (acantholysis) and consequent intraepithelial blister formation. Endemic
pemphigus foliaceus primarily occurs in Brazil, where it is known as fogo selvagem (FS). Other
major subtypes of pemphigus include nonendemic pemphigus foliaceus, pemphigus vulgaris,
immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus. (See "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus".)
Similar to nonendemic pemphigus foliaceus, the pathogenesis of FS involves the formation of

autoantibodies against desmoglein 1 (Dsg1), a transmembrane glycoprotein integral for cell-to-cell
adhesion in the superficial epidermis. Environmental and genetic factors also likely contribute to the
development of FS. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus",
FS and nonendemic pemphigus foliaceus have similar clinical manifestations, both presenting with
a localized or generalized eruption of superficial, flaccid vesicles and bullae, erosions, and skin
erythema (picture 1A-B). The pathologic findings of these conditions are also similar, demonstrating
subcorneal acantholysis and blistering in the epidermis. (See "Pathogenesis, clinical manifestations,
and diagnosis of pemphigus", section on 'Clinical features' and "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus", section on 'Histopathology'.)
The pathogenesis, clinical manifestations, diagnosis, and management of FS will be reviewed here.
Other variants of pemphigus are reviewed separately.
●(See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
●(See "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
●(See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)
●(See "Paraneoplastic pemphigus".)
HISTORY AND TERMINOLOGY FS was first

reported in Brazil in 1903 and was initially misdiagnosed as a dermatomycosis known as "tinea
imbricata" or "Tokelau" [1]. "Fogo selvagem" is a Portuguese term that translates to "wild fire." The
term reflects the skin discomfort that often occurs in FS. (See 'Clinical presentation' below.)
EPIDEMIOLOGY Endemic sites of FS are concentrated in rural areas of

Brazil, with a geographic distribution that varies over time [2]. The disease is most prevalent in the
southeastern and midwestern regions of the country, and the main foci follow the course of rivers.
FS occurs in both children and adults and most often begins during young adulthood. There is no
gender predilection, and familial clustering is common [2-4].
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Outside of endemic areas, pemphigus foliaceus is rare. In contrast, the prevalence of FS is estimated
to be 3 percent in the Amerindian reservation of Limão Verde in the state of Mato Grosso do Sul in
Brazil, a region considered to have one of the highest prevalence rates for FS [5]. Long-term data
suggest urbanization of rural areas is associated with a reduction in the prevalence of FS [4,6].
Minor clusters of endemic pemphigus foliaceus have been described in other South American
countries and Tunisia [7-9]. In contrast to the even sex distribution in FS, reports of endemic
pemphigus foliaceus from Colombia and Tunisia demonstrate a predominance of females [8,9].
PATHOGENESIS The pathogenesis of FS involves the production of

pathogenic autoantibodies that trigger detachment of epidermal keratinocytes (acantholysis) [10-
12]. Environmental and genetic factors may also be important contributors.
Autoimmunity — Studies demonstrating that passive transfer of total

immunoglobulin G (IgG) or the immunoglobulin G4 (IgG4) fraction of antidesmoglein 1 (anti-Dsg1)
autoantibodies from sera of individuals with FS into neonatal mice induces a blistering eruption that
mimics FS support a key role for autoantibodies targeting Dsg1 in the pathogenesis of FS [11,13].
Dsg1 is a transmembrane glycoprotein in the cadherin family that is integral for keratinocyte-to-
keratinocyte adhesion and the primary autoantigen implicated in the development of both FS and
nonendemic pemphigus foliaceus (figure 1) [14,15]. Dsg1 is primarily located in the upper layers of
the epidermis, which correlates with the superficial location of blistering that is characteristic of
pemphigus foliaceus.
The mechanism through which autoantibodies targeting Dsg1 lead to keratinocyte detachment
involves disruption of the binding interaction between Dsg1 and other desmosomal proteins called
desmocollins, impairing adhesive function (figure 1) [12]. Specifically, IgG4 anti-Dsg1 autoantibodies
recognize a calcium-dependent, conformational epitope located on the extracellular 1 (EC1) domain
of Dsg1 [16,17]. Autoantibodies to EC5, another extracellular domain of Dsg1, can be found prior to
the onset of disease in patients who subsequently develop FS as well as in patients in remission
from FS and are not considered pathogenic [17].
Pathogenic IgG4 anti-Dsg1 autoantibodies that recognize EC1 may induce acantholysis through two
possible mechanisms. Direct binding of the autoantibodies to the EC1 epitope may impair the
heterophil interaction of Dsg1 and desmocollins though steric hindrance, triggering cell detachment
[12,18]. The second proposed mechanism involves autoantibody binding to Dsg1, triggering
intracellular signaling pathways that lead to cell detachment [19].
A rise in IgG4 anti-Dsg1 autoantibodies may predict the development of clinical findings of FS
[16,20]. A study in Limão Verde, Brazil, that assessed serum from five patients with FS both before
and after the onset of clinical disease found more than a 100-fold rise in the mean level of IgG4 anti-
Dsg1 autoantibodies at the onset of clinical disease [16]. In addition, subclass switching from
immunoglobulin G1 (IgG1) to IgG4 anti-Dsg1 autoantibodies was associated with a transition from
remission of FS to active disease.
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IgG1 anti-Dsg1 autoantibodies are nonpathogenic autoantibodies that target the EC5 rather than the
EC1 domain of Dsg1 and have been found at similar levels in inhabitants of endemic areas with and
without FS [16]. Nonpathogenic autoantibodies contribute to the relatively high prevalence of anti-
Dsg1 autoantibodies in unaffected individuals in endemic areas. In a study in Limão Verde that did
not assess the subclass of IgG anti-Dsg1 autoantibodies, 51 of 93 individuals (55 percent) without
FS had these autoantibodies [21].
Immunoglobulin M (IgM) and immunoglobulin E (IgE) anti-Dsg1 autoantibodies are also common in
patients with FS and may be a marker of exposure to an environmental trigger [22,23]. In support of
this theory, a study found that in the United States and Japan, IgM anti-Dsg1 autoantibodies were
much less prevalent in healthy individuals and individuals with nonendemic pemphigus foliaceus
than in healthy and FS populations in Limão Verde [23]. In addition, a correlation between levels of
IgE anti-Dsg1 autoantibodies and IgG4 anti-Dsg1 autoantibodies has been detected in the sera of
patients with FS, similar to the correlation seen between IgE and IgG4 antibodies in response to
allergens [22].
T cells may play a supportive role in the autoantibody response in FS. T cells that recognize epitopes
on the ectodomain of Dsg1 have been detected in affected patients [24]. These T cells exhibit a
CD4+ memory T cell phenotype, produce a T helper type 2 (Th2)-like cytokine profile (interleukins 4,
5, and 6), and are postulated to contribute to FS through stimulating B cell production of anti-Dsg1
autoantibodies. Expression of human leukocyte antigen (HLA)-DR molecules on antigen-presenting
cells appears to be necessary for the proliferation of these T cells in response to Dsg1 [24].
Environment — Environmental factors are postulated to contribute to FS based upon

the epidemiology of the disease and the evidence suggesting an immunologic trigger. Exposure to
hematophagous insects in endemic areas is considered the most likely environmental risk factor
[25-27].
In support of the environment as a trigger, FS occurs in subtropical communities in which open-reed

and thatched-roof dwellings are common and nearby rivers and streams are infested with a variety
of hematophagous insects, such as black flies (Simulium spp), sandflies (Lutzomyia longipalpis), and
kissing bugs (Triatoma spp) [2,28,29]. Moreover, IgG4 anti-Dsg1 autoantibodies cross-react with
LJM11, a sandfly salivary protein, suggesting that LJM11 could be an antigenic trigger [30].
Sun exposure may also play a role in the pathogenesis of FS. Ultraviolet B (UVB) radiation-induced
acantholysis has been demonstrated in uninvolved skin in patients with FS [31].
Genetic susceptibility — Familial occurrences of FS are common,

suggesting a role for genetic susceptibility to the disease [2,5,28].
HLA alleles associated with susceptibility to FS include HLA-DRB1-0404, 1402, and 1406. The same
amino acid sequence (LLEQRRAA) has been detected in the third hypervariable region of the DRB1
gene of these alleles, suggesting an important role for this amino acid sequence [32].
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Polymorphisms in the CD59 gene that contribute to higher transcriptional levels of CD59 are
additional proposed genetic contributors to susceptibility to FS [33]. The CD59 glycoprotein is an
essential complement regulator that impacts signal transduction and activation of T lymphocytes.
Single nucleotide polymorphisms in long noncoding RNA genes are also proposed risk factors [34].
CLINICAL PRESENTATION The dermatologic findings

of FS are indistinguishable from nonendemic pemphigus foliaceus. The primary skin lesions are
superficial, flaccid vesicles and bullae. Associated erosions and underlying erythema are often also
present. Mucous membranes are characteristically spared. (See "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.)
Skin involvement may be localized or generalized. The face, neck, scalp, and upper trunk are
common sites for localized disease [3,35,36]. Generalized FS presents with a widespread, blistering
eruption (bullous invasive FS) or exfoliative erythroderma with diffuse erythema, scaling, and
crusting [3,36,37]. Associated pruritus, burning sensations, or skin pain is common in both localized
and generalized disease.
The onset of FS is typically gradual, with slow, progressive development of lesions occurring over
weeks to months. Rare patients develop an acute, fulminating disease in which widespread
blistering occurs over one to three weeks [38]. Persistent disease may evolve to demonstrate
subacute and chronic features, including hyperpigmented, hyperkeratotic, verrucous papules and
plaques that resemble seborrheic keratoses (picture 2) [3,4,35,36].
Rare clinical variants include tinea imbricata-like FS and pemphigus herpetiformis (also known as
herpetiform pemphigus). Tinea imbricata-like FS presents with blister formation in a circinate or
annular pattern and scale at the site of ruptured blisters, resembling the superficial fungal infection
tinea imbricata (picture 3). The pemphigus herpetiformis clinical variant demonstrates blistering in a
herpetiform pattern (picture 4) [39]. (See "Dermatophyte (tinea) infections", section on 'Tinea
imbricata'.)
DIAGNOSIS The diagnostic approach to FS involves confirmation of pemphigus

foliaceus with the detection of consistent clinical, histologic, and immunopathologic findings.
The clinical, histologic, and immunopathologic findings in FS are similar to those of nonendemic
pemphigus foliaceus. There is no definitive way to distinguish FS from nonendemic pemphigus
foliaceus, except that FS occurs in individuals residing in certain endemic areas of Brazil. There is
also absence of evidence of an alternative cause, such as drug-induced pemphigus foliaceus (table
1). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Drug
exposure'.)
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Our approach — FS should be suspected in individuals from endemic areas of Brazil
who develop erythematous, scaly, or crusted plaques and shallow erosions, particularly on the head,
neck, or upper trunk or in a generalized distribution. Our typical approach to confirm the diagnosis if
suspicion for FS remains after the clinical assessment is as follows:
●A lesional skin biopsy for routine hematoxylin and eosin (H&E) staining
●A perilesional skin biopsy for direct immunofluorescence (DIF)
The presence of clinical, histologic, and DIF findings consistent with pemphigus foliaceus confirms
this diagnosis. (See 'Routine histopathology' below and 'Direct immunofluorescence' below.)
Serum testing with enzyme-linked immunosorbent assay (ELISA) to detect desmoglein 1 (Dsg1) or
indirect immunofluorescence (IIF) to detect autoantibodies that bind to the surface of epidermal
keratinocytes are additional tests that can provide support for the diagnosis. However, in isolation, a
positive serum test cannot confirm a diagnosis of FS given that many individuals without FS in
endemic areas also have antidesmoglein 1 (anti-Dsg1) autoantibodies. (See 'Autoimmunity' above.)
History and physical examination — The patient history

serves to identify characteristics consistent with FS and should include assessment of the onset
and course of disease, associated symptoms, medications, and history of residence in an endemic
area. FS most often develops in individuals living and working in rural areas of endemic regions,
such as subsistence farmers.
FS most often presents with a slow onset of blistering and erythema over weeks to months and skin
pain, pruritus, or burning sensations in involved areas. Onset is often, but not exclusively, in young
adulthood. Patients may also report exacerbations associated with sun exposure. A medication
review allows for the identification of patients who may have drug-induced pemphigus foliaceus
rather than FS (table 1). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus",
section on 'Drug exposure'.)
A full skin examination should be performed to identify lesions consistent or inconsistent with FS
and to determine the extent of disease. An absence of erosions should raise suspicion for an
alternative diagnosis. Mucous membranes should be carefully examined; mucosal involvement does
not occur in FS. (See 'Differential diagnosis' below.)
Skin biopsy — Skin biopsies for routine histopathologic examination and DIF are
important for the diagnosis of FS and should be performed whenever feasible.
Routine histopathology — The specimen for histopathologic examination

should be taken from lesional skin (ie, an area of active blistering). A 4 mm punch biopsy is typically
sufficient. Ideally, the specimen should include a portion of a blister and immediately adjacent,
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erythematous skin. For blisters smaller than the punch tool diameter, the entire blister can be
included in the specimen.
The pathologic findings of FS are similar to nonendemic pemphigus foliaceus. Subcorneal or

intramalpighian cleavage and acantholysis are the key findings. Additional features may include
eosinophilic spongiosis or an eosinophilic dermal infiltrate.
Direct immunofluorescence — In contrast to biopsies for routine

histopathologic examination, biopsies for direct immunofluorescence (DIF) should be taken from
perilesional skin (ie, normal-appearing skin adjacent to a pemphigus lesion). A 4 mm punch biopsy is
usually sufficient.
Specimens for DIF should not be placed in formalin. Options for transport include Michel's medium,
Zeus medium, or saline. Appropriate handling of specimens for DIF is reviewed separately. (See
"Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
The DIF finding consistent with FS is IgG deposition in epidermal intercellular spaces (picture 5).
This finding is estimated to be present in 90 to 100 percent of patients [40]. (See "Pathogenesis,
clinical manifestations, and diagnosis of pemphigus", section on 'Direct immunofluorescence'.)
Serology — Serologic tests identify the presence of circulating antibodies to epidermal cell
surface antigens. The two primary methods used in clinical practice are ELISA and IIF.
Immunoblotting and immunoprecipitation are additional tests that may detect the relevant
circulating autoantibodies but are more difficult to perform and are infrequently used in the clinical
setting. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on
'Other'.)
Enzyme-linked immunosorbent assay — Enzyme-linked

immunosorbent assay (ELISA) tests for pemphigus assess for anti-Dsg1 and antidesmoglein 3 (anti-
Dsg3) autoantibodies in serum. ELISA testing for anti-Dsg1 autoantibodies is considered a highly
sensitive test for FS; in one study, 59 of 60 patients (98 percent) with FS tested positive for Dsg1
autoantibodies with ELISA [21]. (See "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus", section on 'Enzyme-linked immunosorbent assay'.)
However, ELISA testing does not distinguish between autoantibodies recognizing pathogenic and
nonpathogenic epitopes of Dsg1, and Dsg1 autoantibodies are also common in unaffected
individuals residing in or near endemic areas [21]. Therefore, a positive ELISA for anti-Dsg1 alone
does not confirm the diagnosis.
The detection of high levels of IgG4 anti-Dsg1 autoantibodies, the pathogenic autoantibodies in FS,
has been proposed as a marker of active FS; however, testing that identifies the subclass of IgG anti-
Dsg1 autoantibodies is not commercially available. A study in Limão Verde that utilized an ELISA to
detect anti-Dsg1 autoantibodies and labeled monoclonal antibodies to distinguish the IgG
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subclasses found a sensitivity and specificity of testing for IgG4 anti-Dsg1 autoantibodies of 92 and
97 percent [20]. The positive predictive value in Limão Verde, which has a 3 percent prevalence of
FS, was 49 percent.
Although the presence of anti-Dsg3 autoantibodies is associated with pemphigus vulgaris, Dsg1 and
Dsg3 autoantibodies are detected in a minority of patients with FS; in one study, 9 of 23 patients (39
percent) with FS had both Dsg1 and Dsg3 autoantibodies [41].
Indirect immunofluorescence — A positive indirect immunofluorescence

(IIF) for pemphigus foliaceus displays intercellular IgG deposition within the epidermis. Normal
human foreskin is the most sensitive substrate for IIF studies for FS.
IIF is estimated to be positive in up to 90 to 100 percent of the patients with FS. Similar to ELISA,
evaluation to specifically detect the IgG4 subclass of autoantibodies may enhance the sensitivity of
IIF [13,42].
Other — The findings of a Tzanck smear may support a diagnosis of FS through the detection
of acantholytic cells. Performance of a Tzanck smear is not necessary for diagnosis and does not
confirm the diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Tzanck
smear'.)
DIFFERENTIAL DIAGNOSIS The differential

diagnosisof FS is broad and dependent upon the clinical manifestations [3,4].
One of the most important conditions to exclude in patients with suspected FS is drug-induced
pemphigus foliaceus given that cessation of the causative drug is usually indicated. Drug-induced
pemphigus should be suspected in patients receiving medications known to induce pemphigus
(table 1). There are no clinical features or tests that definitively distinguish drug-induced pemphigus
from non-drug-induced pemphigus. (See "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus", section on 'Drug exposure' and "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus", section on 'Pemphigus vulgaris and pemphigus foliaceus'.)
Additional disorders often in the differential diagnosis of FS are listed below. In general, skin
biopsies for histopathologic examination and direct immunofluorescence will distinguish FS from
other conditions (see 'Diagnosis' above):
●Localized FS – Localized FS may resemble other diseases that present with erythema, scale,
erosions, or crusts on the head, neck, or upper trunk, such as seborrheic dermatitis, subacute
cutaneous lupus erythematosus, or bullous impetigo:
•Seborrheic dermatitis – Seborrheic dermatitis is a common condition in adolescents and adults.

Characteristic features include scale and/or erythema with a predilection for the scalp, face, upper
trunk, and intertriginous areas (picture 6). Yellowish, greasy scale is a common feature. (See
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"Seborrheic dermatitis in adolescents and adults".)
•Subacute cutaneous lupus erythematosus – Subacute cutaneous lupus erythematosus may occur
as an independent disorder or in the presence of systemic lupus erythematosus. Typical clinical
manifestations are psoriasiform or annular, erythematous, scaly plaques on the shoulders, neck,
arms, or upper trunk (picture 7). Rare vesicobullous presentations can occur. (See "Overview of
cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)
•Bullous impetigo – Bullous impetigo is a Staphylococcus aureus infection characterized by the

development of flaccid bullae that rupture easily, leaving well-demarcated, erythematous erosions
with collarettes of scale and crusting (picture 8). The infection most often occurs in young children.
(See "Impetigo".)
●Generalized FS – Generalized FS presenting as exfoliative erythroderma should be distinguished

from erythroderma of other causes, such as psoriasis, drug exposure, atopic dermatitis, and
cutaneous T cell lymphoma. The diagnostic approach to erythroderma is reviewed in detail
separately. (See "Erythroderma in adults", section on 'Determination of underlying cause'.)
Generalized FS presenting as the bullous, invasive form should be distinguished from pemphigus
vulgaris. Histopathology, direct immunofluorescence testing, and enzyme-linked immunosorbent
assay (ELISA) testing can differentiate pemphigus foliaceus and pemphigus vulgaris. (See
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus vulgaris
and pemphigus foliaceus'.)
Rare variants may also be confused with other entities. Hyperkeratotic FS and tinea imbricata-like FS
may resemble extensive seborrheic keratoses and tinea imbricata (picture 9), respectively. FS
presenting with features of pemphigus herpetiformis should be distinguished from herpetiform
presentations of other blistering disorders, such as bullous pemphigoid and epidermolysis bullosa
acquisita. (See "Dermatophyte (tinea) infections", section on 'Tinea imbricata' and "Clinical features
and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Epidermolysis
bullosa acquisita".)
TREATMENT FS is a chronic, symptomatic, potentially fatal disorder; therefore,

treatment to induce remission is generally indicated. Data on the treatment of FS are limited, and
therapeutic guidance is primarily based upon the experience of experts in FS and data from
nonendemic pemphigus foliaceus.
Similar therapies are used for FS and nonendemic pemphigus foliaceus. Systemic glucocorticoid
therapy is the mainstay of treatment for FS.
General approach — The approach to treatment for FS resembles the approach

for nonendemic pemphigus foliaceus. Systemic glucocorticoid therapy is the mainstay of treatment.
(See "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
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Systemic glucocorticoid therapy can have serious adverse effects, such as adrenal insufficiency and
osteoporosis, particularly when treatment is prolonged or doses are high. Thus, adjuvant therapies
are sometimes incorporated into the treatment regimen in an attempt to reduce dependence on
systemic glucocorticoids. (See "Major side effects of systemic glucocorticoids".)
Systemic glucocorticoids — Systemic glucocorticoid therapy is the most

common initial treatment for FS [38]. Doses for prednisone therapy typically range from 0.5 to 1
mg/kg per day, with the 0.5 mg/kg dose utilized for less severe disease (eg, ≤10 percent total body
surface area [TBSA]) and 1 mg/kg per day utilized for severe disease. Similar to nonendemic
pemphigus foliaceus, cessation of blistering is expected within two to three weeks, and disease
control is often obtained within two months. (See "Initial management of pemphigus vulgaris and
pemphigus foliaceus", section on 'Administration'.)
In our experience, FS usually responds to systemic glucocorticoid therapy. Once disease control is
achieved, tapering of the systemic glucocorticoid should be attempted. A sample tapering regimen
for prednisone therapy for pemphigus is reviewed separately. (See "Initial management of
pemphigus vulgaris and pemphigus foliaceus", section on 'Administration'.)
The efficacy of systemic glucocorticoids specifically for FS has not been evaluated in randomized
trials. Support for the use of systemic glucocorticoids for FS is based upon extensive clinical
experience and trials supporting the efficacy of systemic glucocorticoids for nonendemic
pemphigus foliaceus. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus",
section on 'Systemic glucocorticoids'.)
Potential adverse effects of systemic glucocorticoid therapy are reviewed in detail separately. (See
"Major side effects of systemic glucocorticoids".)
Nonsteroidal adjuvant therapies — As with nonendemic pemphigus

foliaceus, adjuvant therapy may be added to glucocorticoid therapy in an attempt to minimize
glucocorticoid exposure. Adjuvant drugs are usually added when tapering of systemic
glucocorticoids results in disease flares or patients experience adverse events from systemic
glucocorticoids.
Mycophenolate mofetil and azathioprine are the most commonly used adjuvant therapies and are
administered in a similar manner as in other forms of pemphigus [43]. (See "Initial management of
pemphigus vulgaris and pemphigus foliaceus", section on 'Nonsteroidal adjuvant therapies'.)
Side effects of mycophenolate mofetil and azathioprine are reviewed in detail separately. (See
"Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on
'Adverse effects' and "Mycophenolate: Overview of use and adverse effects in the treatment of
rheumatic diseases".)
Alternative therapies — Alternative initial therapies for FS include topical agents,

rituximab, and dapsone.
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Clinical experience suggests that medium to high-potency topical corticosteroids (groups 1 to 4
(table 2)) or topical calcineurin inhibitors can be an effective treatment for FS involving small areas
of skin (eg, <1 percent TBSA) [38]. Patients who do not respond sufficiently may be transitioned to
systemic therapy.
Rituximab may be an alternative first-line treatment based upon benefit demonstrated for pemphigus
vulgaris and nonendemic pemphigus foliaceus. However, studies evaluating the effect of rituximab
in FS are lacking, and the high cost of this drug inhibits use in most patents with FS. (See "Initial
management of pemphigus vulgaris and pemphigus foliaceus", section on 'Alternative first-line
therapy'.)
Dapsone is sometimes used as a nonsteroidal adjuvant therapy for pemphigus, particularly for
presentations consistent with pemphigus herpetiformis. However, data conflict on the efficacy of
this therapy for pemphigus, and its role in the treatment of FS remains uncertain. (See "Initial
management of pemphigus vulgaris and pemphigus foliaceus", section on 'Dapsone'.)
Skin care — Ultraviolet radiation may exacerbate FS [31]. Therefore, sun avoidance and
use of sun-protective measures during periods of sun exposure is advised for all patients. (See
"Selection of sunscreen and sun-protective measures".)
Recommendations for wound care are similar to recommendations for other forms of pemphigus.
(See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Skin care'.)
Refractory disease — The best course of treatment for patients who respond
poorly to standard therapy is unclear. Therapies utilized for refractory nonendemic pemphigus
foliaceus may be attempted. (See "Management of refractory pemphigus vulgaris and pemphigus
foliaceus".)
PROGNOSIS FS is a potentially fatal disorder. Death is estimated to occur in 5

to 10 percent of patients with FS or nonendemic pemphigus foliaceus, and mortality prior to the
availability of systemic glucocorticoids was estimated to be around 90 percent in patients with
generalized disease [2,3].
The major causes of death are complications of prolonged, systemic immunosuppressive therapy
and secondary infections. Opportunistic infections, such as Nocardia,cytomegalovirus, Legionella,
Listeria, Pneumocystis, Sarcoptes, and Trichosporon inkin, have been reported [44]. Severe herpes
simplex virus infections, disseminated Strongyloides stercoralis, or bacterial sepsis can be fatal
[4,36,37,44].
Spontaneous remission of FS is estimated to occur in 10 percent of patients, based upon

observations prior to the use of systemic glucocorticoids [29,35]. Localized FS may spontaneously
resolve, remain stable, or progress to generalized forms [45].
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Progression of FS to other autoimmune blistering diseases has been reported (eg, bullous
pemphigoid, epidermolysis bullosa acquisita). The phenomenon of epitope spreading, in which an
inflammatory process contributes to the exposure and immune recognition of previously hidden
antigens, is a proposed contributor [46,47].
SUMMARY AND
RECOMMENDATIONS
●Fogo selvagem (FS) is an autoimmune blistering disease characterized by the development of
superficial blisters and an absence of mucosal involvement. FS is an endemic variant of pemphigus
foliaceus that occurs in individuals residing in certain regions of Brazil. The disorder often begins
during childhood or young adulthood. (See 'Epidemiology' above.)
●FS shares immunologic and clinical features with the nonendemic form of pemphigus foliaceus.
Like nonendemic pemphigus foliaceus, the pathogenesis involves the production of autoantibodies
that target desmoglein 1 (Dsg1), an adhesion molecule integral for keratinocyte-to-keratinocyte
adhesion. Immunoglobulin G4 (IgG4) antidesmoglein 1 (anti-Dsg1) autoantibodies are the primary
pathogenic antibodies in FS. (See 'Pathogenesis' above.)
●Environmental and genetic factors are postulated to contribute to the development of FS. Exposure
to hematophagous insects is considered the most likely environmental trigger. (See 'Environment'
above and 'Genetic susceptibility' above.)
●FS classically presents with flaccid, superficial vesicles and bullae as well as erosions, erythema,
scale, and crusting. The disorder may appear as a localized condition that exhibits a predilection for
the face, neck, scalp, and upper trunk or with generalized bullae or exfoliative erythroderma. (See
'Clinical presentation' above.)
●The diagnosis of FS involves the recognition of consistent clinical, histologic, and

immunopathologic findings. Therefore, skin biopsies for routine histopathologic examination and
direct immunofluorescence (DIF) should be performed whenever feasible. Similar to nonendemic
pemphigus foliaceus, the characteristic DIF finding in FS is immunoglobulin G (IgG) in the epidermal
intercellular spaces. Enzyme-linked immunosorbent assay (ELISA) testing for Dsg1 and indirect
immunofluorescence (IIF) studies are additional tests that can support a diagnosis of FS. Drug-
induced pemphigus should always be considered in the differential diagnosis of FS. (See 'Diagnosis'
above.)
●FS is a potentially fatal disorder, and treatment is generally indicated. Most patients require
systemic treatment to achieve disease control. We recommend a systemic glucocorticoid as initial
therapy (Grade 1B). Because prolonged, systemic glucocorticoid therapy is associated with risk for
serious adverse effects, nonsteroidal immunomodulatory drugs are often added at the start of
2286
therapy or later in the course of treatment in an attempt to reduce dependence on systemic
glucocorticoids. (See 'Treatment' above and 'Prognosis' above and "Initial management of
pemphigus vulgaris and pemphigus foliaceus", section on 'Systemic glucocorticoids'.)
2287
Epidemiology and pathogenesis of bullous pemphigoid and
mucous membrane pemphigoid
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Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid
INTRODUCTION Bullous pemphigoid and mucous membrane

pemphigoid (MMP) are uncommon autoimmune subepithelial blistering diseases that most
frequently arise in older adults and are characterized by the presence of cutaneous bullae and
erosive mucosal lesions. Significant progress has been made in understanding the pathogenesis of
these diseases. Multiple events, including the binding of immunoglobulins to basement membrane
zone components, the subsequent activation of complement, and the migration of inflammatory
cells into the subepithelial tissue, likely contribute to the clinical manifestations of bullous
pemphigoid and MMP.
The epidemiology and pathogenesis of bullous pemphigoid and MMP will be reviewed here. The
clinical features, diagnosis, and treatment of these disorders and greater detail on the ocular form of
MMP (ocular cicatricial pemphigoid) are available separately. (See "Clinical features and diagnosis
of bullous pemphigoid and mucous membrane pemphigoid" and "Management and prognosis of
bullous pemphigoid" and "Management of mucous membrane pemphigoid" and "Ocular cicatricial
pemphigoid".)
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CLASSIFICATION Pemphigoid disorders, which include bullous
pemphigoid, MMP, anti-laminin 332 pemphigoid (also known as anti-epiligrin cicatricial pemphigoid),
pemphigoid gestationis, Brunsting-Perry pemphigoid, and anti-laminin gamma-1 (anti-p200)
pemphigoid, are characterized clinically by the presence of inflammatory, blistering, and/or erosive
mucocutaneous lesions and immunohistopathologically by subepithelial cleavage and
immunoglobulin G (IgG) and/or complement deposits in a linear pattern at the epidermal basement
membrane zone (picture 1A-B). The location of blistering and immunoglobulin deposition
distinguishes pemphigoid disorders from pemphigus. In pemphigus, blister formation and antibody
deposition occur within the epidermis/epithelium (picture 2A-B) [1]. (See "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Pathogenesis, clinical
manifestations, and diagnosis of pemphigus".)
MMP is not a single disease, rather it represents a group of heterogeneous, chronic subepithelial
blistering diseases that primarily affect mucosal surfaces [2]. Historically, because of the scarring
sequelae that may develop clinically, the term cicatricial pemphigoid was ascribed to diseases now
categorized as MMP.
Some authors also consider mucosal-predominant forms of linear IgA bullous dermatosis and
epidermolysis bullosa acquisita as forms of MMP [2]. However, our preference is to consider these
diagnoses as distinct disease entities. (See "Linear IgA bullous dermatosis" and "Epidermolysis
bullosa acquisita".)
A table summarizing the major forms of pemphigoid and non-pemphigoid autoimmune blistering
disorders is provided (table 1).
EPIDEMIOLOGY Most of the data on the incidence of bullous pemphigoid

are derived from European reports, in which studies documenting incidence rates of 4 to 22 cases
per million individuals per year support the designation of bullous pemphigoid as an uncommon
disorder [3-5]. The results of retrospective studies suggest that the incidence of bullous pemphigoid
may be increasing [5-7]. One of the largest reported increases stems from a French retrospective
study that found that the annual incidence rate for bullous pemphigoid between 2000 and 2005 (22
cases per million inhabitants per year) was three times greater than the estimated incidence rate
between 1986 and 1992 [5]. The findings of a United States study suggest that an increase in the
diagnosis of localized bullous pemphigoid may be one of the factors contributing to the increased
incidence of this disease.
Bullous pemphigoid is considered the most common autoimmune blistering disorder in Europe.
However, in locations such as Thailand and Malaysia, pemphigus may be more common [8,9].
Bullous pemphigoid is primarily a disease of older adults; the vast majority of cases occur in
individuals over the age of 60 years and occurrence in children is rare [10-13]. In a retrospective
study of 869 patients with bullous pemphigoid in the United Kingdom, the median patient age at the
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time of presentation was 80 years [14].
The increased risk of bullous pemphigoid with advancing age was illustrated in two European
prospective studies that were based upon data collected in 2001 and 2002 [3,15]. In a German study,
the estimated incidence rate in the general population was 13 cases per million individuals per year,
but rose to 189 cases per million individuals per year among those over the age of 80 [15]. Similarly,
a sharp rise in incidence was evident in a Swiss study in which the incidence of bullous pemphigoid
increased from 12 cases per million individuals per year in the general population to 163 cases per
million individuals among those over the age of 90 [3].
MMP is less common than bullous pemphigoid; in the German study cited above, the estimated
incidence rate in the general population was two cases per million inhabitants per year [15]. Like
bullous pemphigoid, MMP is most likely to occur in older individuals and is rare in children [10,16].
Patients with MMP most frequently are within the age range of 60 to 80 years [17].
Gender also may play a role in risk for bullous pemphigoid and MMP. Multiple studies have reported
at least a slight female predominance in these disorders [3,8,18]. The reasons for this observation
are unknown.
PATHOGENESIS The mechanisms that lead to bullous pemphigoid and

MMP are not fully understood, but most likely involve autoantibody-mediated damage to epithelial
basement membrane zone, a complex structure that mediates adhesion, permeability, and cellular
organization and differentiation (figure 1A-B) [19-22]. The binding of antibodies to antigens within
the epithelial basement membrane zone stimulates a destructive inflammatory cascade that results
in separation of the epidermis from the dermis in skin and epithelium from subepithelial tissue in
mucous membranes with the formation of characteristic cutaneous and mucosal lesions. Innate
immune cells producing interleukin 17 (IL-17) may be important in the maintenance and extent of
disease [23].
Antigenic targets — Antibodies to several antigens have been identified as

potential contributors to bullous pemphigoid and MMP.
Bullous pemphigoid — In bullous pemphigoid, autoantibodies against two

principal hemidesmosomal proteins are strongly linked to clinical disease: bullous pemphigoid
antigen 180 (BP180), a 180 kilodalton protein also known as bullous pemphigoid antigen 2 (BPAg2)
and type XVII collagen, and bullous pemphigoid antigen 230 (BP230), a 230 kilodalton protein also
referred to as bullous pemphigoid antigen 1 (BPAg1).
BP180 — Antibodies against BP180, a transmembrane protein that extends from the
hemidesmosomal dense plaque in basal keratinocytes into the lamina densa of the basement
membrane zone (figure 1A) [24], are present in the majority of patients with bullous pemphigoid.
Antibodies against the noncollagenous extracellular domain of BP180 known as NC16A (the primary
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site for antibody binding in bullous pemphigoid) are detected via enzyme-linked immunosorbent
assay (ELISA) in 80 to 90 percent of affected patients [20,25-30]. The production of antibodies to
other epitopes of BP180 also occurs in bullous pemphigoid, and may have clinical significance. As
an example, antibodies directed against epitopes in the C-terminal end of BP180 have been
associated with the presence of mucosal disease [31,32].
An important role for antibodies against BP180 in bullous pemphigoid is supported by animal
models in which the transfer of BP180 immunoglobulin (Ig)G antibodies resulted in the development
of skin lesions that resemble bullous pemphigoid (see 'Animal models' below) [33-35]. Additional
support is derived from the observation that serum levels of antibodies against the NC16A epitope
correlate with disease activity [36,37].
The predominant subclass of antibodies that react with the basement membrane zone in bullous
pemphigoid is IgG4 [38,39]. IgG4 antibodies also are present in the prodromal phase of bullous
pemphigoid that often precedes cutaneous blistering [39]. IgG1 and IgG2 antibodies may be present
in bullous pemphigoid, but are less frequently detected than IgG4 antibodies. IgG3 antibodies are
usually absent [38].
Although BP180 antibodies of the IgG class are most frequently detected in bullous pemphigoid, IgA
and IgE BP180 antibodies also may be present [19,38-42]. The relevance of IgA antibodies in bullous
pemphigoid remains uncertain. Cases in which a predominance of IgA basement membrane zone
localization is detected actually may represent linear IgA bullous dermatosis (see "Linear IgA bullous
dermatosis", section on 'Pathogenesis'). There is some evidence to support a pathogenic role for IgE
basement membrane zone antibodies, including a small retrospective study that identified an
association with severe disease [36,43-46]. In addition, a study in which anti-BP180 NC16A serum
IgE was detected in 47 of 117 patients with BP (40 percent) found a correlation between serum
levels of these autoantibodies and disease activity [42].
Of note, antibodies against BP180 also occur in other subepidermal autoimmune blistering
diseases. IgG BP180 antibodies may be detected in patients with MMP and pemphigoid gestationis.
(See 'Mucous membrane pemphigoid' below and "Dermatoses of pregnancy", section on
'Pemphigoid gestationis'.)
BP230 — BP230 is an intracellular hemidesmosomal protein in the plakin family that is found in
basal keratinocytes (figure 1A). In conjunction with plectin, another hemidesmosomal plakin, BP230
links keratin intermediate filaments to hemidesmosomes [24]. Antibodies to BP230 are detected in
approximately 60 to 70 percent of patients with bullous pemphigoid [19,41]. The primary site of
antibody binding on BP230 is the globular C-terminal domain [19,41].
It is unclear whether BP230 antibodies have a pathogenic role in bullous pemphigoid or whether they
occur as a secondary event related to keratinocyte injury [19]. Serum levels of antibodies against
BP230 do not reveal consistent correlation with disease activity [47-49]. In addition, the intracellular
location of BP230 likely limits access of BP230 antibodies to the antigen. Nevertheless, in our
experience, there is a subset of pemphigoid patients with increased BP230 antibody levels and
normal BP180 antibody levels.
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Mucous membrane pemphigoid — Antibodies against several
basement membrane zone antigens have been detected in patients with MMP, some of which
correlate with distinctive clinical features. The major basement membrane zone proteins targeted in
MMP include (figure 1A) [2,50-52]:
●BP180 (C terminal domain)
●BP230
●Laminin 332 (also known as laminin 5 or epiligrin)
●alpha6beta4 integrin
●Type VII collagen
The precise location of antibody binding can have clinical relevance in MMP:
●Scarring – The site of antibody binding may account for the frequent development of scarring in
MMP lesions, a feature that typically is not observed in bullous pemphigoid. In contrast to bullous
pemphigoid, in which antibody binding occurs to epitopes located in hemidesmosomes and the
upper lamina lucida, antibody-binding in MMP is primarily located in the lower lamina lucida and
lamina densa [53]. This deeper location of antibody binding may increase the risk for scarring. (See
on 'Mucous membrane pemphigoid'.)
●Sites of disease – Ocular involvement is associated with antibodies to the beta-4 integrin subunit
of alpha6beta4 integrin, whereas antibodies to the alpha-6 subunit have been linked to oral disease
[54,55]. (See "Ocular cicatricial pemphigoid", section on 'Pathogenesis'.)
A systematic review with pooled analysis found statistically significant associations between the
detection of autoantibodies against laminin 332 with ELISA and both pharyngo-laryngeal and oro-
pharyngo-laryngeal involvement in patients with MMP [56]. However, publication bias may have
contributed to this finding.
●Risk for associated malignancy – Antibodies to laminin 332, which are estimated to occur in
approximately 25 percent of patients with MMP, are associated with an increased risk for internal
malignancy [57]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Malignancy'.)
In addition to the specific epitope or epitopes targeted, the number and type of autoantibodies that
bind to the basement membrane zone may be clinically relevant in MMP. Autoantibodies to multiple
basement membrane antigens or multiple epitopes on BP180, as well as the combined presence of
IgG and IgA basement membrane zone antibodies have been associated with severe disease [54,58].
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Anti-p200 (laminin gamma-1) pemphigoid — Laminins are
heterotrimers composed of one of five alpha chains, one of four beta chains, and one of three
gamma chains. The laminins are named based on their polypeptide chain assortment [59]; for
example, laminin 311 is composed of the laminin alpha-3, beta-1, and gamma-1 chains. At least 16
laminins are described of which at least three are important extracellular matrix glycoproteins in the
basement membrane zone, laminin 311 (laminin 6), laminin 332 (laminin 5 or epiligrin), and laminin
551 (formerly known as laminin 10) [60].
Anti-p200 (laminin gamma-1) pemphigoid is a type of pemphigoid that clinically resembles bullous
pemphigoid [61]. This type of pemphigoid is distinguished by the presence of antibodies to a 200
kilodalton protein that, in most patients, corresponds with the gamma-1 subunit of laminin 311 in the
epithelial basement membrane zone (figure 1A) [61-64]. (See "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Anti-p200 (laminin gamma-1)
pemphigoid'.)
Role of pathogenic antibodies — Antibody-mediated activation of

the complement cascade by antibodies bound to specific antigens in the basement membrane zone
has been proposed as a principal mechanism for lesion formation in bullous pemphigoid and MMP
[19,20,65,66]. The activation of complement may stimulate the local recruitment of inflammatory
cells that release proinflammatory mediators as well as proteases that directly damage the
basement membrane zone [67,68]. In bullous pemphigoid, mast cells and eosinophils may
contribute significantly to clinical disease [69-74].
With respect to anti-p200 (laminin gamma-1) pemphigoid, ex vivo and in vivo studies were unable to
show pathogenic activity of laminin gamma-1 antibodies [75]. Such antibodies appear to be a useful
biomarker for anti-p200 (laminin gamma-1) pemphigoid, but their pathogenic role is yet to be
understood.
The acceptance of basement membrane zone antibodies as the exclusive cause of bullous
pemphigoid is complicated by the observation that some patients with positive circulating basement
membrane zone antibodies lack clinical signs of disease [76,77]. In one study, BP180, BP230, or both
antibody levels determined by ELISA were increased in 5 out of 15 older adult patients with pruritus
and no other clinical or laboratory evidence of bullous pemphigoid [78]. It is unclear whether these
results represented the identification of a prodromal phase of bullous pemphigoid or coincidental
findings unrelated to the disease.
Animal models — Studies utilizing animal models have contributed significantly to

the understanding of the pathogenesis of bullous pemphigoid and MMP. The pathogenic role of
BP180 antibodies is supported by animal models of bullous pemphigoid that indicate that IgG
antibodies to a basement membrane zone antigen analogous to BP180 in the animal species are
capable of activating complement and inducing features consistent with bullous pemphigoid,
including blister development and mast cell degranulation [33-35]. Moreover, passive transfer
2293
experiments in which human BP180 antibodies are delivered to mice humanized with BP180 antigen
demonstrate basement membrane separation that is dependent upon complement, neutrophils, and
mast cells [79].
However, the observations that animal models of bullous pemphigoid primarily demonstrate
neutrophil infiltration (similar to that seen in linear IgA disease), rather than eosinophil infiltration
and eosinophil degranulation, which are characteristic of human bullous pemphigoid, indicate that
pathogenic mechanisms in bullous pemphigoid remain incompletely understood [69,71,72]. It is
likely that additional factors not present in the passive transfer models are responsible for eosinophil
infiltration in humans. A murine model of bullous pemphigoid with IgE antibodies recapitulates the
inflammatory infiltrate in pemphigoid more closely [80]. Additional study is necessary to define the
pathogenic role that IgE plays in bullous pemphigoid [81].
Other factors — Although further study is necessary to elucidate the pathways that
lead to bullous pemphigoid and MMP, genetic factors, environmental exposures, and the
phenomenon of epitope spreading are considered potential contributory factors.
Genetics — Certain human leukocyte antigen (HLA) alleles may play a role in bullous
pemphigoid and MMP. In MMP, increased prevalence of the HLA-DQB1*0301 allele is reported in
multiple studies [82-85], and the same allele is associated with bullous pemphigoid in a small series
of patients in the United States and Germany [83,86]. However, these findings may not be applicable
to all populations, as this allele was not associated with bullous pemphigoid in two studies
performed in Japanese and Chinese patients [87,88]. In the Japanese study, several other potential
susceptibility alleles were identified [87].
The proposed mechanism through which certain HLA alleles might contribute to risk for bullous
pemphigoid or MMP involves the facilitation of antigen presentation of basement membrane zone
antigens to T cells [66]. Further studies are necessary to explore the role of genetic factors in the
development of these diseases.
Infections and drugs — Autoimmune reactions triggered by exposure to infections

or drugs may play a role in bullous pemphigoid and MMP. In theory, these disorders could occur as a
result of cross-reactivity of antibodies that target infectious agents or drugs with antigens in the
basement membrane zone. Although no specific infectious disorder has been definitively associated
with pemphigoid, in a small case-control study, antibodies against hepatitis B, hepatitis C,
Helicobacter pylori, Toxoplasma gondii, and cytomegalovirus were more prevalent among patients with
bullous disease (pemphigus or bullous pemphigoid) [20].
The possibility that pemphigoid is a rare side effect of vaccination against infectious agents is
raised by reports of more than 25 patients with BP and at least 1 patient with MMP that describe the
development of pemphigoid shortly after vaccination [89,90]. However, a causal relationship
between vaccination and pemphigoid is unconfirmed.
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A variety of drugs have been associated with the development of bullous pemphigoid [91,92],
although the strength of these associations is uncertain [93]. A listing of many of the reported
agents is provided (table 2).
In particular, there is increasing support for an association between dipeptidyl peptidase-4 (DPP-4)
inhibitors and the development of BP and MMP [94-98]. A case-control study of 82 patients with BP
and diabetes and 328 age- and sex-matched controls with diabetes but without BP found an
association between DPP-4 inhibitor intake and the development of BP (adjusted odds ratio [OR] 3.2,
95% CI 1.9-5.4) [99]. BP was associated with use of vildagliptin (adjusted OR 10.7, 95% CI 5.1-22.4)
and linagliptin (adjusted OR 6.7, 95% CI 2.2-19.7), but not sitagliptin. Patients younger than 70 years
and males exhibited the strongest associations between DPP-4 inhibitor use and BP. Mucosal
involvement in BP was more common in DPP-4 inhibitor-exposed patients. Patients who
discontinued DPP-4 inhibitors appeared to have better outcomes from standard BP therapy than
those who continued DPP-4 inhibitor use.
Epitope spreading — The term epitope spreading has been used to describe the
induction of an autoimmune response against normally tolerated host antigens and epitopes as a
consequence of the exposure of these antigens and epitopes during immune-mediated tissue
inflammation [100]. Epitope spreading has been proposed as an explanation for cases in which
pemphigoid occurred in the setting of other diseases. As examples, ocular cicatricial pemphigoid
has developed following conjunctival inflammation due to Stevens-Johnson syndrome [101] and, in
lichen planus pemphigoides (a variant of bullous pemphigoid), the onset of bullous lesions occurs
weeks to months after the development of lichen planus [102]. Bullous pemphigoid also develops
after radiation therapy possibly through exposure of basement membrane zone antigens in the
course of the treatment [103]. (See "Ocular cicatricial pemphigoid", section on 'Pathogenesis' and
on 'Bullous pemphigoid'.)
Spreading of the immune response against epidermal basement membrane zone antigens to or
from similarly structured proteins in other body sites also may occur. The development of bullous
pemphigoid in several renal transplant patients has been attributed to the concept that autoantibody
formation against the glomerular basement membrane zone may have contributed to the
development of bullous disease [104]. This phenomenon also has been proposed as a contributor to
the observed link between bullous pemphigoid and certain neurologic disorders [105-108]. (See
on 'Neurologic disorders'.)

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●Basics topic (see "Patient education: Bullous pemphigoid (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune
subepithelial bullous disorders that present with blistering and/or erosive cutaneous and mucosal
lesions (table 1). (See 'Classification' above and "Clinical features and diagnosis of bullous
pemphigoid and mucous membrane pemphigoid".)
●Bullous pemphigoid and MMP primarily occur in the older population. Most patients affected by
these disorders are over the age of 60 years. Bullous pemphigoid and MMP are rare in children. (See
●The clinical manifestations of bullous pemphigoid and MMP likely result from the destructive and
inflammatory consequences related to antibody binding in the epithelial basement membrane zone
in skin and mucous membranes. (See 'Pathogenesis' above.)
●Bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230) are two
principal basement membrane zone antigens targeted by antibodies in patients with bullous
pemphigoid (figure 1A). Although antibodies formed against BP180 are likely pathogenic, a
pathogenic role for BP230 antibodies is uncertain. (See 'Bullous pemphigoid' above.)
●Multiple antigenic targets have been linked to MMP. Of note, antibodies against laminin 332 (also
known as laminin 5 or epiligrin) are associated with an increased risk for malignancy, and antibodies
against the beta-4 subunit of alpha6beta4 integrin are linked to ocular disease (ocular cicatricial
pemphigoid). (See 'Mucous membrane pemphigoid' above and "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Malignancy' and "Ocular
cicatricial pemphigoid", section on 'Pathogenesis'.)
●Genetic factors, environmental exposures, and the phenomenon of epitope spreading may impact
the development of bullous pemphigoid and MMP. Additional studies are necessary to explore the
relationships of these factors to disease expression. (See 'Other factors' above.)
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Clinical features and diagnosis of bullous pemphigoid and
mucous membrane pemphigoid
uptodate.com/contents/clinical-features-and-diagnosis-of-bullous-pemphigoid-and-mucous-membrane-
pemphigoid/print
Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid
INTRODUCTION Bullous pemphigoid and mucous membrane

pemphigoid (MMP) are autoimmune blistering diseases that most commonly arise in older adults.
These disorders are characterized by subepithelial blister formation and the deposition of
immunoglobulins and complement within the epidermal and/or mucosal basement membrane zone.
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Although both bullous pemphigoid and MMP may affect skin and mucosa, the classical clinical
findings in bullous pemphigoid are tense, fluid-filled bullae on skin whereas the prevailing clinical
feature in MMP is mucosal involvement. In MMP, inflamed and eroded mucosa is characteristic,
involving any or all of the oral cavity, ocular conjunctiva, nose, pharynx, larynx, esophagus, anus, and
genital mucous membranes.
The clinical features and diagnosis of bullous pemphigoid and MMP will be reviewed here (algorithm
1). The epidemiology, pathogenesis, and treatment of these disorders as well as greater detail on the
ocular form of MMP (ocular cicatricial pemphigoid) and other autoimmune blistering disorders are
discussed separately. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous
membrane pemphigoid" and "Management and prognosis of bullous pemphigoid" and "Management
of mucous membrane pemphigoid" and "Ocular cicatricial pemphigoid" and "Dermatoses of
pregnancy", section on 'Pemphigoid gestationis' and "Pathogenesis, clinical manifestations, and
diagnosis of pemphigus".)
CLINICAL FEATURES
Bullous pemphigoid — A prodromal phase lasting weeks to months may
precede the development of cutaneous bullae in patients with bullous pemphigoid [1,2]. The
prodromal phase may present with pruritic eczematous, papular, or urticaria-like skin lesions (picture
1D) [3]. Some patients with bullous pemphigoid never develop blistering.
When blisters develop, the classical lesion is a 1 to 3 cm tense bulla on an erythematous, urticarial,
or noninflammatory base, and blisters may be numerous and widespread (picture 1A-C) [4].
Associated pruritus is common and can be severe [5,6]. The tense quality of the bullae differentiates
the lesions of bullous pemphigoid from the flaccid bullae of pemphigus vulgaris (picture 2A) [1,7]
(see "Pathogenesis, clinical manifestations, and diagnosis of pemphigus"). Eventually, the bullae
rupture, leaving moist erosions and crusts that resolve without scarring. When mainly erosions are
present, it may be difficult to clinically distinguish bullous pemphigoid and pemphigus (picture 2B).
The trunk, extremity flexures, and axillary and inguinal folds are common sites for cutaneous
involvement (picture 3A-C) [8]. Mucosal lesions are present in 10 to 30 percent of patients (picture 4)
[1,2,4,9]. The oral mucosa is the most frequent location of mucosal involvement; less frequently,
bullous pemphigoid involves other mucosal sites, such as the larynx, genitals, and anus [9]. Nail
changes also may develop [10,11].
Localized forms of bullous pemphigoid occur and account for up to 30 percent of cases [12].
Examples include disease limited to the lower legs (picture 1E) [12-16], anogenital region [17,18],
peristomal skin [19,20], or sites of incidental or iatrogenic trauma (eg, radiation therapy) [21-27].
Disease that begins in localized areas may remain localized or may progress to generalized
involvement [12,28].
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Other reported clinical variants of bullous pemphigoid include nonbullous presentations, such as
eczematous, urticarial, and prurigo-like (pemphigoid nodularis) presentations, as well as bullous
pemphigoid presenting as pruritus without any primary skin lesions (pruritic nonbullous pemphigoid,
bullous pemphigoid as pruritus in older adults); in such cases, the diagnosis is based upon
consistent laboratory findings [2,29-32]. (See 'Laboratory tests' below.)
It is estimated that approximately 20 percent of patients with bullous pemphigoid present with
nonbullous manifestations [33]. In a retrospective study of 69 patients with nonbullous pemphigoid,
the most common presentations included pruritic papules or nodules (37 percent of patients) and
pruritus without primary skin lesions (22 percent of patients) [32]. Progression to blistering disease
eventually occurs in some patients.
Rare variants include pemphigoid vegetans, which manifests with verruciform plaques in
intertriginous areas [34,35], dyshidrosiform pemphigoid, which occurs on palmar and/or plantar skin
(resembling dyshidrotic eczema) and often is hemorrhagic (picture 1F) [36,37], vesicular bullous
pemphigoid, in which lesions resemble dermatitis herpetiformis [38], and bullous pemphigoid
occurring in association with transient palmoplantar keratoderma [39].
Lichen planus pemphigoides is another rare variant of bullous pemphigoid. It is postulated that the
cellular inflammatory process that occurs at the basement membrane zone in lichen planus results
in exposure of basement membrane zone antigens leading to subsequent development of basement
membrane zone antibodies [40]. Patients with lichen planus pemphigoides typically present with
bullae in sites of previously normal-appearing skin or mucosa. The bullae usually appear weeks to
months after the onset of lichen planus [3].
Mucous membrane pemphigoid — MMP represents a group of

heterogeneous, chronic subepithelial blistering disorders that primarily affect mucosal surfaces [41].
Historically, the term cicatricial pemphigoid also referred to these disorders. Some authors also
consider cases of linear IgA bullous dermatosis and epidermolysis bullosa acquisita that primarily
involve the mucous membranes as forms of MMP [41]. However, our approach is to view these
diagnoses as distinct entities. (See "Linear IgA bullous dermatosis" and "Epidermolysis bullosa
acquisita".)
MMP typically presents as relapsing and remitting mucosal inflammation and erosions (picture 5A-
C). The oral cavity is the most common site of involvement, and cutaneous involvement also may be
present. In a report that summarized the sites of involvement in 457 patients with MMP, the
frequency of affected sites was as follows [42]:
●Oral mucosa (85 percent)
●Ocular conjunctiva (64 percent)
●Skin (24 percent)
●Pharynx (19 percent)
2300
●External genitalia (17 percent)
●Nasal mucosa (15 percent)
●Larynx (8 percent)
●Anus (4 percent)
●Esophagus (4 percent)
In the oral cavity, the gingival and buccal mucosae are most commonly affected. Gingival disease
usually manifests as a desquamative or erosive gingivitis (picture 5A), and, in mild cases, may
manifest only with gingival erythema and edema [43]. The detection of intact vesicles or bullae on
mucosa is uncommon. Compared with the mucosal lesions of pemphigus (picture 2C), pain
associated with oral MMP lesions is usually less intense [2].
Scarring is a common consequence of MMP that distinguishes this variant from mucosal
involvement in bullous pemphigoid, which typically does not scar. Reticulated, white striations
representing mucosal fibrosis often are present at sites of healed lesions, and functional limitations
secondary to scarring may occur [2,43]. As examples, MMP involving the ocular mucosa can lead to
symblepharon, ankyloblepharon, and eventual blindness, and progressive laryngeal and tracheal
involvement can result in asphyxiation [43]. (See "Ocular cicatricial pemphigoid", section on 'Clinical
manifestations'.)
Cutaneous involvement in patients with MMP typically involves the scalp, face, or upper trunk. The
bullous lesions resemble those seen in bullous pemphigoid, but, similar to mucosal lesions of MMP,
often heal with scarring.
ASSOCIATED DISORDERS Patients with bullous

pemphigoid often have multiple comorbidities [44,45]. In a case-control study that included 105
patients with bullous pemphigoid and 315 matched controls, patients with bullous pemphigoid were
more likely to have two or more other chronic diseases (84 versus 65 percent) [44].
Neurologic disorders — Associations between bullous pemphigoid and

neurologic disorders have been reported in several observational studies and case reports [45-57]. In
a hospital-based prospective case-control study of 201 patients with bullous pemphigoid and 345
matched controls, dementia, Parkinson's disease, and unipolar or bipolar disorder were among the
identified independent risk factors for this disease [48]. In addition, a population-based case-control
study of 868 patients with bullous pemphigoid and more than 3400 controls found that patients with
preexisting diagnoses of dementia, Parkinson's disease, or stroke were significantly more likely to
develop bullous pemphigoid [47]. Further, a case-control study with more than 5000 patients with
multiple sclerosis and over 26,000 controls supported an association of bullous pemphigoid and this
disease [58].
2301
Homology between bullous pemphigoid antigens in the skin and neuronal antigens in the central
nervous system has been proposed as a cause for the observed link between bullous pemphigoid
and neurologic disease, along with a genetic predisposition [59-63]. However, further studies are
necessary to explore the relationship between these disorders. (See "Epidemiology and
pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Epitope
spreading'.)
Malignancy — MMP with antibodies directed against laminin 332 (previously known as
laminin 5 and epiligrin) has been associated with an increased risk for internal malignancy (figure 1).
In a cohort of 35 patients with this type of MMP (diagnosed with immunoprecipitation), 10 (29
percent) developed solid organ malignancies, 7 of which were diagnosed within 14 months after a
diagnosis of MMP [64]. Occurrences of non-Hodgkin lymphoma and cutaneous T cell lymphoma
have also been reported in individual patients with anti-laminin 332 MMP [65]. The pathophysiologic
relationship of this subtype of MMP to cancer is unknown. However, expression of laminin 332 has
been detected in malignant cells, and laminin 332 appears to be capable of promoting tumor cell
growth, invasion, and metastasis [65,66].
The clinical manifestations of MMP in patients with laminin 332 antibodies are similar to the
features of MMP with other antibody profiles. Therefore, clinical examination cannot reliably
distinguish anti-laminin 332 MMP from other forms of MMP. Additional studies are necessary to
confirm the findings of a retrospective study of 154 patients with MMP that associated the detection
of laminin 332 antibodies via a novel enzyme-linked immunosorbent assay (ELISA) with a greater
likelihood for severe disease [67].
Since diagnostic laboratory testing for laminin 332 antibodies is not commercially available,
suspicion for laminin 332 primarily is based upon immunofluorescence microscopy findings.
Although not exclusive to laminin 332 MMP, the detection of antibodies bound to the dermal side of
basement membrane zone-split (salt-split) skin suggests the possibility of this diagnosis. (See
'Indirect immunofluorescence of serum' below.)
Until definitive testing for laminin 332 antibodies becomes available, we recommend that patients
with MMP in whom serum indirect immunofluorescence (IIF) studies reveal antibodies bound to the
dermal side of basement membrane zone-split skin undergo age and gender appropriate cancer
screening. Additional evaluation for malignancy should be performed as indicated based upon a
review of symptoms, physical examination, and the results of age-appropriate screening.
The relationship between bullous pemphigoid and malignancy is less clear. While some studies
support an association, others have failed to find a significant increase in malignancy risk,
attributing occurrences of malignancy to age rather than bullous pemphigoid [57,68,69]. Further
study is necessary to confirm the findings of a systematic review and meta-analysis of observational
studies that did not find an association of bullous pemphigoid with malignancy overall but found an
association between bullous pemphigoid and hematologic malignancies [70]. In addition, the results
of a cohort study that found a disproportionate increase in risk for malignancy in young versus old
individuals with bullous pemphigoid need to be confirmed [68]. In our practice, we evaluate young
2302
and middle-aged patients with bullous pemphigoid for underlying malignancy particularly when they
present with severe or refractory disease, present with symptoms or signs in organ systems other
than skin, or if there is a family history of genetically associated malignancy.
DISEASE COURSE Bullous pemphigoid is a chronic disorder

characterized by exacerbations and remissions over the course of months to years. However, in
some patients the disease is self-limited, resulting in disease remissions within a few years. (See
"Management and prognosis of bullous pemphigoid", section on 'Prognosis'.)
In the absence of treatment, MMP is usually a chronic, progressive disease that results in
functionally limiting or, in some cases (such as those with airway involvement), life-threatening
disease [43]. The clinical course and prognosis of ocular MMP is reviewed in greater detail
separately. (See "Ocular cicatricial pemphigoid", section on 'Clinical manifestations' and "Ocular
cicatricial pemphigoid", section on 'Prognosis and cessation of therapy'.)
DIAGNOSIS Although clinical findings may strongly suggest bullous pemphigoid

or MMP, other disorders present with similar mucocutaneous lesions, and nonbullous or other less
typical presentations can occur (table 1). Thus, confirmation of the diagnosis requires the careful
interpretation of both clinical and laboratory findings. (See 'Differential diagnosis' below and 'Clinical
features' above.)
Clinical assessment — Clinical features that suggest bullous pemphigoid or

MMP in patients over the age of 60 years include:
●Blistering skin disease characterized by the presence of tense blisters and erosions that occur
without another identifiable cause
●Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal,
laryngeal, and/or esophageal mucosae
●Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques
The possibility of bullous pemphigoid or MMP also should be considered in the evaluation of
younger individuals (including neonates, infants, and children) with suggestive symptoms in the
absence of another identifiable cause (picture 1G) [71-73]. In patients with signs or symptoms of
these disorders, laboratory assessment is indicated. (See "Epidemiology and pathogenesis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Epidemiology'.)
Laboratory tests — The principal studies used in the evaluation of patients with
lesions suspicious for bullous pemphigoid or MMP include (table 2):
2303
●A lesional skin biopsy fromthe edge ofan intact blister (or other inflamed/affected tissue, urticarial
or eczematous) for hematoxylin and eosin (H&E) staining and a skin biopsy from a perilesional area
for direct immunofluorescence (DIF). DIF is considered the most sensitive test for the diagnosis of
bullous pemphigoid. (See 'Skin biopsy' below and "Approach to the patient with cutaneous blisters",
section on 'Skin biopsy'.)
●A serum specimen for indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay
(ELISA) testing to detect circulating basement membrane zone antibodies. (See "Approach to the
patient with cutaneous blisters", section on 'Serologic tests'.)
Our approach — In patients with clinical findings suggestive of bullous pemphigoid or

MMP, we begin the laboratory assessment by obtaining both a lesional tissue specimen for routine
(fixed tissue) histopathology and a perilesional tissue specimen for DIF examinations. Bullous
pemphigoid antigens may be sparse in distal anatomical locations; therefore, when possible,
choosing a proximal anatomical site for the perilesional DIF specimen is preferred. Obtaining a
lesional specimen often is difficult in MMP involving the mouth and vulva, because affected mucosa
is friable and easily erodes. When this occurs, perilesional tissue with intact epithelium should still
be obtained for DIF.
Serologic studies provide additional information that is useful for diagnosis and management in
most patients. IIF performed on basement membrane zone-split skin substrate aids in distinguishing
bullous pemphigoid from epidermolysis bullosa acquisita and can identify patients with MMP who
are at risk for malignancy-associated laminin 332 (epiligrin) MMP. Because of its value, we perform
serum testing (IIF and ELISA) in all patients with clinical, histopathologic, and/or DIF findings
consistent with bullous pemphigoid or MMP. (See 'Malignancy' above and 'Indirect
immunofluorescence of serum' below and "Epidermolysis bullosa acquisita", section on 'Diagnosis'.)
Routine inclusion of both DIF microscopy and IIF testing on human basement membrane zone-split
skin in the evaluation of suspected bullous pemphigoid may optimize early detection of the disease,
especially in patients who present without blisters. In an analysis of 1125 patients with suspected
bullous pemphigoid, in which 343 received a pemphigoid diagnosis, DIF was the most sensitive
diagnostic test (sensitivity of 88.3 percent, 95% CI 84.5-91.3 percent and specificity of 99.2 percent,
95% CI 98.3-99.7 percent), and IIF on human basement membrane zone-split (salt-split) skin was
less sensitive but highly specific (sensitivity of 77 percent, 95% CI 72.2-81.1 and specificity of 99.9
percent, 95% CI 99.3-100 percent) [33]. Based upon the study findings, the authors proposed
achievement of at least two the following three characteristics as minimal diagnostic criteria:
●Pruritus and/or predominant cutaneous blisters
●Linear immunoglobulin G (IgG) and/or C3 deposits by DIF on a skin biopsy specimen
●Positive epidermal (roof) side IgG staining by IIF basement membrane zone-split skin on a serum
sample
2304
In addition, serologic studies can be of value when DIF is negative in a patient with clinical and
histopathologic findings that are consistent with bullous pemphigoid or when it is not possible to
obtain adequate biopsy tissue [74]. The combination of IIF and ELISA serum testing is useful to
support a clinical diagnosis of bullous pemphigoid [75].
An algorithm depicting our approach to the diagnosis of patients who present with skin lesions
suspicious for bullous pemphigoid and oral lesions suggestive of MMP is provided (algorithm 1).
Skin biopsy — Separate specimens are optimal for H&E (light microscopy of fixed tissue)
and DIF because of differences in the requirements for the preferred biopsy location and tissue
handling. We typically obtain two 4 mm punch biopsies. However, careful splitting of a 5 or 6 mm
punch biopsy specimen or a shave biopsy specimen into lesional and perilesional specimens is an
additional option. If only one small specimen can be obtained, the preferred test to perform is DIF.
(See "Skin biopsy techniques", section on 'Punch biopsy' and "Approach to the patient with
cutaneous blisters", section on 'Skin biopsy'.)
Light microscopy of formalin-fixed tissue — Biopsies for histopathology

(H&E staining) should be taken from lesional skin, preferably of an intact vesicle or the edge of an
intact bulla (table 2). The specimen should include the blister edge and the immediately adjacent
tissue. Care should be taken to avoid excessive torsion and crushing, which may alter tissue
cleavage planes and increase the difficulty of pathologic interpretation. Specimens obtained for H&E
are placed in formalin for processing.
Common histopathologic findings in cutaneous lesions of bullous pemphigoid include [1]:
●Eosinophilic spongiosis (particularly in early lesions) (picture 6)
●Subepidermal blister formation (often with numerous eosinophils within cleft) (picture 7)
●A superficial dermal inflammatory cell infiltrate of variable intensity with lymphocytes, eosinophils,
and neutrophils (picture 6)
Of note, the histopathologic findings in nonbullous pemphigoid are often nonspecific. A dermal
perivascular infiltrate with eosinophils is a common finding [32].
Histopathologic examination of mucosal lesions of MMP shows epithelial-subepithelial cleavage

and a mixed submucosal inflammatory cell infiltrate composed of lymphocytes, histiocytes,
neutrophils, and eosinophils [43]. Additional findings may include plasma cell infiltration and
subepidermal fibrosis; the latter is a finding consistent with the scarring nature of MMP [43].
Direct immunofluorescence — Direct immunofluorescence (DIF) testing is a highly

sensitive, supportive diagnostic test for pemphigoid [33,74,76]. The procedure utilizes labeled
antibodies to detect immunoglobulin binding and complement deposits in tissue. DIF is a more
sensitive test for the diagnosis of bullous pemphigoid than IIF or ELISA tests [33,74]. (See "Approach
to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
2305
In contrast to biopsy specimens for H&E histopathologic evaluation, biopsy specimens for DIF
should be obtained from perilesional, not lesional skin (table 2). For affected skin, this can be an
erythematous or urticarial area adjacent to a blister. For affected mucosa, in which tissue
immediately adjacent to an erosion can be friable, a tissue specimen from normal-appearing
mucosa several millimeters away from the edge of a lesion can be obtained.
The tissue specimen for DIF should not be placed in formalin; rather, the specimen should be placed
promptly in a transport medium compatible with the performance of immunofluorescence studies,
such as Michel's medium or Zeus medium. Specimens for DIF should be transported promptly to an
immunodermatology laboratory for receipt within seven days of obtaining the specimen; transport
medium does not preserve a specimen indefinitely. Some immunodermatology laboratories will also
accept specimens transported on normal saline-soaked gauze (provided they are received during
laboratory working hours within six hours of obtaining them; sooner is better) or specimens that are
flash-frozen with liquid nitrogen, remain frozen, and transported on dry ice (table 2). Specimens
should not be immersed in saline solution or solutions other than Michel's or Zeus medium.
The classical DIF findings in bullous pemphigoid and MMP include [43,74,76,77]:
●Bullous pemphigoid –Linear IgG and/or linear C3 staining along the basement membrane zone is
present in greater than 90 percent of cases (picture 8A-C); less intense linear basement membrane
zone staining for IgM, IgA, and/or IgE may be present. DIF is less likely to be characteristically
positive in nonbullous pemphigoid, supporting performance of both DIF and serologic studies
[32,33]. (See 'Our approach' above.)
●Mucous membrane pemphigoid – Linear IgG and/or linear IgA and/or linear C3 staining along the
basement membrane zone is detected in approximately 70 to 100 percent of cases. Repeat DIF
testing on more than one biopsy specimen may be of value for patients with suspected MMP who
test negative; multiple or repeated biopsies increase the sensitivity of DIF for the diagnosis of MMP
[78]. Linear IgE basement membrane zone staining can be detected in specimens from some
patients [79].
A modified DIF technique has been described utilizing basement membrane zone-split perilesional
skin or mucosa from patients with suspected pemphigoid. Ideally, this allows for more precise
localization of antibody binding within the epithelial basement membrane zone of diseased tissue
and, therefore, additional information for diagnosis. However, the technique is infrequently utilized
with DIF because of its technical difficulty. In particular, basement membrane zone separation often
is difficult with inflamed skin and frequently is impossible to perform on mucosal specimens.
Performing IIF with the patient's serum on basement membrane zone-split skin substrate is a more
practical test. The diagnostic value of IIF is reviewed below. (See 'Indirect immunofluorescence of
serum' below.)
Additional clues for diagnosis may be provided by analysis of the linear pattern of basement
membrane zone antibody staining detected in DIF. Whereas an n-serrated pattern has been
associated with bullous pemphigoid, MMP, anti-p200 pemphigoid, and linear IgA dermatosis (picture
8C), a u-serrated pattern has been described in epidermolysis bullosa acquisita and bullous
2306
systemic lupus erythematosus (picture 9) [80,81]. A true linear pattern is commonly observed along
with the characteristic n-serrated and u-serrated patterns in all of these immunobullous diseases
[80,81].
Indirect immunofluorescence of serum — Indirect

immunofluorescence (IIF) testing is used to detect circulating basement membrane zone antibodies
in patients with pemphigoid (picture 10A). To perform this test, the patient's serum is overlaid on an
epithelial tissue substrate, incubated, and then stained for fluorescent detection of antibodies (table
2). (See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)
Bullous pemphigoid — Various tissue substrates containing epithelial basement

membrane zones have been used to perform IIF in bullous pemphigoid. Monkey esophagus is a
useful substrate because it can broadly categorize immunobullous diseases based on antibody
staining patterns. (See "Paraneoplastic pemphigus" and "Linear IgA bullous dermatosis" and
"Dermatitis herpetiformis" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
Human skin (from cadavers or surgical waste) that is artificially split at the level of the lamina lucida
(basement membrane zone-split skin) using prolonged (48 to 72 hours) exposure to 1 M sodium
chloride (salt-split skin) or short (30 minutes) exposure to ethylenediaminetetraacetic acid (EDTA) is
a useful substrate, particularly when basement membrane zone antibodies are known. This is
because of the value of the test for distinguishing between certain subepithelial immunobullous
diseases [75,82,83].
IIF with a basement membrane zone-split skin substrate aids in distinguishing between certain
subepithelial immunobullous diseases because the test allows for localization of antibody
deposition within the basement membrane zone. Specimens from patients with bullous pemphigoid
typically demonstrate antibody deposition localized to the epidermal side of basement membrane
zone-split skin, whereas in specimens from patients with epidermolysis bullosa acquisita, bullous
lupus erythematosus, anti-laminin 332 pemphigoid, and anti-p200 pemphigoid, antibodies are
typically found on the dermal side (picture 10A-B). Combined epidermal-dermal staining patterns on
basement membrane zone-split skin also are found in bullous pemphigoid and bullous lupus
erythematosus (picture 11).
IIF is a highly specific test for bullous pemphigoid [33,74]. In a retrospective study in which 313
patients with bullous pemphigoid were compared with 488 controls, the specificities of IIF on rabbit
esophagus, IIF on monkey esophagus, and IIF on human salt-split skin for diagnosis were 96.5, 97.1,
and 100 percent, respectively [74]. The sensitivities of these tests for diagnosis were 73.2, 73.3, and
72 percent, respectively. DIF had a similar specificity, but was significantly more sensitive. The
specificity of DIF was 98 percent and the sensitivity of DIF was 90.8 percent.
Mucous membrane pemphigoid — In early studies of MMP, IIF was positive in

fewer than one-third of patients [43]. However, the use of human basement membrane zone-split
skin and/or concentrated serum may increase the likelihood of detecting circulating antibodies
2307
[43,82,84]. In one series of eight patients with MMP, IIF on basement membrane zone-split skin was
positive in 50 percent [82]. A larger series of 67 patients found that IIF on a basement membrane
zone-split skin substrate yielded positive antibodies in 84 percent of patients [84].
In MMP, basement membrane zone split skin IIF is particularly useful for recognizing patients at risk
for malignancy-associated laminin 332 (previously known as laminin 5 and epiligrin) MMP; in this
condition, antibodies are found along the dermal side of the split [85,86]. Specific testing to confirm
a diagnosis of anti-laminin 332 MMP remains limited to specialized centers and research settings
[87]. (See 'Differential diagnosis' below.)
Antigen-specific serologic testing

Bullous pemphigoid — The identification of increased circulating IgG antibodies against
bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230) in patients
with bullous pemphigoid has led to the use of adjunctive antigen-specific serologic testing for these
basement membrane zone antigens in the diagnosis of this disorder (figure 1). The most common
technique used for this purpose is ELISA. (See "Epidemiology and pathogenesis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Bullous pemphigoid'.)
ELISAs for bullous pemphigoid antibodies are commercially available. This testing detects
circulating IgG that reacts with collagen type XVII or BP180 (specifically, the NC16A domain of
BP180, which is the most common antigenic target and which also has been known as bullous
pemphigoid antigen 2 [BPAg2]) and with BP230 (specifically, fused antigenic targets from the N-
terminal domain, central rod domain, and C-terminal domain of human BP230 and which also is
known as bullous pemphigoid antigen 1 [BPAg1]).
ELISA for antibodies to the BP180 NC16A domain is useful for baseline information in the diagnosis
of bullous pemphigoid; studies have documented sensitivity and specificity of 72 to 90 percent and
90 to 99 percent, respectively [74,83,88,89]. Since IgG BP180 NC16A antibody levels also correlate
with disease activity [90], many clinicians (including ourselves) utilize ELISA testing, not only to
support the diagnosis of bullous pemphigoid, but also as a measure of the response to therapy.
ELISA for BP230 antibodies is less likely to be positive in bullous pemphigoid than ELISA testing for
BP180 antibodies [74,83,91]. In a retrospective study that evaluated ELISA results in 190 patients
with bullous pemphigoid, the sensitivity and specificity of the assay for BP230 were 61 and 96
percent compared with 79 and 90 percent for BP180 [83]. Moreover, combined testing for BP180 and
BP230 antibodies was only slightly more sensitive than BP180 alone; the sensitivity and specificity
of conjoint testing were 87 and 88 percent. Although this finding suggests that testing for BP230
should be reserved for patients who test negatively for BP180, immunodermatology laboratories,
including ours, test for antibodies to both antigens in diagnostic panels for bullous pemphigoid [83].
We have observed a subset of pemphigoid patients who have strong epidermal pattern basement
membrane zone IgG antibodies by IIF and relatively high levels of IgG BP230 antibodies by ELISA,
but normal IgG BP180 antibody levels. (See "Epidemiology and pathogenesis of bullous pemphigoid
and mucous membrane pemphigoid", section on 'Pathogenesis'.)
2308
Also, in our experience, approximately 10 percent of patients with bullous pemphigoid demonstrate
characteristic epidermal pattern IgG basement membrane zone antibodies by IIF and normal levels
of both IgG BP180 and IgG BP230 antibodies by ELISA. These patients likely have antibodies to
epitopes of BP180 or BP230 that are not recognized by commercial ELISA tests or may have
antibodies to basement membrane zone antigens other than BP180 and BP230. In support of this
observation, a study of 51 patients with clinical, histopathologic, and DIF findings consistent with
bullous pemphigoid identified four patients (8 percent) in whom ELISA for BP180 NC16A was
negative, three of whom also had negative ELISA for BP230 [92]. Despite the negative ELISA for
BP180, further analysis by immunoblot revealed strong reactivity to BP180 epitopes outside of
NC16A in all four patients. These findings support the use of both IIF and ELISA to identify patients
with bullous pemphigoid. In the study described, IIF on basement membrane zone-split skin was
positive in three of the four ELISA BP180-negative patients. The subset of patients in whom serum
antibodies to the BP180 NC16A domain are not detectable may have milder clinical manifestations
(minimal to no erythema and less severe erosions and blistering) compared with patients who have
increased levels of these antibodies [93].
The potential value of combining serologic studies also was demonstrated in a retrospective study
of 313 patients with bullous pemphigoid and 488 controls that found that the sensitivity of a panel of
serologic tests (IIF on rabbit esophagus, IIF on monkey esophagus, IIF on human salt-split skin,
BP180 ELISA, and BP230 ELISA) for the diagnosis of bullous pemphigoid was 88.8 percent, a figure
that closely approximated the sensitivity of DIF (90.8 percent) [74]. There was very high correlation
between the results obtained with IIF on rabbit esophagus and IIF on monkey esophagus,
suggesting that a similar sensitivity would have been obtained upon elimination of one of these
tests. Lower sensitivities (59 to 76 percent) were detected for the individual serologic tests.
Of note, the detection of BP180 and/or BP230 antibodies in serum does not definitively confirm a
diagnosis of bullous pemphigoid. In one series of 337 people without bullous pemphigoid, 25 (7
percent) tested positively for one or both autoantibodies via ELISA [94]. Correlation of ELISA findings
with IIF and/or DIF will reduce the risk for misdiagnosis [1].
Other techniques that have been utilized for the detection of antibodies in bullous pemphigoid
include immunoblotting and immunoprecipitation. However, these tests are technically demanding
and generally are not utilized in the clinical setting [1,75].
Mucous membrane pemphigoid — MMP may present with autoantibodies

directed against a variety of antigens, including BP180, BP230, laminin 332 (previously known as
epiligrin and laminin 5), alpha6beta4 integrin, and type VII collagen (figure 1) [41,67,95-98]. However,
limited sensitivity of ELISA testing for the diagnosis of MMP prevents the sole use of such testing.
Pooled data analysis in a systematic review of studies reporting autoantibody profiles of patients
with MMP who had positive immunoblot or immunoprecipitation to NC16A found the sensitivity and
specificity of ELISA using both NC16A and C-terminal epitope portions of BP180 to be 73 and 94
percent, respectively [98]. Among patients with IgG reactivity against the C-terminal domain of
BP180, the sensitivity and specificity of ELISA testing were 43 and 56 percent, respectively.
2309
Antigen specific testing of serum for basement membrane zone antibodies other than BP180 and
BP230 primarily is performed in research laboratories, limiting the value of this testing mode in the
MMP population. However, additional tests may be available in the future. Further study is necessary
to clarify whether the detection of salivary IgA and IgG antibodies to BP180 NC16A by ELISA is a
useful diagnostic biomarker for MMP [99]. (See "Epidemiology and pathogenesis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Mucous membrane pemphigoid'.)
Other laboratory findings — Peripheral blood eosinophilia is common in

patients with bullous pemphigoid but is not a diagnostic finding [100,101]. Increased interleukin
(IL)-5, a critical cytokine in eosinophil production and activation, has been observed in peripheral
blood and blister fluid in patients with bullous pemphigoid but has not been systematically studied
[102,103]; these observations may have new significance as eosinophil reduction/elimination
therapies, including monoclonal anti-IL-5, have become available. Increased serum IgE levels also
are commonly found [104,105].
DIFFERENTIAL DIAGNOSIS The clinical findings in

bullous pemphigoid and MMP may resemble a variety of other diseases, including other variants of
pemphigoid and additional blistering or non-blistering diseases (table 1).
Other pemphigoid variants

Pemphigoid gestationis — Pemphigoid gestationis is an autoimmune
subepidermal blistering disorder that develops during pregnancy and the postpartum period.
Patients typically develop intensely pruritic papules, urticarial plaques, vesicles, and bullae that
begin on the abdomen prior to spreading to other areas [106,107]. The face and mucous membranes
are usually spared.
Like bullous pemphigoid, patients with pemphigoid gestationis have circulating BP180 antibodies
that are detected by enzyme-linked immunosorbent assay (ELISA) [108]. On direct
immunofluorescence (DIF), complement deposition predominates at the basement membrane zone.
Pemphigoid gestationis is discussed in greater detail elsewhere. (See "Dermatoses of pregnancy",
section on 'Pemphigoid gestationis'.)
Anti-p200 (laminin gamma-1) pemphigoid — Anti-p200

pemphigoid, also known as anti-laminin gamma-1 pemphigoid, is a variant of pemphigoid that is
characterized by antibodies to a 200 kilodalton component of the dermal-epidermal junction. Indirect
immunofluorescence (IIF) on basement membrane zone-split skin demonstrates dermal localization
of basement membrane zone antibodies [109] (see 'Indirect immunofluorescence of serum' above).
The antigenic target in most cases is the gamma-1 subunit of laminin 311 (previously known as
laminin 6).
2310
Patients with this type of pemphigoid are usually younger than those with bullous pemphigoid, but
present with similar clinical features. In one series of 29 patients with this disorder, 25 patients were
male, and the mean age of patients was 61 years [110]. Additionally, 14 patients had coexistent
psoriasis. In another series of 12 patients, tense acral blisters and mucosal involvement were
characteristic clinical features along with pruritus, and none had psoriasis [111].
Specific testing to confirm the presence of antibodies to p200, or particularly to laminin gamma-1,
remains limited to specialized centers and research settings [112]. As a result, it is likely that
patients with this form of pemphigoid are diagnosed erroneously with bullous pemphigoid or
epidermolysis bullosa acquisita based on DIF findings [111]. Anti-p200 pemphigoid is one of the few
diagnoses indicated by IIF testing that detects serum immunoglobulin G (IgG) basement membrane
zone antibodies binding to the dermal side of split skin substrate, also including epidermolysis
bullosa acquisita, bullous lupus, and anti-laminin 332 pemphigoid. Techniques that have been used
to specifically identify p200 antibodies include immunoblot with human dermal extract, ELISA to
laminin gamma-1, IIF on skin substrates deficient in type VII collagen and laminin 332, and
localization of collagen type IV to the floor of blistering skin [111,113].
Brunsting-Perry pemphigoid — Brunsting-Perry pemphigoid is a cicatricial

(scarring) form of pemphigoid that most commonly occurs in older men. Affected patients develop
subepidermal blisters localized to the head or neck (picture 12). A variety of basement membrane
zone antibodies have been detected in this variant [114-116].
Other disorders — Examples of nonpemphigoid disorders in the differential

diagnosis for patients with cutaneous lesions are included below (table 1 and algorithm 1):
●Urticaria and eczematous dermatitis – The prodromal phase lesions of bullous pemphigoid may
resemble the erythematous and edematous plaques of urticaria or the erythematous papules or
plaques of eczematous dermatitis. Unlike true urticaria, the lesions of bullous pemphigoid are not
transient. DIF studies of biopsy specimens are useful for distinguishing both of these disorders from
bullous pemphigoid. (See "New-onset urticaria" and "Atopic dermatitis (eczema): Pathogenesis,
●Skin-predominant epidermolysis bullosa acquisita –Epidermolysis bullosa acquisita is a rare

disorder characterized by subepidermal blister formation involving the skin and mucous membranes
(picture 13). Unlike bullous pemphigoid, IIF on basement membrane zone-split skin demonstrates
serum antibody bound to the dermal side of the split, and residual scarring and milia are common.
Specific ELISA testing for antibodies to type VII collagen is useful for making this diagnosis. (See
"Epidermolysis bullosa acquisita".)
●Pemphigus –Pemphigus is a group of autoimmune blistering disorders characterized by

autoantibodies directed against epithelial cell surface antigens (also known as intercellular
substance antigens). The flaccid nature of blisters in pemphigus contrasts with the tense,
subepidermal bullae in pemphigoid (picture 2A-C). DIF studies are essential for diagnosis. Several
2311
pemphigus variants exist, including paraneoplastic pemphigus (picture 2D), which may show
basement membrane zone antibodies in addition to cell surface antibodies. (See "Paraneoplastic
pemphigus" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
●Linear IgA bullous dermatosis –Linear IgA bullous dermatosis is an autoimmune subepithelial
blistering disorder that usually presents with annular and grouped tense vesicles arising on inflamed
skin (picture 14). The skin lesions often are described as resembling a cluster of jewels. Mucosal
sites also may be affected. The DIF finding of linear IgA antibody staining at the basement
membrane zone in a perilesional skin biopsy specimen is essential for this diagnosis. (See "Linear
IgA bullous dermatosis".)
●Dermatitis herpetiformis –Intensely pruritic inflammatory papules, vesicles, or crusts with a

predilection for the elbows, knees, and buttocks are characteristic of dermatitis herpetiformis,
another autoimmune subepidermal blistering disorder (picture 15). The histopathologic finding of
neutrophilic microabscesses in dermal papillary tips by H&E and the immunohistopathologic
detection of granular and/or fibrillar IgA deposits in the papillary dermis by DIF are consistent with
this diagnosis. (See "Dermatitis herpetiformis".)
●Bullous lupus erythematosus –Bullous systemic lupus erythematosus is a rare disorder. The
development of subepidermal blisters with neutrophilic infiltrates in a patient with systemic lupus
erythematosus suggests this disease. (See "Overview of cutaneous lupus erythematosus", section
on 'Bullous cutaneous lupus erythematosus'.)
Mucosal lesions — Other causes of mucosal erosions that must be distinguished

from those associated with MMP and bullous pemphigoid include pemphigus variants (picture 2C-
D), linear IgA bullous dermatosis or epidermolysis bullosa acquisita with mucosal involvement, oral
and genital mucosal lichen planus (picture 16A-B), erythema multiforme (picture 17A-B), Stevens-
Johnson syndrome (picture 18), HIV-associated mucosal lesions, Behçet syndrome, and aphthous
ulcers (picture 19) [41]. (See "Paraneoplastic pemphigus" and "Linear IgA bullous dermatosis" and
"Epidermolysis bullosa acquisita" and "Oral lichen planus: Pathogenesis, clinical features, and
diagnosis" and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis" and "Stevens-
Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and
diagnosis" and "Clinical manifestations and diagnosis of Behçet syndrome" and "Oral lesions",
section on 'Erosions and ulcerations' and "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus".)
The differential diagnosis for ocular involvement is reviewed separately. (See "Ocular cicatricial
pemphigoid", section on 'Differential diagnosis'.)

provided separately. (See "Society guideline links: Bullous pemphigoid".)
2312
SUMMARY AND
RECOMMENDATIONS
●Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune
subepithelial blistering disorders that affect skin and mucous membranes. (See 'Clinical features'
above.)
●Features of bullous pemphigoid
•The onset of blistering lesions in bullous pemphigoid is frequently preceded by a prodromal phase
characterized by pruritic inflammatory plaques that resemble eczematous dermatitis or urticaria.
Once the bullous phase develops, patients exhibit multiple tense 1 to 3 cm bullae as well as erosions
and crusts at sites of ruptured bullae (picture 1A-G, 3A-C). The lesions of bullous pemphigoid usually
heal without scarring. (See 'Bullous pemphigoid' above.)
•The trunk and extremities are typically involved in bullous pemphigoid; localized presentations also
may occur. Mucosal disease is present in 10 to 30 percent of patients (picture 4). (See 'Bullous
pemphigoid' above.)
●Features of MMP
•MMP most commonly presents as desquamative gingivitis or erosions of the oral mucosa. Other
potential sites of mucosal involvement include the ocular conjunctiva, skin, pharynx, genitalia, nasal
mucosa, larynx, anus, and esophagus (picture 5A-C). (See 'Mucous membrane pemphigoid' above
and "Ocular cicatricial pemphigoid", section on 'Clinical manifestations'.)
•Unlike bullous pemphigoid, lesions of MMP tend to scar. Scarring may result in serious functional
impairment. (See 'Mucous membrane pemphigoid' above.)
•Patients with the anti-laminin 332 (previously known as anti-laminin 5 or anti-epiligrin) form of MMP
have an increased risk for internal malignancy. An evaluation for associated malignancy should be
performed in patients with immunohistopathologic findings that suggest this disorder. Specific
testing for antibodies against laminin 332 is not yet widely available. (See 'Malignancy' above.)
●Diagnosis
•The evaluation of patients with clinical findings suggestive of bullous pemphigoid or MMP begins
with obtaining skin or mucous membrane biopsy specimens from both lesional tissue for H&E (light
microscopic histopathology) and perilesional tissue for direct immunofluorescence (DIF) (algorithm
1). DIF is highly sensitive for the diagnosis and demonstrates characteristic basement membrane
zone antibody localization in almost all patients with bullous pemphigoid and the majority of
patients with MMP (picture 8A-C). (See 'Skin biopsy' above.)
2313
•Serologic studies to detect circulating basement membrane zone antibodies by indirect
immunofluorescence (IIF) and enzyme-linked immunoassay (ELISA) also are useful for the
diagnosis of bullous pemphigoid. Both DIF and serologic studies should be performed as part of the
diagnostic evaluation (picture 10A and algorithm 1). (See 'Indirect immunofluorescence of serum'
above and 'Antigen-specific serologic testing' above.)
•The differential diagnosis of bullous pemphigoid and MMP is broad (table 1). The possibility of
other pemphigoid disorders, other blistering disorders, and nonbullous diseases must be
considered. (See 'Differential diagnosis' above.)
2314
Ocular cicatricial pemphigoid - UpToDate
uptodate.com/contents/ocular-cicatricial-pemphigoid/print
INTRODUCTION Mucous membrane pemphigoid is a heterogeneous

group of chronic inflammatory blistering diseases that affect oral, ocular, pharyngeal, laryngeal,
genital, or anal mucosa. The characteristic pathologic feature that unites these disorders is the
presence of linear deposits of immunoglobulin (Ig)G, IgA, IgM, or C3 in the epithelial basement
membrane zone. The term ocular cicatricial pemphigoid (OCP) refers to mucous membrane
pemphigoid that clinically presents as a chronic cicatrizing (scarring) conjunctivitis. Involvement of
other mucosal sites and nonmucosal skin may also occur in OCP.
Left untreated, OCP eventually results in severe conjunctival scarring and visual loss secondary to
keratopathy, with scarring and neovascularization. Thus, early diagnosis and prompt initiation of
therapy are essential for optimal management. The treatment of OCP involves the suppression of
autoimmune conjunctival inflammation via the use of systemic immunomodulatory drugs.
Conscientious ocular care to minimize the secondary consequences of chronic inflammation also is
important.
The pathogenesis, clinical manifestations, diagnosis, and treatment of OCP will be reviewed here.
Other forms of pemphigoid are discussed separately. (See "Clinical features and diagnosis of
2315
EPIDEMIOLOGY The incidence of OCP is estimated to be between 1 in
8000 and 1 in 46,000 ophthalmic patients [1-4]. No geographical or racial predilection has been
detected.
OCP is primarily a disease of older adults, with an average age of diagnosis between the ages of 60
and 70 years [5-7]. However, due to the nonspecific conjunctival inflammation that characterizes
early stage OCP, in some patients the disease may be present for years prior to recognition of the
diagnosis.
OCP appears to have a predilection for women. The female to male ratio is estimated to be between
1.5:1 and 3:1 [5]. The occurrence of OCP in children is rare; as of 2011, less than 20 pediatric
patients have been reported [8].
PATHOGENESIS The chronic, cicatrizing conjunctivitis of OCP is a

manifestation of a systemic autoimmune disorder characterized by the aberrant production of
antibodies that recognize normal components of the mucosal epithelial basement membrane zone.
As in other forms of pemphigoid, the interaction of these antibodies with their target antigens is
believed to precipitate the clinical manifestations of OCP. (See "Epidemiology and pathogenesis of
Several components of the basement membrane zone have been identified as potential antigenic
targets in cicatricial pemphigoid, including:
●Beta 4 peptide of alpha 6 beta 4 integrin (a transmembrane anchoring protein that links basal cell
hemidesmosomes to the underlying basement membrane zone) [9-11]
●Laminin 5 [12,13]
●Bullous pemphigoid antigen 2 (BP 180) [14,15]
●Unspecified 168 kilodalton and 45 kilodalton antigens [16,17]
In particular, in OCP, the 205 kilodalton beta 4 peptide of alpha 6 beta 4 integrin appears to be a
frequent target antigen [9,10,18]. An epitope in the large cytoplasmic domain of the beta 4 peptide
has the strongest binding affinity for autoantibodies in sera from patients with OCP [18]. A study has
identified specific epitopes of beta 4 integrin that may be involved in the pathobiology of OCP [19].
In contrast to pemphigoid involving cutaneous surfaces, which typically manifests as disassociation

of the epidermis and dermis (eg, blistering skin in bullous pemphigoid), in OCP the immune-mediated
process manifests as a chronic, scarring conjunctivitis. The following sequence of events may
contribute to the development of the clinical findings in OCP [20-22]:
●Autoantibody binding in the basement membrane zone stimulates an inflammatory cascade that
involves the secretion of cytokines and the recruitment of inflammatory cells
2316
●Recruited inflammatory cells sustain inflammation through the secretion of additional
proinflammatory cytokines
●The release of profibrotic cytokines by inflammatory cells, such as transforming growth factor
(TGF)-beta and interferon (IFN)-gamma contributes to the development of scarring
The inciting factors for OCP are not definitively known. It is suspected that a combination of genetic
susceptibility and environmental insults contributes to the production of pathogenic autoantibodies
[5]. The HLA DQW7 (HLA DQ-beta*0301) allele has been identified as a potential risk factor for OCP
[23,24], and medications or microbial organisms may be relevant environmental contributors.
In a small subset of patients with OCP, a potential contributing factor is detected. Cases in which
topical ophthalmic medications or systemic practolol have been linked to the development of OCP
(also known as pseudopemphigoid or pseudo-OCP) have been reported [25-32].
In addition, intense conjunctival inflammation has been proposed as a potential inciting factor for
OCP via a process referred to as epitope spreading [33]. The epitope spreading theory describes the
immune detection of normal host antigens during tissue inflammation and the subsequent mounting
of an aberrant autoimmune response against those antigens. The development of OCP following
Stevens-Johnson syndrome has been attributed to this theory [34]. Additional studies are necessary
to determine whether this is a legitimate pathway for the induction of OCP. (See "Stevens-Johnson
syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
CLINICAL MANIFESTATIONS The clinical

manifestations of OCP vary according to the stage of the disease. Extraocular involvement may or
may not be present.
Ocular findings — At the time of initial symptoms, OCP may present with unilateral
eye involvement. However, bilateral disease usually develops within two to four years [5,35].
Early disease may present only with signs of a chronic or relapsing conjunctivitis, with symptoms
such as tearing, irritation, burning, or mucus drainage (picture 1A) [36]. Frank vesicles on the
conjunctiva are infrequently detected.
As the disease progresses, fibrosis ensues, resulting in conjunctival shrinkage (picture 1B).
Symblephara (fibrotic adhesions between the bulbar and palpebral conjunctivae), which typically
begin in the inferior fornix, can become so severe that they impair eye movement (picture 1C) [35,36].
As a consequence of scarring, some patients also may develop lagophthalmos (loss of the ability to
completely close the eye).
Moreover, involvement of the eyelid margin can lead to ankyloblepharon (fusion of the lid margins of
the upper and lower eyelids). Inflammation and scarring in this area may also disrupt the orientation
of eyelash follicles, resulting in trichiasis (inward growth of the eyelashes) or distichiasis (a
duplicate row of eyelashes in which one or both grow inward against the eye) (picture 2).
2317
Visual impairment eventually occurs if OCP is not adequately controlled. Xerophthalmia leading to
corneal keratinization occurs as a consequence of the destruction of the ducts of the lacrimal
glands, the elimination of goblet cells, which produce the mucus component of the tear film, or the
development of lagophthalmos. Additionally, direct trauma to the corneal surface in the setting of
entropion or trichiasis contributes to corneal keratinization, neovascularization, and scarring (picture
3) [5].
Staging — Staging systems have been developed to assist in the assessment of disease
severity and treatment response [5,37,38]. In 1986, we proposed the following categories for the
classification of OCP [5]:
●Stage I – Chronic conjunctivitis with subepithelial fibrosis (picture 1A)
●Stage II – Shortening of the inferior fornix (picture 1B)
●Stage III – Symblepharon (picture 1C)
●Stage IV – End stage disease manifesting as ankyloblepharon, severe sicca syndrome, severe
ocular surface keratinization (picture 3)
In the modified version of this staging system, stages II and III are further subdivided in to four
groups that describe the degree of involvement (a = 0 to 25 percent, b = 25 to 50 percent, c = 50 to 75
percent, and d = 75 to 100 percent) [37]. For stage II, the designation describes the percent loss of
the inferior fornix depth, while in stage III this describes the percentage of horizontal involvement by
symblephara. The number of symblephara is also noted. For example, a patient with stage IIcIIIb(2)
would have an eye with 50 to 75 percent loss of the inferior fornix and 25 to 50 percent involvement
by two symblephara.
Extraocular involvement — Concomitant oral disease is common in

patients with OCP. Oral lesions are estimated to occur in approximately 40 percent of patients [35].
Erosive gingivitis is the most common oral manifestation, but involvement manifesting as erosions
or vesicles may also occur on the buccal mucosa, palate, alveolar ridge, tongue, and lip [36]. Other
mucosal sites affected less frequently than the oral cavity include the pharynx, nose, larynx,
genitalia, anus, and esophagus [39].
Compared with oral disease, a smaller subset of patients with OCP has involvement of nonmucosal
skin [5]. In one study from an ophthalmologic practice, 16 percent of patients had skin disease [35].
Such patients most frequently present with inflammatory bullae and erosions on the head, neck, and
upper trunk [33].
ESTABLISHING THE DIAGNOSIS The

systemic immunomodulatory therapies required for the treatment of OCP are associated with a
number of potential adverse effects. This, and the fact that the approach to treatment differs
2318
significantly from the therapeutic approach for some of the other disorders that clinically resemble
OCP, strongly favor confirmation of the diagnosis whenever feasible (see 'Differential diagnosis'
below). A conjunctival biopsy with immunohistochemical studies is a valuable tool for confirming
the diagnosis in patients with clinical findings suggestive of OCP. However, clinicians must remain
cognizant that inconclusive or negative results do not rule out the diagnosis.
Biopsy — In patients who have extraocular lesions, such as skin or other mucosal lesions,
the tissue biopsy for diagnosis should first be attempted in these more easily accessible sites
[33,35]. Conjunctival biopsies are generally performed in patients with active disease limited to the
ocular mucosa or in patients in whom the disease is strongly suspected despite negative or
inconclusive results from extraocular biopsies.
Conjunctival biopsies should always be performed on inflamed conjunctival tissue [33]. Conjunctival
biopsies may be obtained from a variety of sites; we typically biopsy the bulbar conjunctiva. The
approach to cutaneous biopsies in patients with concomitant skin involvement is reviewed
separately. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid", section on 'Skin biopsy'.)
Negative or inconclusive results can occur due to poor biopsy technique or poor handling of the
specimen. Conjunctival biopsies should only be performed by ophthalmologists, and only
experienced laboratory technicians should process conjunctival tissue. Disease exacerbation and
the induction of scarring are potential risks of conjunctival biopsies [33].
Hematoxylin and eosin — The findings in specimens stained with hematoxylin

and eosin (H&E) are nonspecific. Examination typically demonstrates an inflammatory infiltrate of
variable intensity composed of neutrophils, macrophages, plasma cells, lymphocytes, and
Langerhans cells (picture 4) [35]. Squamous metaplasia may also be present (picture 5). The
performance of additional histopathologic stains facilitates the identification of other common
features, such as decreased goblet cells (PAS stain) (picture 6) and increased mast cells (Giemsa
stain) [5].
Immunohistochemistry — Direct immunofluorescence should be performed on

all conjunctival biopsy specimens. Linear deposition of immunoglobulin (Ig)G, IgA, IgM, and/or C3 is
the characteristic finding (picture 7). However, because the diagnostic sensitivity of direct
immunofluorescence in most laboratories may be only around 50 percent, a negative test does not
rule out the diagnosis [40].
The utilization of an immunoperoxidase assay may improve the likelihood of diagnosis, and the
technique should be performed if immunofluorescence is negative in a patient with clinical features
strongly suggestive of OCP (picture 8) [35]. In a retrospective study of 166 patients with suspected
OCP, performance of an immunoperoxidase avidin-biotin-complex assay on specimens that yielded
2319
negative or inconclusive immunofluorescence results was associated with the detection of
additional diagnoses of OCP [40]. The addition of the immunoperoxidase assay increased the
sensitivity of testing from 52 to 83 percent.
Of note, immunohistochemical findings consistent with OCP do not definitively rule out all other
possible diagnoses. Epidermolysis bullosa acquisita and linear IgA bullous dermatosis, both of
which may involve skin and ocular tissue, present with similar findings [33]. Thus, other diagnostic
clues are utilized to distinguish OCP from these disorders. The presence of prominent milia
formation in skin lesions and the detection of antibodies against type VII collagen via enzyme-linked
immunosorbent assay, immunoblotting, or immunoprecipitation support a diagnosis of
epidermolysis bullosa acquisita. Predominant linear IgA binding at the basement membrane zone in
combination with classic skin lesions resembling a "cluster of jewels" suggests the possibility of
linear IgA bullous dermatosis.
Indirect immunofluorescence — Circulating antibodies against

the basement membrane zone are less consistently detected in patients with cicatricial pemphigoid
than in patients with bullous pemphigoid, and are of little value for diagnosis. Reported rates of
antibody detection vary widely, and the probability of a positive result may be affected by the type of
technique performed and by individual patient characteristics such as the level of disease activity
and sites of involvement [41-43].
Other laboratory studies — No specific laboratory assays are useful for

monitoring the activity of OCP. Although one study found increased levels of tumor necrosis factor
(TNF)-alpha and decreased levels of interleukin (IL)-6 in sera from patients with active OCP [44] and
another study found elevated IL-6, IL-12, and IL-17 levels in conjunctival tissue of patients with OCP
[45], additional studies are necessary to determine whether these assays are clinically useful [45].
DIFFERENTIAL DIAGNOSIS In addition to OCP, a wide

variety of other ocular disorders can present with conjunctival inflammation or scarring. Examples
include:
●Conjunctivitis and conjunctival scarring
•Toxic epidermal necrolysis or Stevens-Johnson syndrome sequelae (see "Stevens-Johnson

syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis")
•Epidermolysis bullosa acquisita
•Linear IgA bullous disease with cicatrizing conjunctivitis
•Bullous systemic lupus erythematosus (see "Overview of cutaneous lupus erythematosus", section
on 'Bullous cutaneous lupus erythematosus')
2320
•Adenoviral conjunctivitis sequelae (see "Conjunctivitis", section on 'Viral conjunctivitis')
•Paraneoplastic pemphigus (see "Paraneoplastic pemphigus")
•Sebaceous cell carcinoma of the conjunctiva (see "Sebaceous carcinoma")
•Intraepithelial epithelioma (squamous cell carcinoma of the conjunctiva)
•Corynebacterium diphtheriae conjunctivitis
●Conjunctival scarring
•Damage from ionizing radiation
•Trauma
•Porphyria cutanea tarda (see "Porphyria cutanea tarda and hepatoerythropoietic porphyria:
Pathogenesis, clinical manifestations, and diagnosis")
•Progressive systemic sclerosis (scleroderma) (see "Clinical manifestations and diagnosis of

systemic sclerosis (scleroderma) in adults")
•Congenital ichthyosiform erythroderma (see "Overview and classification of the inherited

ichthyoses", section on 'Lamellar ichthyosis and congenital ichthyosiform erythroderma')
The clinical history and assessment of other signs and symptoms are often useful for narrowing the
differential diagnosis. If OCP remains in the differential, a biopsy of involved skin or mucosal tissues
can be of value. (See 'Establishing the diagnosis' above.)
INDICATIONS FOR REFERRAL All patients with

known or suspected OCP require referral to an ophthalmologist, preferably one with significant
experience in this disease. Additionally, treatment should be managed by a clinician with expertise in
immunosuppressive therapy, such as an ophthalmologist, dermatologist, rheumatologist,
hematologist, or other clinician who is comfortable with this role.
Continued ophthalmology follow-up is essential for evaluating the response to therapy. Moreover, the
presence of extraocular involvement warrants assessment and follow-up by specific clinical
specialists based upon the sites of disease (eg, dermatologist, dentist, otolaryngologist, or
gastroenterologist). (See 'Extraocular involvement' above.)
TREATMENT The primary goal of treatment in OCP is the prevention of

scarring and vision loss. Whenever possible, patients should be managed by clinicians who have
experience in treating this disease.
2321
The most important therapeutic interventions are the initiation of systemic immunomodulatory
drugs to suppress conjunctival inflammation and the implementation of practices that minimize
secondary ocular damage. While patients with mild to moderate conjunctival inflammation and
slowly progressing disease can often be managed with ocular care and conventional
immunomodulatory therapies such as dapsone, methotrexate, mycophenolate mofetil, or
azathioprine, patients with more aggressive or refractory disease typically require treatment with
cyclophosphamide. In addition, several studies suggest that intravenous immune globulin (IVIG) and
rituximab may have benefits for severe cases.
Ocular care — A variety of nonpharmacologic measures are beneficial in the

management of OCP:
●Ocular lubrication – Xerophthalmia (dry eye) can lead to corneal damage, and the liberal use of
ocular lubricants may help to prevent vision loss. Punctual plugs and punctual cautery, which
prevent drainage of liquid from the eye, also can be helpful in the treatment of xerophthalmia [35].
●Prevention and treatment of infection – Patients with OCP are at increased risk for ocular
infections due to the presence of a compromised ocular surface [46]. The use of lid hygiene
techniques on a daily basis may minimize the occurrence of ocular infections [35]. We instruct
patients to apply warm compresses for two minutes followed by vertical lid massage (10 strokes
downward on the upper lid and 10 strokes upward on the lower lid) twice daily. This procedure
expresses the lipid contents of the meibomian glands. Prompt identification and treatment of
infections also is important.
●Eyelash removal –Injury to the cornea as a result of trichiasis (inward turning of the eyelashes) can
lead to visual impairment or blindness if left untreated. Eyelashes can be removed temporarily with
manual epilation or permanently with cryoepilation or electrolysis. Cryoepilation should be
performed when the disease is well controlled to reduce the risk for procedure-related exacerbations
of OCP [35,46]. Other potential adverse effects of cryoepilation include ocular edema and
depigmentation.
Mild to moderate disease — In 2004, an international consensus panel

of experts released recommendations for the medical management of patients with mucous
membrane pemphigoid, which included patients with OCP. Based upon a review of the published
literature and clinical experience, the consensus panel concluded that dapsone (50 to 200 mg/day
for 12 weeks) was an appropriate initial therapy for patients with mild ocular disease [33]. A
systematic review of randomized trials and uncontrolled studies also found evidence to support the
use of dapsone in cicatricial pemphigoid [47].
Although there are relatively fewer data on other systemic therapies such as methotrexate,
mycophenolate mofetil, and azathioprine, these agents have also been used successfully by
clinicians (including ourselves) for patients with OCP. No randomized trials have been performed
2322
that compare the efficacy of these therapies in OCP. Thus, factors such as concern for drug adverse
effects, patient tolerance, drug availability, and drug cost heavily influence the choice of therapy.
●Dapsone– Dapsone is a sulfonamide antibiotic with antiinflammatory properties and proven

efficacy in OCP [5,6,33,47]. The benefit of dapsone for ocular involvement was documented in a 12-
week randomized trial in which 40 patients with stage III (see 'Staging' above), biopsy-proven OCP
were treated with either dapsone (2 mg/kg per day) or cyclophosphamide (2 mg/kg per day) [5].
Among the 20 patients treated with dapsone, 14 (70 percent) had complete suppression of
conjunctival inflammation and scar formation. All of the patients treated with cyclophosphamide
responded, but we reserve the use of cyclophosphamide for patients with severe or refractory
disease. (See 'Severe or refractory disease' below.)
Dapsone was also effective in a retrospective study in which the majority of patients had stage III,
biopsy-proven OCP [6]. Dapsone (2 mg/kg per day for at least three months) inhibited cicatrization in
31 of 69 patients (45 percent), including 26 of 28 patients with milder conjunctival inflammation
defined as <2+ severity on a 0 to 4+ scale (93 percent).
Dapsone is typically administered in doses of 50 to 200 mg per day [33]. A 12-week period is a
reasonable trial of therapy; alternative therapy should be considered if no response is observed after
this time [33]. Hemolytic anemia is a common adverse effect of dapsone that occurs to some degree
in most patients who take dapsone but can be catastrophic in individuals with glucose-6-phosphate
dehydrogenase (G6PD) deficiency [48,49]. In addition, idiosyncratic leukopenia and aplastic anemia
may occur in the first three months of treatment; thus, patients must receive frequent hematologic
monitoring early in the course of therapy. Methemoglobinemia, another potential adverse effect of
dapsone, is a dose-dependent event unrelated to G6PD status.
Sulfasalazine and sulfapyridine are additional sulfonamide agents that have been used in the
management of patients with OCP [50,51]. These agents may be less effective than dapsone [50].
●Methotrexate– Methotrexate is a folic acid antagonist that may improve OCP [52,53]. Methotrexate
(5 to 25 mg given once weekly) was effective in a retrospective study of 17 patients with non-drug-
induced OCP (12 patients) or drug-induced OCP (5 patients). Fifteen patients (88 percent, including
all patients with drug-induced disease) achieved or maintained complete control of inflammation
and 12 out of 17 patients (71 percent, including all but one patient with drug-induced disease) had
no progression of cicatrization [52]. A potential limitation of this study is that only four patients had
biopsy-proven OCP.
Gastrointestinal distress, oral ulcers, myelosuppression, hepatotoxicity, pulmonary fibrosis, and renal
toxicity are potential adverse effects of methotrexate. The coadministration of folic acid may lessen
the gastrointestinal symptoms and oral ulcers. Dose adjustments are necessary if methotrexate
must be administered in patients with renal insufficiency. The drug also is teratogenic and is
relatively contraindicated in patients who abuse alcohol or who have preexisting liver disease. (See
"Major side effects of low-dose methotrexate".)
2323
●Mycophenolate mofetil – Mycophenolate mofetil is an immunosuppressive agent that reversibly
inhibits de novo purine synthesis via inhibition of the enzyme inosine monophosphate
dehydrogenase. In a retrospective study in which mycophenolate mofetil (500 to 1000 mg twice
daily) was given to 34 patients who had failed azathioprine and a sulfonamide or who received
mycophenolate mofetil as a step-down therapy after cyclophosphamide, the drug was beneficial
[50]. Out of 46 treatment episodes in which mycophenolate mofetil was the principal treatment
agent, 59 percent were associated with complete clinical resolution of conjunctival inflammation.
When only treatment episodes in patients with biopsy-proven disease were considered (11
episodes), the response rate rose to 73 percent. Additional support for the efficacy of
mycophenolate mofetil stems from a separate retrospective study in which 19 of 23 OCP patients
treated with mycophenolate mofetil (500 mg twice daily, then adjusted according to response)
achieved control of inflammation within one year, including 16 of 19 who received mycophenolate
mofetil as monotherapy [54].
Mycophenolate mofetil is generally a well-tolerated drug, with gastrointestinal distress (eg, nausea,
vomiting, diarrhea) as its most common associated adverse effect. Additionally, mycophenolate
mofetil may induce cytopenia and the drug has teratogenic effects. (See "Mycophenolate: Overview
of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)
●Azathioprine– Azathioprine, a purine derivative that exerts immunosuppressive effects through the
inhibition of RNA and DNA synthesis and repair, has been effective for OCP in case reports and
retrospective studies [6,50,55,56]. In a retrospective study in which 60 patients received azathioprine
as principal therapy after failure to respond sufficiently to a sulfonamide or as a step-down therapy
after cyclophosphamide, azathioprine controlled ocular inflammation in 47 percent of 80 treatment
episodes in all patients and 48 percent of 37 treatment episodes in patients with biopsy-proven OCP
[50].
Bone marrow suppression is a potential severe adverse effect of azathioprine, which may be related
to the activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of the
drug. The assessment of TPMT activity should be performed prior to the administration of
azathioprine. Dose adjustments may be necessary based upon the result. (See "Pharmacology and
side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "6-
mercaptopurine (6-MP) metabolite monitoring and TPMT testing in patients with inflammatory bowel
disease", section on 'TPMT enzyme determination'.)
Severe or refractory disease — Aggressive treatment is warranted

for patients with severe or rapidly progressive OCP to minimize scarring and visual loss. Based upon
the limited available data, combination therapy with cyclophosphamide and prednisone is highly
effective and is the treatment of choice for severe OCP [6,7,33]. Newer evidence indicates that
intravenous immune globulin (IVIG) and rituximab used independently or together may also be
effective.
2324
Although systemic glucocorticoids are sometimes utilized to suppress acute inflammation in
patients with OCP, they are not recommended as primary therapy due to the multiple adverse effects
of long-term treatment and the high likelihood for disease relapse following tapering or
discontinuation [5]. The preferred role of systemic glucocorticoids is as adjunctive therapy while
awaiting the onset of action of other agents in patients with severe or rapidly progressive disease.
Cyclophosphamide plus prednisone — Cyclophosphamide is an

alkylating agent commonly used as an antineoplastic agent in oncology. The immunosuppressive
properties of cyclophosphamide account for its beneficial effects in autoimmune blistering disease.
The efficacy of cyclophosphamide is supported by two randomized trials:
●In a six-month randomized trial, 24 patients with bilateral stage III, biopsy-proven OCP were treated
with either cyclophosphamide (2 mg/kg per day) plus prednisone or prednisone plus a placebo pill
[5]. Prednisone was administered as 1 mg/kg per day for one week followed by a taper over 12
weeks to 0.25 mg/kg every other day. Prednisone was subsequently discontinued in the
cyclophosphamide group.
By eight weeks, all 12 patients treated with cyclophosphamide and prednisone achieved complete
resolution of conjunctival inflammation. In addition, progression of scarring did not occur in the
cyclophosphamide group during the course of the study. In contrast, only 5 out of 12 patients in the
prednisone group had complete resolution of conjunctival inflammation, and, among those who
responded, disease recurred when the dose fell below 0.25 mg/kg every other day.
●In a 12-week randomized trial in which 40 patients with stage III, biopsy-proven OCP were treated
with cyclophosphamide (2 mg/kg per day) plus prednisone or dapsone (2 mg/kg per day), all 20
patients treated with cyclophosphamide exhibited resolution of clinically evident inflammation and
no patients had progression of conjunctival scarring [5]. In contrast, similar results were observed in
only 14 out of 20 patients treated with dapsone.
Efficacy of cyclophosphamide is also documented in prospective and retrospective case series

[57,58].
Cyclophosphamide can be administered orally or intravenously. A response to therapy takes

approximately six to eight weeks, which provides the rationale for the use of prednisone at the
initiation of therapy [5]. We typically begin intravenous cyclophosphamide therapy with 1 g/m2 given
every two weeks, and adjust the dose according to the degree of resultant leukopenia. We aim to
maintain the white blood cell count above 3000/mm3, the absolute neutrophil count above
1000/mm3, and the platelet count above 70,000/microL. When utilizing oral cyclophosphamide
therapy we prescribe initial doses of 1 to 2 mg/kg per day [33]. Prednisone (1 to 1.5 mg/kg/day) is
initiated at the same time as cyclophosphamide therapy. Once improvement is achieved, we taper
the prednisone over the course of approximately three months.
2325
As noted above, leukopenia is expected during treatment with cyclophosphamide, and a complete
blood count should be monitored weekly for the first two to three months of therapy and at least
monthly thereafter [59]. Gastrointestinal distress, hemorrhagic cystitis, bladder cancer, infections,
hair loss, and reproductive problems such as amenorrhea, premature ovarian failure, and
azoospermia also can occur with cyclophosphamide. The drug is teratogenic and, thus, is
contraindicated in pregnancy. (See "General toxicity of cyclophosphamide in rheumatic diseases".)
Due to the potential long-term effects of cyclophosphamide, we limit the duration of treatment with
cyclophosphamide to 12 months. Patients who reach this duration of therapy are transitioned to
other immunomodulatory agents.
Intravenous immune globulin — Intravenous immune globulin (IVIG) may

be effective for the treatment of OCP that is refractory to other therapies [60-63]. In a nonrandomized
study of 16 patients with OCP, the administration of IVIG with gradual withdrawal of conventional
therapy was associated with a shorter time to clinical remission compared with the time required in
patients who were maintained on conventional therapy (4 versus 8.5 months). In addition, total
control of disease activity was achieved in all patients treated with IVIG compared with only three
out of eight patients who continued conventional therapy. Sustained remissions of 24 to 48 months
have been reported after completion of IVIG therapy [62].
Although the initial cost of treatment with IVIG can be limiting, a retrospective study in the United
States that compared the cost of IVIG and conventional immunosuppressive therapy in patients with
severe mucous membrane pemphigoid found that the overall cost of disease management was
lower in patients treated with IVIG [64].
Adverse effects of IVIG include hypersensitivity reactions, headache, vasculitis, aseptic meningitis,
renal failure, myocardial infarction, and thrombosis. (See "Intravenous immune globulin: Adverse
effects".)
Rituximab — Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen on
pre-B and mature B lymphocytes. Uncontrolled studies and a case report support its efficacy in OCP
[65-69].
In a series of 25 patients with biopsy-proven, severe, refractory mucous membrane pemphigoid that
included 10 patients with active stage III or IV OCP, rituximab (375 mg/m2 once weekly for four
weeks for one or two cycles) was associated with resolution of conjunctival inflammation in 9 of the
10 patients after one treatment cycle and in all patients after two cycles (median time to remission
10 weeks) [67]. Long-lasting improvement after rituximab occurred in 76 percent of the patients with
mucous membrane pemphigoid, with maintenance of complete or partial responses during a
median follow-up period of 24 months.
Of note, two patients who were simultaneously treated with systemic immunosuppressive therapy
developed severe, fatal infections. Additional potential side effects of rituximab include nausea,
serum sickness-like reactions, and infusion reactions. A boxed warning on the drug label of
2326
rituximab has been mandated by the US Food and Drug administration due to reports of progressive
multifocal leukoencephalopathy. (See "Rituximab: Principles of use and adverse effects in
rheumatoid arthritis".)
Combination therapy with rituximab and IVIG may be of value for the management of patients with
severe OCP. In a retrospective study of 12 patients with OCP that was refractory to conventional
therapies, disease progression ceased in the six patients who were treated with rituximab and IVIG
and in none of the patients who were given other aggressive therapies (cyclophosphamide,
infliximab, and/or IVIG) [66]. Additional studies are necessary to explore the efficacy of rituximab
with and without IVIG.
Other — Other systemic therapies that have been used for patients with severe or refractory
OCP include subcutaneous cytosine arabinoside and daclizumab [35]. Oral cyclosporine and oral
tacrolimus are poorly effective for arresting disease progression in OCP [70,71].
Local therapy — Local therapy with agents such as topical corticosteroids, topical
tacrolimus, topical cyclosporine, and topical or subconjunctival mitomycin C has a limited role in the
management of OCP, as they have no effect on suppressing the underlying immune dysfunction
[5,72-74].
Surgical intervention — Surgical procedures are used to treat ocular damage

related to OCP. Examples include the removal of symblephara that inhibit lid function, the repair of
entropion, and the use of surgical procedures that address visual impairment due to corneal
damage. Corneal procedures that have been used in OCP include amniotic membrane
transplantation, limbal stem cell transplantation, lamellar or penetrating keratoplasty (corneal
transplants), and the placement of keratoprostheses (artificial corneas) [35].
Prior to the performance of ocular surgery, complete control of inflammation should be obtained
with immunomodulatory drugs to improve the likelihood of a good surgical outcome. In addition, the
level of immunosuppression is typically increased in the perioperative period to reduce the risk of
surgery-induced disease exacerbations [35,36].
PROGNOSIS AND CESSATION OF

THERAPY In most patients, OCP is a slow, progressive disease process.
Advancement of the disease from initial conjunctival inflammation to end stage disease
characterized by bilateral blindness may take 10 to 30 or more years [5]. However, some patients
progress more quickly, and periods of severe exacerbation and rapid scarring may occur. Early
identification of the disease and the prompt implementation of appropriate treatment are key factors
in the prevention of adverse disease sequelae.
2327
Although OCP is a chronic, relapsing disease, long-term remission amounting to cure of the disease
is possible in some patients [7,50,75]. In one series of 104 patients followed for an average of four
years, prolonged periods of remission off therapy occurred in approximately one-third of patients
(average length of remission of 34 months, range 2 to 75 months) [70,75]. Since disease relapse is
unpredictable, continued long-term follow-up of patients in remission is essential.
We proceed with attempts to slowly taper therapy in patients in whom disease activity (conjunctival
inflammation) has been quiescent for two years. Inflammation related to trichiasis or glandular
dysfunction may be confused with active pemphigoid, and interventions to minimize the effects of
such findings are important for the accurate assessment of disease status. (See 'Ocular care'
above.)
CATARACT SURGERY Cataracts are a common occurrence in

patients with OCP, a finding related to the age at which OCP typically occurs and the chronic use of
topical or systemic corticosteroids for treatment. Data on cataract surgery in patients with OCP are
limited, and there is concern that surgery may induce exacerbations of conjunctival inflammation
and contribute to the progression of OCP. (See "Cataract in adults".)
However, case series document successful cataract surgery in patients with OCP, suggesting that
cataract surgery can be safely performed in patients in whom optimal medical control of OCP is
achieved prior to cataract surgery [76-78]. The author has successfully performed cataract surgery
with posterior lens chamber implantation (small incision surgery without suture or disturbance of
the conjunctiva) in many patients with quiescent OCP through perioperative management with oral
prednisone (1 mg/kg for two days prior to surgery and for ten or more days postoperatively),
continuation of the chemotherapeutic agent that put the OCP into remission until at least six months
after surgery, and the use of topical corticosteroids and topical antibiotics as adjunctive therapies.
SUMMARY AND
RECOMMENDATIONS
●Ocular cicatricial pemphigoid (OCP) is a form of mucous membrane pemphigoid that manifests as
a chronic cicatrizing conjunctivitis. Early diagnosis and treatment are essential for the prevention of
severe scarring and blindness. (See 'Introduction' above.)
●OCP is a relatively uncommon disorder that preferentially affects older adults. Women are more
likely to be affected than men. OCP rarely occurs in children. (See 'Epidemiology' above.)
●The pathogenesis of OCP is likely to involve the stimulation of an inflammatory response by

autoantibodies that bind to normal components of the conjunctival basement membrane zone. The
beta 4 peptide of alpha 6 beta 4 integrin appears to be a frequent target antigen. (See 'Pathogenesis'
above.)
2328
●The clinical findings in OCP vary according to the stage of the disease. Disease initially manifests
as a chronic conjunctivitis and progresses to conjunctival fibrosis manifesting and conjunctival
contracture or symblepharon (picture 1A-C). Xerophthalmia (dry eye) and trichiasis (inward turning
of the eyelashes) are additional common findings (picture 2). Corneal damage resulting in visual
impairment may also occur (picture 3). (See 'Clinical manifestations' above.)
●The treatments used for the management of OCP have multiple potential adverse effects, and
confirmation of the diagnosis with immunohistochemical studies on biopsy specimens should be
performed whenever feasible. The characteristic immunohistochemical finding is linear deposition
of IgG, IgA, or C3 along the basement membrane zone. Negative direct immunofluorescence results
are common and should not be used to rule out the diagnosis. (See 'Establishing the diagnosis'
above.)
●In patients with extraocular skin or mucosal lesions, initial biopsies for diagnosis can be performed
at those sites. Conjunctival biopsies are necessary in patients with disease limited to the ocular
mucosa or in those in whom the diagnosis is highly suspected despite negative extraocular biopsy
results. (See 'Biopsy' above.)
●All patients with known or suspected OCP require referral to an ophthalmologist. Whenever
possible, patients should be managed by clinicians experienced in the management of this disease.
(See 'Indications for referral' above.)
●Systemic immunomodulatory therapy and eye care practices aimed at reducing the risk for
scarring and visual impairment are the most important components of the management for patients
with OCP. For patients with mild to moderate OCP, we recommend treatment with dapsone based
upon the evidence in support of its efficacy (Grade 1B). Other effective therapies that have been less
studied include mycophenolate mofetil, methotrexate, and azathioprine. Topical therapy alone
should not be used for the management of OCP. (See 'Treatment' above and 'Mild to moderate
disease' above.)
●Patients with severe, rapidly progressive, or refractory disease require aggressive treatment. We
recommend treatment with cyclophosphamide and prednisone (Grade 1B). IVIG and rituximab are
additional treatments that have shown promising results in early studies. Additional studies are
necessary to determine whether these interventions should be considered first-line treatment
options for severe OCP. (See 'Severe or refractory disease' above.)
2329
Management and prognosis of bullous pemphigoid
uptodate.com/contents/management-and-prognosis-of-bullous-pemphigoid/print
INTRODUCTION Bullous pemphigoid (BP) is an autoimmune blistering

disease characterized by autoantibody deposition at the epithelial basement membrane zone. The
disorder most frequently affects elderly adults and classically presents with generalized pruritic
urticarial plaques and tense subepithelial blisters (picture 1A-C).
First-line therapy for bullous pemphigoid consists of topical or systemic corticosteroids; both
interventions are rapidly effective for this disease. Additional immunomodulatory therapies are often
added to treatment to minimize the adverse effects of chronic corticosteroid therapy or to augment
improvement in the disease.
The management of bullous pemphigoid will be reviewed here. The epidemiology, pathogenesis,
potential triggers, clinical features, and diagnosis of bullous pemphigoid are discussed separately.
(See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid"
and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
APPROACH TO THERAPY
2330
Goals of treatment — The major goals for the treatment of bullous pemphigoid
(BP) are as follows:
●Decrease blister formation and pruritus
●Promote healing of blisters and erosions
●Improve quality of life
These goals are fulfilled through an approach to treatment that includes a therapeutic regimen that
attenuates autoantibody production and antibody-mediated inflammation while minimizing the risk
for serious drug-induced adverse effects. In addition, the implementation of skin care measures and
referrals to appropriate specialists for mucosal involvement may help to manage and minimize
morbidity.
Identification of drug-induced disease — Although drug-

induced pemphigoid likely accounts for a small proportion of cases of bullous pemphigoid, a wide
variety of drugs have been associated with the development of this disease (table 1) [1]. Therefore, a
medication history should be obtained and drugs suspected of inducing bullous pemphigoid should
be discontinued if feasible. Bullous pemphigoid may develop several months or more than one year
after ingestion of the inciting medication [1,2]. (See "Epidemiology and pathogenesis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Infections and drugs'.)
Approach to pharmacologic therapy — In addition to

treatment efficacy, cost, and availability, other factors influence the approach to therapy for bullous
pemphigoid [3]. Since patients are often elderly and dependent upon relatives or health care workers
for personal care activities, their ability to comply with treatment must be considered. As an
example, topical corticosteroid therapy is not a favorable option for patients who are unable to
properly apply the medication and lack access to assistance.
Because much of the morbidity and mortality related to bullous pemphigoid results from the
combined effect of patient comorbidities and adverse effects of treatment, rather than from direct
effects of the disease, treatment should be conservative. Elderly patients often have medical
conditions that may increase risk for drug-related side effects. Thus, the minimal amount of
medication required to achieve remission should be given.
Our preferred first-line therapy for patients with bullous pemphigoid is a high potency topical
corticosteroid due to evidence that supports the efficacy and relative safety of this treatment. A
systemic glucocorticoid is another acceptable first-line treatment option that we typically use when
factors such as drug cost, drug availability, or an inability to properly administer topical treatment
preclude the use of topical therapy. In addition, patient preference for systemic therapy based upon
quality of life concerns may prompt the selection of systemic treatment for patients who are more
2331
likely to tolerate oral glucocorticoids well (eg, nonelderly, otherwise healthy individuals). Particularly
for patients with widespread involvement, systemic therapy is faster and easier to administer than
topical therapy.
Due to the chronic nature of bullous pemphigoid and the multiple adverse effects of systemic
glucocorticoids, adjunctive agents are often added in an attempt to reduce long-term glucocorticoid-
dependence. Immunosuppressants such as mycophenolate mofetil, azathioprine, and methotrexate
are commonly prescribed. Anti-inflammatory agents, including tetracyclines administered with
nicotinamide or dapsone may also be of benefit.
Biologic therapies may be effective for bullous pemphigoid which cannot be satisfactorily managed
with the treatments above alone. Rituximab and intravenous immunoglobulin are options for
additional therapy.
General skin care — The best approach to the care of blistered skin has not
been definitively established. In our experience, daily rupturing of tense blisters is useful for reducing
lateral extension of the blister edges. We instruct patients and caregivers to cleanse blisters with
alcohol prior to rupturing them with a sterile needle. Since the overlying epithelial layer (blister roof)
can act as a natural wound dressing, it should be left in place. Open erosions should be covered with
non-stick dressings to reduce pain and the risk for infection.
Superinfection is a significant concern in patients with bullous pemphigoid, particularly when

numerous skin lesions are present and systemic immunosuppressants are being utilized for
treatment. Patients and caregivers should be informed about the warning signs of infection to
facilitate prompt diagnosis and treatment.
Indications for referral — The management of bullous pemphigoid is a

multidisciplinary affair that ideally consists of management by a dermatologist in conjunction with
the patient’s primary care physician. Because mucosal surfaces can be involved, additional
specialists may be added as needed. As an example, patients with signs of ocular involvement (eg,
itching, burning sensations, visual changes) should be referred promptly to an ophthalmologist.
Likewise, referral to a gastroenterologist or otolaryngologist should be performed for the rare patient
who exhibits symptoms suggestive of esophageal, laryngeal, or pharyngeal disease.
FIRST-LINE THERAPY Corticosteroids, administered topically

or systemically, are the cornerstone of therapy. A topical corticosteroid is our preferred first-line
treatment. When the clinical scenario indicates that topical corticosteroids are not an appropriate
choice, we utilize a systemic glucocorticoid as the initial treatment. (See 'Approach to
pharmacologic therapy' above.)
Topical corticosteroids — The topical corticosteroid selected should be a

high potency agent (table 2). We typically utilize clobetasol 0.05% cream.
2332
Efficacy — The use of topical corticosteroids as monotherapy for bullous pemphigoid (BP) is
supported by a multicenter randomized trial which found that patients with extensive bullous
pemphigoid who were treated with topical corticosteroids had better clinical outcomes than patients
with extensive bullous pemphigoid who were treated with systemic glucocorticoid therapy [4]. The
trial included 341 patients with newly diagnosed bullous pemphigoid (153 patients with moderate
bullous pemphigoid [defined as ≤10 new bullae per day] and 188 patients with extensive bullous
pemphigoid [defined as >10 new bullae per day]). The patients were treated with either topical
clobetasol propionate 0.05% cream (a total daily dose of 40 g that was given through twice-daily
applications of clobetasol to the entire cutaneous surface by the patient, a caregiver, or nurse) or
prednisone (0.5 mg/kg per day for moderate disease and 1 mg/kg per day for severe disease).
Treatment was continued in this manner until 15 days after disease control. Subsequently,
clobetasol was gradually reduced over the course of 12 months. The dose of prednisone was
reduced by 15 percent every three weeks until treatment was discontinued after 12 months.
The results of the trial are as follows:
●One-year survival rates were significantly higher for patients with extensive bullous pemphigoid
who were treated with topical clobetasol than for patients with extensive bullous pemphigoid who
were treated with prednisone (76 versus 58 percent).
●Patients with extensive bullous pemphigoid who were treated with clobetasol responded
significantly more quickly to treatment than patients with extensive disease who were treated
systemically. By day 21, disease control was achieved in 99 versus 91 percent of patients.
●Severe complications were significantly less common in the extensive bullous

pemphigoid/clobetasol group than in the extensive bullous pemphigoid/prednisone group (29
versus 54 percent).
The results of this study suggest that for patients with extensive bullous pemphigoid, topical
corticosteroid therapy is preferable to systemic glucocorticoid treatment. Among the patients with
moderate bullous pemphigoid, the differences between the topical and systemic therapy groups for
one-year survival (both 69 percent), likelihood of disease control by day 21 (100 versus 95 percent,
respectively), and severe complications (32 versus 38 percent, respectively) were not statistically
significant.
Administration — The efficacies of two treatment regimens with clobetasol propionate

0.05% cream were compared in a second randomized trial of 312 patients with newly-diagnosed
bullous pemphigoid [5]. A milder regimen (10 to 20 g per day for moderate disease and 20 to 30 g
per day for extensive disease until 15 days after disease control, then tapered to discontinuation
over four months) was as effective for attaining control of moderate and extensive bullous
pemphigoid as the regimen used in the trial above (40 g per day tapered slowly over 12 months). In
the trial, disease control was achieved by day 21 in 98 versus 100 percent of patients, respectively.
2333
As may have been expected, relapses were more likely to occur during the one-year trial in patients
in the less aggressive treatment group (this group discontinued treatment after four months); one
year disease-free survival rates were 30 versus 45 percent, respectively.
In addition, after adjustments were made for patient age and general health status (Karnofsky
score), a statistically significant reduction in the risk for mortality and life-threatening adverse
effects was detected among patients with moderate bullous pemphigoid who were treated with the
milder regimen compared to those treated with the higher dose regimen (HR 0.54, 95% CI 0.30-0.97).
A significant difference in these factors was not seen among patients with extensive disease (HR
1.18, 95% CI 0.76-1.82).
When treating patients with topical corticosteroid therapy, we typically prescribe twice daily
applications of clobetasol propionate 0.05% cream. For patients with limited involvement, we focus
on application to affected areas. For patients with widespread lesions, we instruct patients and
caregivers to apply the treatment to the trunk and extremities.
After active inflammation, new blister formation, and pruritus have ceased for at least two weeks
and 80 percent of existing blisters have healed, we begin to taper topical corticosteroid therapy by
slowly reducing the amount of medication applied and the frequency of treatment [6]. Tapering is
continued as tolerated, and typically lasts four months or longer.
The cost of topical corticosteroids (generally higher than prednisone) and limited access to these
agents may inhibit the use of topical corticosteroids in some clinical settings.
Adverse effects — High potency topical corticosteroids can result in cutaneous

atrophy, striae, and folliculitis. Adrenal suppression is an additional concern with the extensive
application of topical corticosteroids [7-9]. Among a subset of 28 patients evaluated for adrenal
suppression in the dose-comparison trial above, only 5 of 18 patients in the mild regimen group (28
percent) and 1 of 8 patients in the higher dose regimen group (12 percent) had positive cosyntropin
tests (an indicator of adrenal sufficiency) after seven days of therapy [5]. The adverse effects of
topical corticosteroids are reviewed in greater detail separately. (See "Major side effects of systemic
glucocorticoids" and "Diagnosis of adrenal insufficiency in adults".)
Systemic glucocorticoids — When topical corticosteroid therapy is not

practical or feasible due to patient-specific characteristics or preferences, we utilize a systemic
glucocorticoid (eg, prednisone) as initial therapy. (See 'Approach to pharmacologic therapy' above.)
Efficacy — Systemic glucocorticoids are well-accepted as effective treatments for BP and are
widely used for this indication. As was evident in the randomized trial that compared topical
clobetasol and prednisone, the response to prednisone is usually rapid [4]. In the trial, 95 and 91
percent of patients with moderate or extensive bullous pemphigoid, respectively, who were treated
with a systemic glucocorticoid achieved disease control by 21 days. (See 'Efficacy' above.)
2334
Administration — Systemic glucocorticoids are typically administered orally.
Prednisone and prednisolone are commonly utilized, though other formulations may also be
effective [10,11].
The optimum regimen for systemic glucocorticoid therapy remains to be determined. The efficacy of
two different doses of prednisolone was investigated in a French multicenter randomized trial of 50
patients that compared starting doses of 0.75 mg/kg per day and 1.25 mg/kg per day. The difference
in the proportion of patients in the 0.75 mg/kg group and the 1.25 mg/kg group who achieved clear
skin by day 21 was not statistically significant (58 versus 64 percent) [11,12].
In our practice, we typically treat patients with prednisone or prednisolone with starting doses
ranging from 0.5 mg/kg to 0.75 mg/kg per day, with the initial starting dose dependent on the
severity of disease and patient comorbidities. We continue the effective dose until active
inflammation, new blister formation, and pruritus have ceased for at least two weeks and 80 percent
of existing blisters have healed. This is followed by a slow taper of the glucocorticoid as tolerated
over the course of several months.
Adverse effects — Systemic glucocorticoid therapy can lead to serious acute and
long-term side effects [13]. The adverse effects of systemic glucocorticoid therapy are reviewed
separately (see "Major side effects of systemic glucocorticoids"). Measures to prevent osteopenia
should be implemented in patients receiving chronic systemic glucocorticoid therapy. (See
"Prevention and treatment of glucocorticoid-induced osteoporosis".)
GLUCOCORTICOID-SPARING
AGENTS Although data to support the efficacy of glucocorticoid-sparing agents in
bullous pemphigoid (BP) are limited, in clinical practice, immunosuppressive and anti-inflammatory
drugs are commonly used with the intent of minimizing dependence on systemic glucocorticoid
therapy. The clinical response to glucocorticoid-sparing agents tends to be slower than for systemic
glucocorticoids; these drugs often take several weeks to take effect [14].
We usually begin treatment with a glucocorticoid-sparing agent just prior to the start of
glucocorticoid tapering. The systemic glucocorticoid is then tapered slowly over the course of
several months, with the goal of completely discontinuing the systemic glucocorticoid and
sustaining improvement with only the glucocorticoid-sparing agent. The systemic drugs utilized as
glucocorticoid-sparing agents have also been utilized in place of glucocorticoids as initial therapy
for bullous pemphigoid. We consider this option when patient comorbidities or other factors limit the
use of topical corticosteroid and systemic glucocorticoid therapy.
2335
Immunosuppressive agents — Immunosuppressants are frequently
used as glucocorticoid-sparing agents in bullous pemphigoid. However, the decision to add an
immunosuppressive agent should not be taken lightly, since like systemic glucocorticoids, these
agents may cause serious adverse effects. In some elderly patients, the risks of adding an
immunosuppressant may exceed those of maintaining low dose (eg, 5 mg per day or less)
prednisone therapy.
Azathioprine — Data are limited on the efficacy of azathioprine in bullous pemphigoid

[15-18]. Although a randomized trial that compared azathioprine plus prednisolone to treatment with
the same regimen of prednisolone given alone did not find that the addition of azathioprine
increased the likelihood of achieving disease control [15], a separate randomized trial of 25 patients
with bullous pemphigoid that allowed for adjustments in the dose of prednisone based upon the
clinical response found support for a glucocorticoid-sparing effect [16]. After three years, less
prednisone had been taken by patients in the combination therapy group than in the group solely
treated with prednisone (mean total dose of 6732 mg versus 3688 mg).
Despite the limited evidence to support its use, azathioprine is commonly used as a glucocorticoid-
sparing agent [19]. Doses between 0.5 and 2.5 mg/kg per day are typically used [18].
A major side effect of azathioprine therapy is myelosuppression. A thiopurine methyltransferase

(TPMT) level should be checked prior to the initiation of azathioprine to determine the appropriate
dose and minimize the risk for myelosuppression. The maximum doses of azathioprine for patients
with high (>19 U), medium (13.7 to 19 U), and low TPMT (5 to 13.7 U) activity are 2.5 mg/kg per day,
1.5 mg/kg per day, and 0.5 mg/kg per day, respectively [20].
Other potential adverse effects include malignancy, gastrointestinal disorders, and infections. We
typically monitor a complete blood count, renal function tests, and liver function tests every two
weeks for the first three months of therapy and periodically (every two to three months) thereafter.
The adverse effects of azathioprine are reviewed separately. (See "Pharmacology and side effects of
azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)
Mycophenolate mofetil — Case reports suggest that mycophenolate mofetil

may be of value for the treatment of bullous pemphigoid [21-25]. The only randomized trial of
mycophenolate mofetil in bullous pemphigoid was an unblinded randomized trial of 73 patients that
compared treatment with methylprednisolone (0.5 mg/kg per day) plus mycophenolate mofetil (2 g
per day) to methylprednisolone (0.5 mg/kg per day) plus azathioprine (2 mg/kg per day) [18]. The
two regimens appeared similarly effective. All patients in both groups (with the exception of two
patients who died and one patient who was lost to follow-up in the azathioprine group) achieved
clinical remission. The differences between the mycophenolate mofetil and azathioprine groups in
the mean number of days to remission (42±55 versus 24±19 days, respectively) and the mean
cumulative doses of methylprednisolone (5754±9693 versus 4967±12,191 mg, respectively) were
not statistically significant. However, mycophenolate mofetil was better tolerated.
2336
In adults, we typically utilize mycophenolate mofetil at a dose of 1.5 to 2 g per day, with a maximum
dose of 3 g per day. Treatment with mycophenolate mofetil is often well tolerated; gastrointestinal
distress is the most common side effect. An enteric-coated formulation of mycophenolate sodium
has improved gastrointestinal tolerability, and has appeared effective for bullous pemphigoid in
several patients [26,27]. If feasible, it is good to check MMF serum levels as these may vary widely
on standard doses.
Our laboratory monitoring schedule typically consists of a complete blood count, renal function
tests, and liver function tests every two to four weeks for the first three months of therapy and then
periodically thereafter. The adverse effects of mycophenolate mofetil are reviewed in greater detail
separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic
diseases".)
Serum levels of mycophenolate may vary widely among individuals given similar doses [28]. Thus,
when patients have a poor clinical response or develop drug toxicity at standard dosing, we check a
mycophenolic acid trough level when such testing is feasible. The dose is adjusted to maintain a
therapeutic blood level prior to concluding that a patient is unresponsive to mycophenolate mofetil.
In one retrospective study, mycophenolic acid trough levels among three patients who responded to
treatment with 1 to 3 g per day of mycophenolate mofetil were between 1.5 and 6.3 mcg/mL [28].
Methotrexate — No randomized trials have evaluated the efficacy of methotrexate in

bullous pemphigoid. However, case reports and uncontrolled studies suggest that methotrexate may
be beneficial when used alone or in combination with topical corticosteroid or systemic
glucocorticoid therapy [29-35]. A 2009 retrospective review of published reports (English language)
with at least five patients identified 62 patients with bullous pemphigoid who were treated with
methotrexate (5 to 25 mg per week), including 45 who received methotrexate without another
systemic therapy [33]. Among the 45 patients who received only methotrexate and a topical
corticosteroid, 93 percent responded well to treatment, and all 17 patients treated with methotrexate
and systemic glucocorticoids achieved disease control. The results of a subsequent retrospective
study suggest that monotherapy with methotrexate may also be effective [31].
Methotrexate is typically administered at a dose of between 5 and 20 mg per week. A low dose (eg, 5
mg per week) is used as initial therapy and the drug is slowly titrated upward (eg, by 2.5 mg per
week) based upon patient tolerance and the response to therapy. Patients treated with methotrexate
should also be given folic acid to reduce the risk for hematologic and common gastrointestinal side
effects. Frequent hematologic monitoring for pancytopenia is essential. We typically obtain a
complete blood count, renal function tests, and liver function tests five to six days after the initial
dose and every one to two weeks for two to four weeks and one to two weeks after dose escalation.
Subsequently, we obtain these tests every three months. Additional potential side effects include
hepatotoxicity and pulmonary fibrosis. The side effects of methotrexate are reviewed separately.
(See "Major side effects of low-dose methotrexate".)
2337
Anti-inflammatory agents — Data to support the use of antimicrobial
agents with anti-inflammatory properties, such as tetracyclines and dapsone, in bullous pemphigoid
are limited. However, the favorable tolerability of these agents makes them reasonable options for
therapy. We typically consider these agents when a glucocorticoid-sparing regimen is required for
patients with mild bullous pemphigoid (patients with localized BP or patients who develop only a few
new bullae per day). In these patients, the risks of immunosuppressants often outweigh the benefits.
We also consider a trial of these agents in patients with more severe bullous pemphigoid who are
not good candidates for immunosuppressants.
Antibiotics and nicotinamide — Tetracycline antibiotics (eg, tetracycline,

doxycycline, minocycline), often in combination with nicotinamide (niacinamide), have been utilized
for the treatment of bullous pemphigoid [36-42].
Few randomized trials have evaluated these therapies. Doxycycline was beneficial in a randomized
trial that compared doxycycline and oral prednisolone (BLISTER trial). In the trial, 253 adults with
bullous pemphigoid (with at least three clinically significant blisters) were randomly assigned to
receive either doxycycline (200 mg per day) or prednisolone (0.5 mg/kg per day) as initial treatment
[43]. Application of a potent topical corticosteroid (mometasone furoate) to active lesions was
permitted during the first three weeks and after six weeks. At six weeks, doxycycline was noninferior
to prednisolone based upon the specified noninferiority margin of a 37 percent difference in effect.
In the doxycycline group, 83 of 112 patients (74 percent) achieved treatment success (three or fewer
significant blisters) compared with 92 of 101 patients (91 percent) in the prednisolone group. The
adjusted difference in effect was 18.6 percent (90% CI 11.1-26.1). In addition, over 52 weeks, fewer
severe, life-threatening, or fatal events occurred in the doxycycline group than in the prednisolone
group (22 of 121 patients [18 percent]) compared with 41 of 113 patients (36 percent) in the
prednisolone group (adjusted difference of 19 percent, 95% CI 7.9-30.1).
In addition, a small unblinded randomized trial did not find significant differences in efficacy
between prednisone and tetracycline plus nicotinamide in patients with BP. In the randomized trial (n
= 20), eight weeks of tetracycline (500 mg four times per day) plus nicotinamide (500 mg three times
per day) was compared to prednisone (40 to 80 mg per day) [39]. Out of the 14 patients treated with
tetracycline and nicotinamide, there were five complete responses, five partial responses, one failure
to respond, and one case of worsening disease. Two patients were unavailable for follow-up. Among
the six patients treated with prednisone, one had a complete response and the remainder responded
partially to therapy. A larger, blinded randomized trial is necessary to confirm the comparative
efficacy of these regimens.
When treating with tetracyclines in adults, we typically administer tetracycline as 500 mg four times
daily; doxycycline and minocycline are often given as 100 mg twice daily. We use nicotinamide at a
dose of 500 mg four times daily.
2338
Common side effects of tetracyclines include photosensitivity and gastrointestinal distress.
Tetracyclines are contraindicated in children under the age of nine years due to adverse effects on
tooth development. Nicotinamide therapy is occasionally associated with headaches or
gastrointestinal distress.
Erythromycin, another antibiotic with anti-inflammatory properties, may also be beneficial for bullous
pemphigoid. Erythromycin has been associated with improvement in children with bullous
pemphigoid when given alone or in conjunction with other therapies [44,45].
Dapsone — Support for a glucocorticoid-sparing effect of dapsone comes from an open trial
in which 54 patients with bullous pemphigoid were randomly assigned to receive
methylprednisolone (0.5 mg per day) in combination with either azathioprine (1.5 or 2.5 mg/kg per
day based upon thiopurine methyltransferase activity) or dapsone (1.5 mg/kg per day) [46].
Methylprednisone was tapered to discontinuation as tolerated prior to tapering azathioprine or
dapsone. Five patients in the azathioprine group and three patients in the dapsone group achieved
the primary end point of discontinuation of methylprednisolone after a median time of 251 and 81
days, respectively. There was a nonstatistically significant trend towards a lower median cumulative
methylprednisolone dose in the dapsone group compared with the azathioprine group (1.92 versus
2.65 g). The small study size may have contributed to the lack of statistical significance. The number
of adverse effects were similar in the two groups.
Additional support for benefit of dapsone comes from a 2009 review of published case reports and
case series that found clinical improvement documented in 139 of 170 patients who were treated
with dapsone (50 to 300 mg per day) alone or in combination with topical corticosteroids, systemic
glucocorticoids, or immunosuppressive agents [47]. In particular, the efficacy of dapsone as
monotherapy was reviewed in a retrospective series of 36 patients with bullous pemphigoid. Among
15 patients treated with dapsone alone (50 to 200 mg per day), 20 percent appeared to respond to
therapy, with 7 percent achieving complete remission [48]. Patients who were concomitantly treated
with topical corticosteroids and dapsone (n = 19) seemed to have better outcomes; the rates of
response and complete response were 63 and 47 percent, respectively.
Dapsone is usually initiated at a low dose (eg, 25 or 50 mg per day in adults) and titrated upward as
tolerated. Adverse effects include hemolytic anemia, methemoglobinemia, agranulocytosis,
hypersensitivity, and motor neuropathy. We typically obtain a complete blood count with differential
at baseline and once weekly for four weeks, then every two weeks for two months, and every three to
four months thereafter. We obtain renal and liver function tests at least at baseline and every three
months.
Severe hemolytic anemia may occur in patients with glucose-6-phosphate deficiency during
treatment with dapsone. We evaluate patients for G6PD deficiency prior to initiating dapsone
therapy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD)
deficiency".)
2339
REFRACTORY DISEASE Biologic therapies are a treatment
option for patients who fail to respond to topical corticosteroids, systemic glucocorticoids, and
glucocorticoid-sparing agents.
Intravenous immunoglobulin — Intravenous immunoglobulin

(IVIG) is occasionally utilized for the treatment of bullous pemphigoid (BP). A 2012 review of
published reports identified 45 patients (including 43 adults and 2 infants) with bullous pemphigoid
who were treated with IVIG with or without concomitant immunosuppressive therapy [49]. Most
adults were treated with 2 g/kg per cycle, with cycles repeated every four weeks. Among the adult
patients, 86 percent attained clinical improvement; improvement occurred within an average of three
months.
Although further studies are necessary to determine the optimal regimen and indications for IVIG,
factors that have been proposed to contribute to favorable responses include multiple treatment
cycles [49,50], coadministration of an immunosuppressant [51], and shorter durations of disease
prior to the initiation of therapy [52].
The beneficial effects of IVIG on bullous pemphigoid are supported by evidence that serum levels of
BP180 and BP230 antibodies decline in response to treatment. In an uncontrolled study of 10
patients with BP, treatment with IVIG was associated with the induction of both serologic and clinical
remissions in all patients [53]. (See 'Assessing response to therapy' below.)
The adverse effects of IVIG are reviewed separately. The high cost of IVIG limits the use of this
therapy. (See "Intravenous immune globulin: Adverse effects".)
Rituximab — Rituximab is a humanized chimeric monoclonal antibody that targets and

destroys CD20+ B and pre-B cells. Case reports and small case series indicate that rituximab may be
effective for bullous pemphigoid that is refractory to conventional therapies [54-56]. In a
retrospective series of patients with refractory pemphigoid who were given four weekly infusions of
rituximab (375 mg/m2), three of the five patients with bullous pemphigoid achieved complete
remission. One patient achieved only partial remission, and the remaining patient died shortly after
the first infusion. All patients were concomitantly treated with prednisone, dapsone, and/or other
systemic immunosuppressive therapies.
Major side effects of rituximab are reviewed separately. (See "Rituximab: Principles of use and
adverse effects in rheumatoid arthritis".)
Other therapies — Additional medications that have appeared to be of benefit for

bullous pemphigoid in a small number of patients include topical tacrolimus [57,58], cyclosporine
[59,60], chlorambucil [61,62], cyclophosphamide [63,64], leflunomide [65], omalizumab [66-70], and
2340
dupilumab [71]. A few case reports document beneficial effects of immunoadsorption in patients
with refractory bullous pemphigoid [72,73]. Data conflict on the efficacy of plasmapheresis (plasma
exchange) [15,74].
MUCOUS MEMBRANE
INVOLVEMENT Oral mucosal involvement, which usually manifests as oral
erosions, occurs in 10 to 30 percent of patients with bullous pemphigoid (BP) [75]. Similar to
mucous membrane pemphigoid, oral mucous membrane involvement in bullous pemphigoid can
often be managed with topical corticosteroid therapy (see "Management of mucous membrane
pemphigoid"). In addition, our experience suggests that mucous membrane involvement frequently
improves during systemic therapy for cutaneous disease.
ASSESSING RESPONSE TO
THERAPY The level of BP180 antibodies in serum usually correlates with the
clinical activity of bullous pemphigoid (BP) [76]. Thus, many clinicians, including ourselves, use
measurement of these antibodies in conjunction with the clinical evaluation to assess the response
to therapy. Marked decreases in BP180 antibody levels and lesser decreases in BP230 antibody
levels have been detected soon after the start of topical corticosteroid treatment [77].
Discontinuation of treatment may be attempted once patients have remained in complete remission
on minimal therapy (eg, ≤0.1 mg/kg per day of prednisone or ≤20 g of clobetasol propionate per
week) for at least two months [6]. If relapse occurs, treatment is reinitiated.
High titers of BP180 antibodies at the time of cessation of therapy may portend an increased
likelihood for disease relapse. In a prospective study of 114 patients with bullous pemphigoid, a high
ELISA anti-BP180-NC16A titer at the time of cessation of oral glucocorticoid or topical corticosteroid
therapy was an independent predictor of disease relapse within one year [78]. (See "Clinical features
and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Antigen-
specific serologic testing'.)
PROGNOSIS The clinical course of bullous pemphigoid (BP) is variable. In

general, BP follows a chronic, relapsing course [78-81]. Long-term remission may occur after months
to years. In an early report that preceded the use of systemic glucocorticoids, 8 of 30 patients
entered remission after 3 to 38 months of active disease.
In addition to high titers of BP180 antibodies at the time of cessation of therapy [78], other factors
may portend an increased risk for relapse. A one-year prospective multicenter observational study of
120 patients with newly diagnosed BP found that extensive disease at baseline (HR 2.37, 95% CI 1.2-
4.8) and associated dementia (HR 2.09, 95% CI 1.0-4.2) were independent risk factors for disease
2341
relapse within the first year of treatment [77]. In addition, the change in BP antibody levels after the
start of treatment appeared to correlate with risk for relapse. The mean decrease in BP180 antibody
levels during the first 60 days of treatment was smaller among patients who relapsed than among
patients who remained in remission (-10.0 versus -45.2 percent). A similar but lesser effect was
observed for BP230 antibodies.
BP is a potentially fatal disease. Estimates for one-year overall mortality of patients with BP have
ranged from 11 to 48 percent, with most studies finding increased rates of mortality compared
subjects without BP [82-86]. Examples include:
●A French prospective cohort study of 312 patients with BP found an overall one-year mortality rate
of 38 percent [83]. The risk for death was more than six times greater for patients with BP than for
age and sex matched subjects in the general population.
●A Swiss study that evaluated the course of BP in 115 patients found probabilities of death one, two,
and three years after diagnosis of 21, 28, and 39 percent, respectively. The mortality rate for patients
with BP was approximately three times greater than for age and sex-matched subjects in the general
population [82]. The increase in likelihood for death was most pronounced among patients less than
70 years in age.
For unknown reasons, the mortality rates reported in Europe (19 to 48 percent) [81-83,87-92] have
generally been higher than those reported in the United States (11 to 23 percent) [82,93]. One
retrospective cohort study in the United States failed to find an increase in mortality compared to the
general population [80].
The reasons for an increase in death among patients with BP may be multifactorial. Complications
secondary to therapeutic agents are likely a contributing factor. In the Swiss study, the most
common causes for death were heart disease, infection, and neurologic disease [82].
PATIENT SUPPORT The International Pemphigus and Pemphigoid

Foundation (www.pemphigus.org) is a resource that provides patients and clinicians with
information about bullous pemphigoid.

provided separately. (See "Society guideline links: Bullous pemphigoid".)

2342
●Basics topic (see "Patient education: Bullous pemphigoid (The Basics)")
SUMMARY AND
RECOMMENDATIONS
●Bullous pemphigoid (BP) is an uncommon autoimmune blistering disease that most commonly
affects elderly adults. Multiple immunomodulatory therapies are utilized for the management of this
disease. (See 'Introduction' above and 'Approach to therapy' above.)
●For patients with bullous pemphigoid we recommend treatment with a high-potency topical
corticosteroid such as clobetasol 0.05% cream (Grade 1A). If topical corticosteroid therapy is not
practical or feasible due to patient-specific characteristics or preferences, we recommend treatment
with a systemic glucocorticoid (Grade 1A). (See 'First-line therapy' above.)
●Because bullous pemphigoid often persists for years, an immunosuppressive glucocorticoid-

sparing agent, such as mycophenolate mofetil, azathioprine, or methotrexate, is often added to
reduce the risk for glucocorticoid side effects. Tetracyclines and dapsone are additional options.
Data to confirm the value of glucocorticoid-sparing agents in BP are lacking. (See 'Glucocorticoid-
sparing agents' above.)
●For patients who require systemic treatment, but in whom systemic glucocorticoid therapy cannot
be utilized (due to comorbidities or other factors), a glucocorticoid sparing agent may be utilized as
the primary therapy. We typically use mycophenolate mofetil, azathioprine, or doxycycline in this
setting. (See 'Glucocorticoid-sparing agents' above.)
●Biologic therapy may be useful for the management of patients who fail to respond to topical
corticosteroids, systemic glucocorticoids, and glucocorticoid-sparing agents. For these patients, we
suggest treatment with intravenous immunoglobulin or rituximab (Grade 2C). (See 'Refractory
disease' above.)
●The clinical course of bullous pemphigoid is variable. In addition to the clinical assessment, the
measurement of serum levels of BP180 antibodies is useful for following the response to treatment.
(See 'Assessing response to therapy' above.)
2343
●Remission may occur after months or years. Bullous pemphigoid is a potentially fatal disease. (See
'Prognosis' above.)
2344
Management of mucous membrane pemphigoid
uptodate.com/contents/management-of-mucous-membrane-pemphigoid/print
INTRODUCTION Mucous membrane pemphigoid (MMP) is a rare,

chronic, autoimmune, subepithelial blistering and erosive disease that affects the mucosal surfaces
of the mouth (gingiva, movable mucosa, tongue, and palate), eyes, nose, nasopharynx, hypopharynx,
larynx, esophagus, genitals, and/or anus (picture 1A-C) [1,2]. Limited cutaneous involvement
(typically localized to the head, neck, or upper trunk) also may be present. (See "Clinical features and
diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucous
membrane pemphigoid'.)
MMP may cause significant morbidity due to the tissue destruction and functional limitations that
result from chronic mucosal inflammation, pain, and scarring. As examples, gingival inflammation
and scarring may lead to gingival recession and loss of teeth, conjunctival scarring may contribute
to blindness, and laryngeal scarring may result in airway loss.
The treatment of MMP, particularly MMP involving the oral cavity, will be reviewed here. The
management of ocular MMP (ocular cicatricial pemphigoid) and the clinical manifestations and
diagnosis of MMP are discussed separately. (See "Ocular cicatricial pemphigoid" and "Epidemiology
2345
and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features
and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Management and
prognosis of bullous pemphigoid".)
APPROACH TO TREATMENT The primary goals of

the treatment of mucous membrane pemphigoid (MMP) are to halt the progression of the disease,
improve symptoms, and prevent adverse sequelae of chronic tissue inflammation and scarring [3,4].
Few high-quality trials have evaluated interventions for MMP [5]. Thus, treatment is largely guided by
clinical experience and small uncontrolled studies. Consistent use of the recommended measures
for disease activity and treatment outcomes published in 2014 may aid in the systematic
interpretation of data from future studies [6].
The approach to therapy is influenced by the following clinical factors [1]:
●Site(s) of involvement
●Severity of disease
●Rate of disease progression
While patients with limited disease of the oral mucosa may be successfully managed with local
therapies, patients with even mild involvement of sites associated with a higher risk of serious
morbidity (ocular, genital, nasopharyngeal, laryngeal, or esophageal MMP) require systemic agents
as initial therapy. Patients with severe or rapidly progressive disease also may benefit from early
treatment with systemic agents. (See 'Extraoral disease' below and "Ocular cicatricial pemphigoid".)
After clinical remission is attained, treatment is slowly tapered. The pace of tapering should be slow
(eg, over several months) to minimize the risk for disease flares. If discontinuation of all therapy is
not possible due to relapses, patients are maintained on the lowest effective topical or systemic
maintenance regimen.
In addition to pharmacologic interventions, proper management of MMP includes consideration of

the need for multidisciplinary care. Based upon the sites of known or suspected involvement,
comanagement between dermatologists, dentists, ophthalmologists, otolaryngologists, urologists,
internists, gastroenterologists, or colorectal surgeons is often needed. Whenever feasible, patients
should be managed by clinicians experienced in the treatment of MMP. (See 'Extraoral disease'
below.)
ORAL DISEASE The oral cavity is the most common site of mucous
membrane pemphigoid (MMP) (picture 1A-C) [7]. Our approach to the treatment of oral MMP varies
based upon the severity of disease. (See "Clinical features and diagnosis of bullous pemphigoid and
mucous membrane pemphigoid", section on 'Mucous membrane pemphigoid'.)
2346
Mild disease — Patchy, localized involvement of the oral mucosa and skin can often
be treated effectively with local therapy. Topical corticosteroids are the first-line local treatment due
to extensive clinical experience with the use of these agents for MMP. Topical tacrolimus and
intralesional corticosteroid injections are additional therapeutic options.
Topical corticosteroids — Topical corticosteroids, which may be used as

monotherapy for patients with mild oral disease or as an adjunct to systemic treatment in patients
with more extensive disease, are important components of the therapeutic arsenal. Randomized
trials to evaluate the efficacy of topical corticosteroids have not been performed. As noted above,
clinical experience supports the use of these agents [1].
Administration — Class I, super high-potency topical corticosteroids (eg, 0.05% clobetasol

propionate) in an ointment or gel base are recommended by most experts for treatment of oral MMP
(table 1). Gels and ointments can be easily applied to mucosal surfaces and lack the gritty texture of
topical corticosteroids formulated in dental pastes that some patients find unpleasant.
Treatment is applied two to four times per day immediately after the affected areas are dried with
soft disposable tissue paper. Drying the mucosa prior to application may enhance the adherence of
the medication to the treatment area. Patients should avoid eating or drinking for at least 30 minutes
after application.
We encourage patients to do one of their daily applications immediately before bed since oral
secretions are lessened during sleep. This may allow the medication to stay in place for a longer
period.
An alternative mode of topical corticosteroid administration for patients who find the direct
application of topical corticosteroids difficult is the use of 5 mL of dexamethasone (0.1 mg/mL) as a
swish and spit mouth rinse two to three times per day. Patients treated in this manner should be
instructed to avoid swallowing the medication.
Drug delivery via gingival trays is an additional method of drug administration that can be useful for
patients with gingival involvement. The trays aid in the application of topical corticosteroids to
lesional sites under occlusion [8,9]. The gingival tray should be fashioned in soft vinyl and fitted to
cover the patient's gingiva (ie, not the patient's teeth). Trays containing topical corticosteroids are
left in place for 10 to 20 minutes per treatment.
Beneficial effects of topical corticosteroid therapy are usually evident within several weeks. If topical
corticosteroid therapy is successful, treatment can be tapered slowly (over several months) by
reducing the frequency of application and using lower-potency agents. In our experience, patients
who experience disease flares during topical corticosteroid tapering may benefit from a
maintenance regimen in which treatment with a topical corticosteroid is alternated with topical
tacrolimus (eg, topical tacrolimus applied Monday to Friday and a topical corticosteroid applied on
weekends). Intermittent use of topical corticosteroids may help to reduce the risk for corticosteroid
side effects.
2347
Side effects — Examples of potential adverse effects of topical corticosteroid therapy include
mucosal atrophy, oropharyngeal candidiasis, and dyspepsia. Topical or systemic antifungal therapy
is effective for secondary candidiasis. (See "Topical corticosteroids: Use and adverse effects",
section on 'Adverse effects'.)
Topical tacrolimus — Topical tacrolimus, a calcineurin inhibitor, appears to be

effective for some patients. Case reports document marked improvement in oral MMP with topical
tacrolimus, including some patients who failed to respond well to topical corticosteroids [10-12].
Topical tacrolimus 0.1% ointment initially is applied two to three times per day and is tapered as
tolerated. The method of administration mirrors that for topical corticosteroid treatment (see
'Administration' above). The higher cost of tacrolimus relative to many topical corticosteroids
prohibits use of this therapy for some patients.
A transient burning sensation may occur following the application of topical tacrolimus. In addition,
concern has been raised regarding a relationship between the use of topical calcineurin inhibitors
and cancer, resulting in the issuing of a public health advisory by the US Food and Drug
Administration [13]. However, a causative relationship has not been proven. (See "Treatment of
atopic dermatitis (eczema)", section on 'Long-term safety concerns'.)
Intralesional corticosteroids — Intralesional corticosteroid therapy is an

option for disease in the anterior aspects of the mouth that do not respond sufficiently to other local
measures. Support for the efficacy of this treatment is limited to clinical experience [14].
Injections should be placed into the superficial submucosa beneath erosions; deeper injections may
increase the risk for mucosal atrophy. We inject 0.1 to 0.5 mL of triamcinolone acetonide (10
mg/mL) per injection site. We limit the total dose of triamcinolone acetonide administered during a
single treatment session to 20 mg. (See "Intralesional corticosteroid injection", section on 'Side
effects, complications, and pitfalls'.)
Moderate to severe disease — Patients with oral MMP that fails to

respond adequately to local therapy or who present with widespread oral disease may benefit from
systemic agents. Systemic glucocorticoids and dapsone are frequently used to manage these
patients [1]. The local therapies used for mild oral MMP are often prescribed as adjunctive agents.
(See 'Mild disease' above.)
Systemic glucocorticoids — Systemic glucocorticoids are frequently used for

oral MMP [1]. However, data to support the efficacy of systemic glucocorticoids are limited. Our
treatment regimen for systemic glucocorticoids is based upon clinical experience.
We typically treat patients with 0.25 to 0.5 mg/kg of prednisone per day given as a single morning
dose. Since long-term treatment with systemic glucocorticoids is unfavorable due to drug-related
side effects, we taper and discontinue prednisone within six months, if possible. Topical therapy or a
2348
systemic drug (eg, dapsone, azathioprine, mycophenolate mofetil) is used as a glucocorticoid-
sparing agent to maintain clinical improvement during and after prednisone tapering. Patients who
respond insufficiently to 0.25 to 0.5 mg/kg of prednisone may require higher doses of prednisone or
alternative therapies. (See 'Severe and refractory disease' below.)
Systemic glucocorticoid therapy may lead to endocrinologic, musculoskeletal, cardiovascular, and

other system abnormalities. The adverse effects of systemic glucocorticoids are reviewed
separately. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of
glucocorticoid-induced osteoporosis".)
Dapsone — Dapsone in doses of 50 to 200 mg per day may be used for oral MMP that
cannot be adequately managed with local therapy [15]. Data on the efficacy of dapsone for oral
manifestations of MMP are limited to a few uncontrolled studies and case series in which some
patients improved after the initiation of dapsone therapy [15-21]. As an example, dapsone appeared
to be effective in a retrospective study that included 11 patients with MMP localized to the gingiva.
Treatment with dapsone (up to 150 mg per day) for at least 12 weeks was associated with major or
complete improvement in 10 patients (91 percent) [20]. Additional support for the use of dapsone
comes from studies performed in patients with ocular MMP [22,23]. (See "Ocular cicatricial
pemphigoid", section on 'Mild to moderate disease'.)
Dapsone is initiated at a low dose (eg, 25 to 50 mg per day) and is titrated upward as tolerated (eg,
25 to 50 mg per week depending on patient age and tolerance). The slow dose escalation is
accompanied by close laboratory monitoring for adverse effects.
Hemolysis and methemoglobinemia are pharmacologic side effects of dapsone that occur in
virtually all treated patients. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
have an increased risk for adverse consequences due to these pharmacologic effects of dapsone.
We assess for G6PD deficiency prior to initiating treatment. Other potentially severe (and usually
rare) adverse effects of dapsone include leukopenia, agranulocytosis, aplastic anemia,
hypersensitivity reactions, and neuropathy (usually motor, though a sensory component may
coexist). More common adverse effects include headache, nausea, weakness, dizziness, and
fatigue. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD)
deficiency".)
Due to the potential for serious hematologic side effects, laboratory monitoring is necessary for
patients receiving dapsone therapy. We typically obtain a complete blood count (CBC) with
differential, liver function tests, and renal function tests prior to the start of therapy and repeat the
CBC with differential every week during the first month of therapy and twice monthly for the
subsequent two months. Thereafter, monitoring of the CBC, liver function tests, and renal function
tests can be performed every three to four months [24]. The more frequent monitoring schedule is
repeated following dose increases.
2349
Severe and refractory disease — Aggressive immunosuppressive
regimens and biologic therapies may lead to improvement in patients with severe MMP that cannot
be managed with the interventions described above. The potential for serious adverse effects and/or
high cost of these agents limit their use as first-line therapy.
Immunosuppressants — Immunosuppressants, such as azathioprine,

mycophenolate mofetil, and cyclophosphamide, are typically used in combination with systemic
glucocorticoids for patients with severe, refractory oral MMP [25]. Support for the use of these
agents primarily stems from uncontrolled studies of patients with ocular involvement and clinical
experience with patients with oral disease [1,22,26-32]. (See "Ocular cicatricial pemphigoid", section
on 'Treatment'.)
When treating patients with severe, refractory oral MMP, we typically utilize a higher dose of
prednisone than the dose we use as initial therapy for patients with moderate to severe oral MMP.
We prescribe 1 mg/kg per day of prednisone in addition to one of the following immunosuppressive
agents [25]:
●Azathioprine (2 to 2.5 mg/kg per day; dose adjustments may be indicated based upon thiopurine
methyltransferase [TPMT] activity)
●Mycophenolate mofetil (1 to 2.5 g per day)
●Cyclophosphamide (1 to 2 mg/kg per day)
We continue treatment with both drugs until disease control is achieved and has remained stable for
at least four to six months. We then attempt to taper prednisone gradually (eg, over another four to
six months) while maintaining the dose of the nonsteroidal immunosuppressant. Once disease
control is maintained without prednisone for four to six months, we attempt a slow taper to
treatment discontinuation. However, because MMP is a chronic disease, most patients require
continuation of some level of therapy. Whenever feasible, we attempt to maintain improvement with
local rather than systemic therapy. (See 'Mild disease' above.)
Other regimens may be beneficial. Based upon the findings of a retrospective study of six patients
with MMP, combination therapy with prednisone, dapsone, and mycophenolate mofetil may be
another useful treatment regimen for oral MMP [33]. In another retrospective study, 9 of 13 patients
given oral cyclophosphamide without systemic glucocorticoids responded to this treatment [34].
Potential adverse effects of immunosuppressive therapies include bone marrow suppression and
increased risk for infection or malignancy. The adverse effects of azathioprine, mycophenolate
mofetil, and cyclophosphamide are reviewed in greater detail separately. (See "Pharmacology and
side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and
"Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases",
section on 'Adverse effects' and "General principles of the use of cyclophosphamide in rheumatic
diseases".)
2350
Biologic therapies — Intravenous immune globulin (IVIG) and rituximab may be
effective for oral MMP. The high cost of these agents is a limiting factor for therapy.
Intravenous immune globulin — IVIG (1 to 2 g/kg body weight administered over

two to three days every two to six weeks for four to six months) is an often well-tolerated therapy
that may be beneficial for patients with severe, refractory MMP, although the response to treatment
is variable [35-42]. The use of IVIG for oral MMP is supported by a retrospective study of 20 patients
with severe oral MMP in which 12 patients were treated with conventional immunosuppressive
therapy and 8 patients, in whom conventional therapy was contraindicated, were treated with IVIG (1
to 2 g/kg per three-day cycle, initially repeated every four weeks). The mean follow-up period was
four years. Patients treated with IVIG had better outcomes than those treated with conventional
therapy; IVIG-treated patients had significantly shorter durations of treatment, fewer relapses, higher
remission rates, fewer adverse effects, and better quality-of-life assessments [40]. The mean time to
disease control was six months for patients who received IVIG compared with approximately nine
months for patients who received conventional therapy.
IVIG (1 to 2 g/kg per three-day cycle, initially repeated every four weeks) also appeared to be
effective in an uncontrolled study of 15 patients with severe MMP involving multiple mucosal
surfaces that was poorly responsive to conventional immunosuppressive therapies [41]. All patients
responded to therapy and were eventually able to discontinue concurrent systemic treatments.
Treatment efficacy was evident within a mean of five months.
The frequency of IVIG infusions is slowly tapered once disease control is attained, often by
progressively increasing the period between treatments by two weeks and discontinuing treatment
after a 16-week, disease-free interval occurs [40,41]. Potentially severe adverse effects of IVIG
include anaphylaxis (especially in patients with immunoglobulin A [IgA] deficiency), aseptic
meningitis, acute renal failure, hypertension, thrombotic events, and fluid overload. Other adverse
effects of IVIG include headache, back pain, chills, fever, flushing, myalgias, hypertension, nausea,
vomiting, and phlebitis at the site of infusion. The adverse effects of IVIG are discussed in greater
detail separately. (See "Intravenous immune globulin: Adverse effects".)
Rituximab — Rituximab, a chimeric, murine/human immunoglobulin G1 (IgG1) kappa

monoclonal antibody directed against CD20 on pre-B and B lymphocytes, has been used
successfully for the treatment of severe MMP [42-50]. The drug usually is given in combination with
a systemic glucocorticoid, with or without other immunosuppressive agents:
●In a series of 25 patients with severe, refractory MMP involving the eyes, pharynx, larynx, or
esophagus (including five patients classified as having mucous membrane predominant
epidermolysis bullosa acquisita), one cycle of rituximab (375 mg/m2 given weekly for four weeks)
was associated with complete responses in 17 patients (68 percent) [44]. All patients were
simultaneously treated with dapsone, sulfasalazine, and/or immunosuppressants.
2351
The median time to remission after one cycle of rituximab was 12 weeks, and five additional patients
responded completely after a second cycle. Relapses were common after treatment; 10 patients
who achieved complete responses after one cycle of rituximab relapsed (mean time to relapse = four
months after a complete response). However, seven of eight of the relapsed patients regained
complete responses after a second cycle of rituximab. Two patients who were simultaneously
treated with conventional immunosuppressants and high-dose systemic glucocorticoids died due to
serious infections.
●In a retrospective study including a total of 49 patients with moderate to severe MMP treated with
conventional immunosuppressive therapy, 24 patients who had failed therapy with
immunosuppressants were concurrently treated with rituximab (four weekly infusions of 375 mg/m2
or two infusions of 1000 mg given 15 days apart) [48]. Eleven patients received a single course of
rituximab, whereas 13 required 2 to 16 additional infusions.
All 24 patients treated with rituximab achieved disease control an average of 10 months after the
first dose of rituximab; of the 25 patients treated with conventional therapy alone, 10 achieved
disease control an average of 38 months after starting immunosuppressive therapy. Relapse
occurred in 10 of the 24 patients treated with rituximab 3 to 19 months after complete response and
was controlled with additional rituximab therapy in five patients. Three of the 10 patients who
achieved disease control with conventional therapy relapsed after one to three months and required
increased immunosuppressive therapy to regain control.
Additional data on rituximab in patients with ocular MMP are reviewed separately. (See "Ocular
cicatricial pemphigoid", section on 'Rituximab'.)
Adverse effects of rituximab include dizziness, nausea, itching, fever, chills, sneezing, myalgias,
weakness, and/or dyspnea. Severe adverse effects of rituximab include severe infusion reactions,
tumor lysis syndrome, acute renal failure, severe mucocutaneous reactions, cardiac arrhythmias,
angina, and progressive multifocal leukoencephalopathy. (See "Rituximab: Principles of use and
adverse effects in rheumatoid arthritis".)
Other therapies — Examples of additional agents that have been reported to be

effective in small numbers of patients include tetracyclines with nicotinamide [51], minocycline
[52,53], sulfapyridine [20], thalidomide [54], and bortezomib [55].
Adjunctive measures — Patients with oral involvement should follow a

strict regimen of oral hygiene to avert the accumulation of plaque, the loss of gingiva, and
acceleration of tooth decay. This includes brushing of the teeth two to three times each day along
with daily flossing and obtaining regular dental cleanings every three to four months. Use of a
pediatric toothbrush with soft bristles, toothpaste that lacks sodium lauryl sulfate, and
mouthwashes free of alcohol facilitate patient compliance with oral hygiene measures by
minimizing pain.
2352
Topical anesthetics (eg, viscous lidocaine, topical dyclonine) may be used to reduce pain. Patients
may apply topical anesthetics before meals, toothbrushing, dental procedures, or other occasions in
which pain control is required. The anesthetic should be manually applied directly to painful
erosions, rather than used as a mouth rinse. Care should be taken to avoid spread of the anesthetic
to pharyngeal, hypopharyngeal, or laryngeal areas to diminish the likelihood of aspiration.
EXTRAORAL DISEASE Patients with extraoral mucous

membrane pemphigoid (MMP; ocular, nasal, laryngeal, esophageal, or anogenital MMP) are
considered to be at high risk for developing serious functional limitations as a consequence of
mucosal inflammation and scarring. Thus, the approach to the treatment of patients with these
manifestations of MMP differs from the approach to patients with only oral disease. Overall,
pharmacologic therapy is more aggressive; systemic agents are often utilized initially regardless of
the severity of disease [1]. In addition, early involvement of ophthalmologists, otolaryngologists, and
gastroenterologists are indicated for patients with ocular, laryngeal, or esophageal symptoms,
respectively. Consultation with an urologist or colorectal surgeon may be useful for patients with
anogenital disease.
Data are limited on the management of patients with nonocular extraoral MMP. In general, the
approach to drug therapy of nasal, laryngeal, esophageal, and anogenital MMP mirrors the approach
to ocular involvement [1,25]. The treatment of ocular MMP (ocular cicatricial pemphigoid) is
reviewed in detail separately. (See "Ocular cicatricial pemphigoid", section on 'Treatment'.)
In addition to systemic pharmacologic therapy, other interventions may be useful for managing the
extraoral manifestations of MMP:
●Nasal involvement
•Twice-daily irrigation of nasal passages with saline or tap water via a bulb syringe, a piston syringe,
a neti pot, or a nasal irrigation device helps to gently remove crusts.
•Humidified environment.
•Nasal emollients.
•Topical corticosteroid nasal sprays or drops.
●Esophageal involvement
•Soft diet
•Interventions to diminish gastroesophageal reflex and/or gastric acidity
•Esophageal dilation of strictures
●Anogenital involvement
2353
•Topical corticosteroids or topical calcineurin inhibitors
•Stool softeners
•Dilation
Adjunctive measures for ocular MMP (eg, lubrication, lid hygiene, and management of trichiasis) are
reviewed separately. (See "Ocular cicatricial pemphigoid", section on 'Ocular care'.)
SUMMARY AND
RECOMMENDATIONS
●Mucous membrane pemphigoid (MMP) is a rare, autoimmune blistering and erosive disorder that
may affect multiple mucous membranes. The oral cavity is the most common site of involvement.
(See 'Introduction' above and "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Mucous membrane pemphigoid'.)
●The approach to the treatment of MMP is influenced by the site(s) of mucosal involvement and the
severity of disease. Multidisciplinary management is often needed to minimize risk for adverse
sequelae of this disease. (See 'Approach to treatment' above.)
●Patients with mild oral MMP (patchy, localized involvement of the oral mucosa) may respond well
to local therapy. For patients with mild oral MMP, we suggest a high-potency topical corticosteroid
as initial therapy (Grade 2C). Topical tacrolimus and intralesional corticosteroid injections are
additional options for local therapy. (See 'Mild disease' above.)
●Gingival trays may facilitate treatment of patients with significant gingival involvement by allowing
application of topical corticosteroids to lesional sites under occlusion. Patients who have difficulty
applying topical corticosteroids directly to affected sites may benefit from treatment with a
corticosteroid mouth rinse. (See 'Administration' above.)
●Patients with extensive oral involvement or who fail to improve adequately with local therapy are
candidates for systemic treatment. We suggest treating these patients with prednisone or dapsone
(Grade 2C). We use prednisone more frequently based upon personal experience of better results
with this drug. However, the side effect profile of prednisone is a limiting factor for therapy. (See
'Moderate to severe disease' above and "Major side effects of systemic glucocorticoids".)
●Since long-term treatment with prednisone therapy is not desired, topical or systemic
glucocorticoid-sparing agents (eg, dapsone, azathioprine, mycophenolate mofetil) are used to
maintain improvement during and after prednisone tapering. (See 'Systemic glucocorticoids' above.)
●Patients with severe, refractory MMP may benefit from more aggressive therapy. High-dose
prednisone given in combination with immunosuppressants, intravenous immune globulin (IVIG),
and rituximab are options for therapy. (See 'Severe and refractory disease' above.)
2354
●Pharmacologic therapy for the nonoral forms of MMP is similar to the approach used for ocular
MMP (ocular cicatricial pemphigoid). Nonpharmacologic interventions are also useful for the
management of these patients. (See 'Extraoral disease' above and "Ocular cicatricial pemphigoid",
section on 'Treatment'.)
2355
Dermatitis herpetiformis - UpToDate
uptodate.com/contents/dermatitis-herpetiformis/print
INTRODUCTION Dermatitis herpetiformis (DH) is an uncommon

autoimmune cutaneous eruption that is a manifestation of gluten sensitivity. Affected patients
typically develop intensely pruritic inflammatory papules and vesicles on the forearms, knees, scalp,
or buttocks (picture 1A-G). The vast majority of patients with DH also have an associated gluten-
sensitive enteropathy (celiac disease). In most of these patients, the enteropathy is minimally
symptomatic or asymptomatic.
2356
DH usually responds well to treatment. Dapsone and a gluten-free diet are the primary interventions
for the management of this disease.
The pathogenesis, diagnosis, and treatment of DH will be discussed here. Celiac disease is reviewed
separately. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults"
and "Diagnosis of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical
manifestations of celiac disease in children".)
EPIDEMIOLOGY DH is an uncommon disorder that most frequently

occurs in individuals of northern European heritage. Epidemiologic studies from northern Europe
have found incidence rates between 0.4 and 3.5 per 100,000 people per year and prevalence rates
between 1.2 and 75.3 per 100,000 people [1-8]. A population-based study in Utah, a location with a
relatively high proportion of individuals with northern European ancestry, found incidence and
prevalence rates similar to those reported in Europe [9]. Between 1978 and 1987, the incidence of DH
was 0.98 per 100,000 people per year, and the prevalence of DH in 1987 was 11.2 per 100,000
people.
The incidence of DH may be decreasing. An analysis of patient data from the Clinical Practice
Research Datalink in the United Kingdom found a decline in incidence from 1.82 per 100,000 person-
years in 1990 to 0.8 per 100,000 person-years in 2011 [10]. A Finnish study that compared the
incidence of DH diagnosed within a university hospital district in three successive decades,
beginning in 1970, also found decreasing rates of DH [3]. The estimated annual incidence for each
decade was 5.2, 2.9, and 2.7 per 100,000 people, respectively. The reason for the observed decline in
DH incidence has not been confirmed. Increased detection and treatment of mild celiac disease is a
potential contributor. (See 'Pathogenesis' below.)
Epidemiologic studies have found that males are more likely to develop DH than females; reported
male to female ratios have ranged from 1.1:1 to 1.9:1 [3]. The reason for a male predominance in DH
is unknown.
Although the mean age of disease onset is often reported to be in the fourth or fifth decade [3],
individuals of all ages may be affected [3,11]. DH is uncommon in children. In the Finnish study
mentioned above, only 18 of 477 patients with DH were children (4 percent) [3].
PATHOGENESIS The pathogenesis of DH appears to be complex,

involving both intrinsic and extrinsic factors. Like celiac disease, DH is considered a manifestation
of gluten-sensitivity that is most likely to occur in genetically susceptible individuals. The
importance of gluten in the pathogenesis of these disorders is supported by the observation that the
elimination of dietary gluten results in the remission of both diseases. (See 'Gluten-free diet' below
and "Management of celiac disease in adults" and "Management of celiac disease in children".)
2357
Histologic examination of skin biopsy specimens supports an important role for the immune system
in DH. Subepidermal deposition of immunoglobulin A (IgA) and neutrophilic dermal infiltrates in the
superficial dermis are characteristic findings of this disease. (See 'Histopathology' below.)
Genetic predisposition — Certain human leukocyte antigen (HLA) genes

predispose to the development of DH. Virtually all patients with DH carry the HLA DQ2 or HLA DQ8
haplotype [12]. This concept was evident in a comparative study of 50 subjects with DH and 290
healthy controls [13]. The study found that genes encoding HLA DQ2 were carried by 86 percent of
the patients with DH, compared with only 25 percent of the healthy controls. In addition, six of the
seven patients with DH who were negative for HLA DQ2 were positive for HLA DQ8. The importance
of HLA DQ2 and HLA DQ8 is likely related to their role in the promotion of an immune response
against gliadin peptides (see 'Gluten sensitivity' below). Non-HLA genetic factors may also influence
the risk of developing DH [14].
A genetic contribution to DH is supported further by familial studies that demonstrate that first-
degree relatives of patients with DH have an increased risk for both DH and celiac disease [15-17]. In
a Finnish cohort of over 1000 patients with DH, 4 percent reported that they had a first-degree
relative with DH, and 6 percent reported that they had a first-degree relative with celiac disease [17].
Gluten sensitivity — The strong epidemiologic link between DH and celiac

disease strongly supports a shared pathogenesis involving gluten-sensitivity. More than 90 percent
of patients with DH exhibit small bowel biopsy findings consistent with some degree of gluten-
sensitive enteropathy. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac
disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in
children".)
Both the adaptive and innate immune systems may contribute to the development of the clinical
manifestations of gluten-sensitivity. Gliadin peptides (peptides derived from the digestion of gluten)
and tissue transglutaminase (a calcium-dependent enzyme that catalyzes crosslinks between
glutamine and lysine protein residues and forms covalent bonds with gliadin) are key antigens [18].
Antibodies against tissue transglutaminase are present in serum from affected patients and are
used to support the diagnosis of DH and celiac disease. (See 'Serology' below.)
A potential pathway through which exposure to dietary gluten could lead to DH is as follows [19-22]:
●Following the ingestion and digestion of gluten-containing food, gliadin is absorbed into the
intestinal mucosa.
●Gliadin is deaminated by tissue transglutaminase in the intestinal mucosa and covalent crosslinks
are formed between gliadin and tissue transglutaminase.
●Deaminated gliadin peptides bind to HLA DQ2 or HLA DQ8 molecules on antigen presenting cells,
where they are recognized by helper T cells.
2358
●The activated T cells then produce proinflammatory cytokines and matrix metalloproteinases that
stimulate damage to the gut mucosa and the production of antibodies against tissue
transglutaminase by B cells.
●Over time, epitope spreading (the development of an immune response against an endogenous
antigen or multiple endogenous antigens due to exposure of an endogenous antigen during tissue
damage) may occur and contribute to the production of antibodies that are capable of binding to
epidermal transglutaminase.
●The IgA antiepidermal transglutaminase antibodies travel through the bloodstream, and upon
reaching the skin, complex with epidermal transglutaminase in the dermis.
●The deposition of immune complexes in the dermis stimulates neutrophil chemotaxis and
proteolytic cleavage within the lamina lucida, leading to blistering.
Other factors — In addition to genetic predisposition and dietary gluten exposure,

other environmental factors may play a role in the development of DH. This concept is supported by
a study that identified six patients with DH who had a monozygotic twin [23]. Although the presence
of a manifestation of gluten sensitivity (celiac disease, DH, or both disorders) was concordant in five
of six twin sets, DH was present in both twins in only three twin sets. Additional study is necessary
to confirm the pathogenic mechanisms of DH.
CLINICAL FINDINGS Patients with DH may experience cutaneous,

oral, and gastrointestinal manifestations related to gluten-sensitivity.
Cutaneous manifestations — The classic clinical finding in DH is the

development of multiple intensely pruritic papules and vesicles that occur in grouped ("herpetiform")
arrangements. The elbows, dorsal forearms, knees, scalp, back, and buttocks are among the most
common sites for lesion development (picture 1A-F). The face and groin are less frequent sites of
involvement [24].
Due to the associated pruritus, very few intact papules or vesicles are usually seen on clinical
examination. Erosions and excoriations tend to be the most abundant clinical findings (picture 1G).
The extent of cutaneous involvement varies widely. Patients with mild disease present with
involvement limited to a few localized areas, such as the knees or dorsal forearms, while patients
with severe disease present with widely distributed lesions on the trunk and extremities. The skin
lesions usually heal without scarring. However, postinflammatory pigmentary changes may develop
[18].
Petechiae or purpuric macules on the fingers or palms are uncommon clinical features of DH. These
lesions are more likely to occur in children, but may also appear in adults [25-29]. Occasionally, acral
petechiae or purpura are the primary cutaneous manifestations of this disease [29].
2359
Oral manifestations — Involvement of the oral mucosa is rare. Since most
reports that document oral involvement in DH have not confirmed the diagnosis through direct
immunofluorescence microscopy, there is some uncertainty regarding whether some cases have
actually represented aphthous stomatitis or other disorders [18]. Oral mucosal involvement may
manifest as vesicles, erosions, or erythematous macules on the oral mucosa or tongue. Discomfort
may or may not be present.
As with celiac disease, tooth enamel defects may occur in patients with DH. Patients may present
with horizontal grooves, pits, or discoloration [18]. In a series of 30 adults with DH, 53 percent had
enamel defects compared with only 2 percent of 66 healthy controls [30]. A series of 10 children with
DH and no clinical symptoms of celiac disease also found an elevated rate of tooth abnormalities
among patients with DH; 80 percent had bilateral enamel defects, whereas similar defects were seen
in only 13 percent of healthy children [31].
Gastrointestinal disease — Nearly all patients with DH (75 to 90 percent)

have associated subclinical or clinical small bowel disease related to gluten-sensitivity [11,32].
Findings on small bowel biopsy may demonstrate the villous atrophy and crypt hyperplasia
classically associated with celiac disease; other cases may demonstrate only mild findings, such as
an increase in intraepithelial lymphocytes in intestinal microvilli [33]. (See "Diagnosis of celiac
disease in adults", section on 'Endoscopy with small bowel biopsy'.)
Despite the common presence of histologic abnormalities in the gut, only a minority of DH patients
develop clinically significant gastrointestinal symptoms. Symptomatic patients may present with
abdominal bloating, cramping, pain, diarrhea, or constipation. (See "Epidemiology, pathogenesis, and
clinical manifestations of celiac disease in children", section on 'Clinical manifestations' and
"Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on
Clinical course — DH is usually a life-long condition. However, the clinical course of

skin disease is variable. While some patients experience intermittent eruptions that last only a few
days and are separated by long asymptomatic periods, others develop continuous symptoms that
wax and wane in severity [34]. Occasionally, spontaneous remissions occur [35]. (See 'Prognosis'
below.)
ASSOCIATED DISEASES In addition to celiac disease, other

diseases may occur at increased frequencies in patients with DH. The most common associated
condition is autoimmune thyroid disease [33]. As an example, in a retrospective study of 264 adults
with DH, thyroid disease was documented in 11 percent [33]. Hypothyroidism is more likely to occur
than hyperthyroidism [33,36,37].
2360
Type I diabetes mellitus and pernicious anemia also may be more likely to develop in patients with
DH. The prevalence of type 1 diabetes mellitus in patients with DH is estimated to be between 2 and
5 percent [18]. Between 1 and 3 percent of patients with DH may have pernicious anemia [33]. Other
diseases that may occur with increased frequency in patients with DH include vitiligo, Addison's
disease, alopecia areata, and several other autoimmune diseases [33,37].
Celiac disease has been associated with an increased risk for non-Hodgkin lymphoma [38] (see
"Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults"). An increased
risk for lymphoma may also occur in association with DH, though estimates of this risk have varied
[39-45]. As an example, a Swedish population-based study that included 1354 patients with DH
found a slightly increased overall risk for cancer (standard incidence ratio [SIR] 1.2, 95% CI 1.0-1.4),
which primarily appeared due to an increase in lymphoma and leukemia [39]. In addition, a cohort
study in the United Kingdom that included 84 patients with DH who were followed for a mean of 22
years found that the risk for non-Hodgkin lymphoma was increased in comparison to the general
population (SIR 5.14, 95% CI 1.05-15.0) [40]. In this study, the overall risk for malignancy was not
increased (SIR 0.99, 95% CI 0.65-1.44).
The impact of a gluten-free diet on the risk for malignancy in patients with DH is uncertain. One
retrospective study suggested a reduced risk for lymphoma among patients with a history of long-
term adherence to a gluten-free diet [46]. However, additional studies are necessary to explore the
impact of a gluten-free diet on the risk for malignancy.
DIAGNOSIS In addition to the recognition of consistent clinical findings,

obtaining laboratory studies, including tissue pathology, direct immunofluorescence microscopy
(DIF), and serology can aid in the diagnosis of DH. DIF is considered the gold standard test for
diagnosis.
Our initial approach to the diagnosis of DH in patients who present with suggestive clinical findings
involves obtaining a lesional skin biopsy for routine hematoxylin and eosin (H&E) staining and a
perilesional skin biopsy for DIF. We use serologic studies as adjunctive tests to support the
diagnosis. Serology can also be useful for assessing adherence to dietary therapy. (See 'Serology'
below.)
Histopathology — A 4 mm punch biopsy is usually sufficient for obtaining a tissue

specimen for routine histologic examination. The biopsy specimen ideally should be taken from the
site of a small, intact vesicle. If no intact vesicles are present, the biopsy should be taken from an
area of intact, inflamed skin. Biopsies of excoriated lesions may yield nonspecific findings. (See
"Skin biopsy techniques", section on 'Punch biopsy'.)
The histologic findings vary based upon the age of the lesion. The earliest lesions may demonstrate
only collections of neutrophils (with or without eosinophils) and fibrin at the tips of the dermal
papillae (papillary microabscesses) [47]. Lesions older than 48 hours begin to demonstrate
subepidermal vesiculation at the papillary tips, which eventually connect to form larger
2361
subepidermal blisters that contain neutrophils, eosinophils, and fibrin (picture 2). A perivascular
lymphohistiocytic infiltrate with varying numbers of neutrophils and eosinophils is usually found in
the dermis [47].
The histologic findings in DH may resemble other subepithelial blistering disorders. In particular, DH
can be difficult to distinguish from linear IgA bullous dermatosis and bullous systemic lupus
erythematosus. Bullous pemphigoid may also resemble DH histologically, but typically is
characterized by a greater abundance of eosinophils [47].
Direct immunofluorescence microscopy — DIF is the

gold standard test for the diagnosis of DH. A 4 mm punch biopsy is typically utilized to obtain the
tissue specimen. The biopsy should be taken from perilesional skin (normal-appearing skin adjacent
to a lesion) because biopsies taken from lesional skin are more likely to yield falsely negative
findings [48]. Michel's medium may be used to transport the specimen. Tissue for DIF should not be
placed in formalin. (See "Skin biopsy techniques", section on 'Punch biopsy' and "Approach to the
patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
The characteristic finding on DIF is the presence of granular deposits of immunoglobulin A (IgA)
within the dermal papillae (picture 3). Deposits of immunoglobulin M (IgM) and C3 may also be
present [47]. Infrequently, a fibrillar, rather than granular, pattern of IgA deposition is detected [49,50].
Granular deposits of IgA along the basement membrane may also be seen in DH, and may lead to
the misdiagnosis of DH as linear IgA bullous dermatosis (picture 4) [51,52]. Serologic studies are
useful for clarifying the diagnosis in ambiguous cases. (See "Linear IgA bullous dermatosis", section
on 'Direct immunofluorescence'.)
DIF is usually positive in DH. In a retrospective study of 264 patients with DH, DIF was positive in
244 patients (92 percent) [33]. DIF can become negative in patients on strict gluten-free diets since
adherence to the diet reduces IgA deposits in the dermis. In a retrospective series, 10 of 41 patients
with DH who were on strict gluten-free diets no longer had detectable IgA deposits in the skin after
an average of 13 years [53]. IgA deposition is not affected by pharmacologic therapy [54].
Serology — We obtain serologic studies to confirm the diagnosis of DH in patients with

consistent clinical, histologic, and DIF findings and to aid in the diagnosis of DH in cases in which
DIF is negative or equivocal. Elevated levels of IgA tissue transglutaminase antibodies, IgA
epidermal transglutaminase antibodies, and IgA endomysial antibodies are often present in patient
serum [33,55-59].
Serology is also useful for clinical follow-up. Serum levels of these antibodies fall with gluten
restriction and may be useful for monitoring the adherence and response to a gluten-free diet [60].
(See "Management of celiac disease in adults", section on 'Monitoring the response to a gluten-free
diet'.)
2362
The serologic tests utilized in DH are generally sensitive and specific. The sensitivity of enzyme-
linked immunosorbent assay (ELISA) for IgA tissue transglutaminase antibodies ranges between 47
and 95 percent, and the specificity for this test is reported to be greater than 90 percent [51]. The
sensitivity of ELISA for IgA epidermal transglutaminase antibodies ranges between 60 and 81
percent, and the specificity for this test is between 93 and 100 percent [54,60].
Endomysium is the connective tissue found in smooth muscle of the esophagus, stomach, and
small intestine. The test for endomysial antibodies is performed via indirect immunofluorescence on
monkey esophagus [54]. The sensitivity of this test for celiac disease and DH ranges from 52 to 100
percent and the specificity of the test approximates 100 percent [51]. (See "Approach to the patient
with cutaneous blisters", section on 'Indirect immunofluorescence'.)
Our typical serologic work-up for patients with suspected DH includes the following:
●Enzyme-linked immunosorbent assay (ELISA) for IgA tissue transglutaminase antibodies
●ELISA for IgA epidermal transglutaminase antibodies (when available)
●Indirect immunofluorescence for IgA endomysial antibodies
●Total IgA level
The total IgA level is necessary because selective IgA deficiency, which decreases the likelihood of
detecting IgA transglutaminase and endomysial autoantibodies, occurs at an increased frequency in
patients with celiac disease [54]. IgA deficiency appears to be less common in DH [61]. The
assessment of immunoglobulin G (IgG) antibodies against tissue transglutaminase and
endomysium may be useful in this setting [54].
ADDITIONAL TESTS Since DH is considered a cutaneous

manifestation of celiac disease and the treatment for both disorders is similar (a gluten-free diet),
performance of a small bowel biopsy to confirm bowel pathology is not indicated [54,62]. (See
"Diagnosis of celiac disease in adults" and "Diagnosis of celiac disease in children".)
Due to the association of DH with thyroid disease, we typically obtain thyroid function tests in
patients with DH [54]. We also screen patients for diabetes. Additional tests may be ordered based
upon clinical suspicion for other autoimmune diseases. (See 'Associated diseases' above and
"Laboratory assessment of thyroid function".)
DIFFERENTIAL DIAGNOSIS The clinical features of

DH can resemble the clinical findings of other dermatologic disorders. Intensely pruritic conditions
that present with excoriations and inflammatory papules, such as atopic dermatitis, scabies, and
arthropod bites should be considered.
2363
Other subepidermal blistering diseases such as bullous pemphigoid (picture 5), linear IgA bullous
dermatosis (picture 6A-B), and bullous systemic lupus erythematosus are also included in the
differential diagnosis. Blistering tends to be more prominent in these conditions than in DH.
However, in the prodromal phase of bullous pemphigoid, blistering may be minimal or absent
(picture 7). (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid" and "Linear IgA bullous dermatosis" and "Bullous systemic lupus erythematosus".)
The careful assessment of the patient history as well as the clinical, histopathologic,
immunopathologic, and serologic findings usually successfully distinguishes DH from other
disorders. (See 'Diagnosis' above.)
TREATMENT The two most important therapeutic interventions for DH include

a strict gluten-free diet and dapsone therapy [63-65]. A gluten-free diet is effective for both DH and
the often associated gluten-sensitive enteropathy. However, several months to a few years may be
required to achieve complete remission of DH with a gluten-free diet as monotherapy [11,63].
In contrast to a gluten-free diet, dapsone is rapidly effective for DH, resulting in the resolution of
active skin lesions within days of the start of therapy. Disadvantages of dapsone therapy include the
potential for drug-related adverse events and its lack of effect on the gastrointestinal manifestations
of gluten-sensitivity [63]. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac
disease in adults".)
Our preferred approach to the treatment of DH consists of a combination regimen that allows
patients to benefit from the favorable features of both interventions. At the start of treatment, we
prescribe dapsone to induce rapid clearance of symptoms and simultaneously strongly encourage
patients to eliminate gluten in their diets. We then slowly taper dapsone as tolerated, with a goal of
eventually maintaining clinical improvement only on dietary therapy.
Indications for referral — Patients are usually managed by a dermatologist

(for the management of DH) and a nutritionist (for dietary counseling) [32]. Additional specialists are
added as needed based upon patient comorbidities (eg, thyroid disease, diabetes).
First-line therapy — First-line therapy for DH consists of both dapsone and the
elimination of gluten from the diet.
Dapsone — The efficacy of dapsone in DH is well-accepted based upon extensive clinical

experience and the clear correlation with rapid clinical improvement immediately after the initiation
of treatment [11,54,62,63,65,66]. Pruritus usually improves within 72 hours, and the skin
manifestations typically resolve within days [18]. No randomized trials have evaluated the efficacy of
dapsone in DH.
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In adults with DH, treatment with dapsone is typically begun at 25 to 50 mg per day. The dose is
slowly titrated upward (eg, a 25 mg increase in the daily dose every one to two weeks up to a dose of
2 mg/kg per day) based upon patient tolerance and the response to therapy. Our experience
suggests that most adult patients on unrestricted diets respond fully to doses between 50 and 150
mg per day [67]. Mild eruptions (eg, one to two new lesions per week) are expected at optimum
dosing and are not an indication for increasing the dose of dapsone. Symptoms from these mild
outbreaks can be treated with application of a potent topical corticosteroid. (See 'Corticosteroids'
below.)
Dapsone therapy is associated with a variety of potential adverse effects (table 1). Some degree of
hemolysis occurs in essentially all patients. Although this is tolerated by most patients, individuals
with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for severe
hemolytic anemia. Examples of additional side effects include methemoglobinemia,
agranulocytosis, and a dapsone hypersensitivity reaction. When it occurs, agranulocytosis usually
appears 2 to 12 weeks after the initiation of dapsone therapy. Dapsone-associated hypersensitivity
syndrome classically presents with flu-like symptoms, a morbilliform cutaneous eruption, fever,
lymphadenopathy, hepatitis, and eosinophilia. (See "Diagnosis and management of glucose-6-
phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia' and "Drug
reaction with eosinophilia and systemic symptoms (DRESS)".)
Careful laboratory monitoring is necessary during dapsone therapy. We typically obtain a complete
blood count (CBC), liver function tests, and renal function tests prior to the start of therapy. A G6PD
screen is also recommended since dapsone therapy is contraindicated in patients with G6PD
deficiency. We repeat a CBC every one to three weeks for one month, and every one to three months
during the first six months of therapy. Subsequently, we obtain a CBC every three to six months
provided the dose of dapsone is not increased. Liver and renal function tests are performed every
three to four months. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase
(G6PD) deficiency".)
Slow, progressive tapering of dapsone can be attempted after the patient has been on a strict gluten-
free diet for at least two to three months [68] (see 'Gluten-free diet' below). Tapering too rapidly can
result in disease flares. The best regimen for reducing the dose of dapsone has not been
determined. We usually attempt to taper the drug by 25 mg every four to six weeks. In one study,
tapering of dapsone to treatment cessation required an average of two years [69].
Gluten-free diet — The designation of a gluten-free diet as a first-line treatment for DH

is based upon uncontrolled studies and extensive clinical experience that support its benefit in DH
and the dual efficacy of the diet for the cutaneous and gastrointestinal manifestations of gluten-
sensitivity [53,63,69-73]. Although dapsone is highly effective for inducing clinical remissions of DH,
a gluten-free diet is our preferred option for long-term therapy. (See "Management of celiac disease
in adults" and "Management of celiac disease in children".)
2365
Patients who adhere to a gluten-free diet are usually able to reduce the requirement for dapsone and
eventually may be able to discontinue dapsone therapy. As an example, in a 36-month study of 81
patients with DH who were on a gluten-free diet for 6 to 36 months and 49 patients with DH who
maintained a normal diet, reductions in the dose of dapsone were achieved in 93 versus 16 percent
of patients, respectively [69]. After one year, the average reduction in the dose of dapsone in patients
on a gluten-free diet was 60 percent; the percentage reduction increased to 80 percent after three
years. During the study period, 28 percent of patients on the gluten-free diet were able to discontinue
dapsone completely. Among these patients, the mean amount of time required to discontinue
dapsone was two years.
Strict adherence to a gluten-free diet is challenging. Counseling with a dietician is recommended to

help patients to identify and eliminate both obvious and hidden sources of dietary gluten and to
assist patients with finding alternatives to gluten-containing foods. Multiple resources that provide
information on gluten-free diets are available. Examples include the Celiac Disease Foundation and
the Gluten Intolerance Group. Whether a gluten-free diet reduces the risk for autoimmune diseases
and malignancy in patients with DH is not clear. (See "Management of celiac disease in adults",
section on 'Is strict gluten avoidance necessary?'.)
If a relapse of DH occurs in a patient on a strict gluten-free diet, the possibility of exposure to hidden
sources of gluten or other triggers (iodide, medications) should be considered. Close review of the
diet with a dietician may identify unintentional sources of gluten intake. For severe recurrences,
dapsone can be reinstituted with the same regimen used for initial therapy. (See 'Dapsone' above.)
Other therapies
Other sulfa-based drugs — In patients who cannot tolerate treatment with
dapsone, other sulfonamide drugs are options for pharmacotherapy. However, there is much less
experience with the use of these therapies.
Case reports document successful treatment of DH with sulfapyridine [74,75] and sulfasalazine [76-
78]. Although sulfasalazine is metabolized to sulfapyridine in the intestine, the absorption of
sulfapyridine (the active drug) is more predictable when sulfapyridine is administered [76,79]. Thus,
our preference is to use sulfapyridine. Sulfapyridine may be given to adults at a starting dose of 0.5
g three times per day, which may be increased to up to 6 g per day if necessary to control patient
symptoms. Sulfasalazine has been reported to be effective in doses between 1 and 2 g per day [76].
Of these two agents, only sulfasalazine is commercially available in the United States. Sulfapyridine
may be obtained through compounding pharmacies.
Although sulfapyridine and sulfasalazine do not cause the hemolysis seen with dapsone therapy,
agranulocytosis and hypersensitivity reactions are potential adverse effects. In addition, adequate
fluid intake is recommended during treatment with these drugs to reduce the risk for drug-induced
nephrolithiasis. As with dapsone, laboratory monitoring should be performed periodically. We
typically follow a CBC, liver function panel, and urinalysis.
2366
Sulfamethoxypyridazine has also been reported to be effective for DH [80,81]. This agent is not
Corticosteroids — Topical superpotent corticosteroids may help alleviate pruritus

(table 2). These agents are not sufficient for the management of DH, and should be used in
conjunction with dapsone and a gluten-free diet. Systemic glucocorticoids are usually ineffective for
DH.
Treatment of children — As with adults, the treatment of children with DH

typically consists of dapsone and a gluten-free diet. Dapsone is usually initiated at a low dose (<0.5
mg/kg per day) and titrated upward as tolerated; the therapeutic dose is typically between 0.5 and 2
mg/kg per day [82]. As the gluten-free diet begins to take effect, dapsone is tapered as tolerated [83].
The duration of time to improvement without dapsone therapy was evaluated in a study in which 41
children with DH were treated with only a gluten-free diet [11]. The study found that 33 of 41 children
(80 percent) treated with a gluten-free diet alone had resolution of their symptoms within one to six
months. However, since the relief attained with dapsone is almost immediate, we typically use
combination therapy.
PROGNOSIS Most often, DH is a life-long condition that requires continued

treatment with dapsone and/or a gluten-free diet to maintain remission. Symptoms can recur within
two days after the discontinuation of dapsone, and within three months after the resumption of
gluten intake [62,66]. However, 10 to 15 percent of patients may develop remissions that persist
despite the discontinuation of both pharmacologic and dietary therapy [35,53].
ln contrast to celiac disease, which may be associated with an increased risk for mortality compared
with the general population, patients with DH may have a reduced mortality rate [45,84]. A Finnish
cohort study of 476 patients with DH found a lower than expected mortality rate for all causes
despite a significant increase in the standardized mortality rate due to lymphoproliferative
malignancies in the first five years of follow-up [84]. Further studies are necessary to clarify the
factors that may contribute to a reduction in mortality.
SUMMARY AND
RECOMMENDATIONS
●Dermatitis herpetiformis (DH) is an uncommon cutaneous disorder that occurs as a manifestation
of gluten sensitivity. DH is usually accompanied by a gluten-sensitive enteropathy (celiac disease).
(See 'Introduction' above and "Pathogenesis, epidemiology, and clinical manifestations of celiac
disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in
children".)
2367
●DH most frequently occurs in individuals of northern European ancestry. Both children and adults
may be affected. (See 'Epidemiology' above.)
●Genetic predisposition and gluten-sensitivity are key factors in the pathogenesis of DH. Virtually all
patients with DH carry the HLA DQ2 or HLA DQ8 haplotype. Antibodies against epidermal
transglutaminase produced in association with an immune response to ingested gluten play a key
role in the disease pathogenesis. (See 'Pathogenesis' above.)
●DH classically presents as an intensely pruritic skin eruption characterized by the development of
inflammatory papules and vesicles (picture 1A-G). Due to the pruritus, excoriations and erosions are
often the most prominent clinical manifestations. The elbows, forearms, knees, buttocks, back, and
scalp are common sites for lesion development. (See 'Clinical findings' above.)
●Patients with DH may have an increased risk for the development of other autoimmune diseases.
Thyroid disease is the most common autoimmune disorder associated with DH. Patients with DH
may also have an increased risk for lymphoma. (See 'Associated diseases' above.)
●The diagnosis of DH is made based on both the clinical findings and laboratory studies. The gold
standard test for diagnosis is direct immunofluorescence (DIF) of perilesional skin. DIF classically
demonstrates granular deposits of immunoglobulin A (IgA) within the papillary dermis (picture 3).
Serologic studies that identify circulating IgA antibodies against tissue transglutaminase, epidermal
transglutaminase, and endomysium are useful for confirming the diagnosis. (See 'Diagnosis' above.)
●Our preferred approach to the treatment of DH consists of both pharmacotherapy and dietary
therapy. For children and adults with DH, we suggest treatment with both dapsone and a gluten-free
diet as initial therapy (Grade 2A). Subsequently, dapsone may be slowly tapered with the goal of
sustaining remission with dietary therapy. (See 'Treatment' above.)
●DH is usually a life-long condition that requires continued treatment. Spontaneous remission may
occur in a minority of patients. (See 'Prognosis' above.)
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Epidermolysis bullosa acquisita - UpToDate
uptodate.com/contents/epidermolysis-bullosa-acquisita/print
INTRODUCTION Epidermolysis bullosa acquisita (EBA) is a rare,

sporadic, subepithelial, mucocutaneous blistering disease that usually develops in adulthood. EBA is
classically described as a mechanobullous disorder characterized by skin fragility, noninflammatory
tense bullae, milia, and scarring. Alternatively, EBA can present as an inflammatory bullous eruption
reminiscent of bullous pemphigoid or other subepithelial autoimmune blistering diseases.
The pathogenesis of EBA involves the production of antibodies against type VII collagen, a major
component of anchoring fibrils in the basement membrane zones of skin and mucosa (figure 1). The
immune-mediated disruption of the anchoring fibrils likely contributes to cleavage within the
basement membrane zone and clinical blistering.
2369
The pathogenesis, clinical manifestations, and management of EBA will be discussed here.
Hereditary epidermolysis bullosa is reviewed separately. (See "Epidemiology, pathogenesis,
classification, and clinical features of epidermolysis bullosa" and "Diagnosis of epidermolysis
bullosa" and "Overview of the management of epidermolysis bullosa".)
TERMINOLOGY Although the name "epidermolysis bullosa acquisita"

arose from the original view of EBA as a disorder reminiscent of recessive dystrophic epidermolysis
bullosa (RDEB), EBA and epidermolysis bullosa are distinct diseases. RDEB is a hereditary disease
that results from mutations in the COL7A1 gene that encodes type VII collagen. In contrast to EBA,
RDEB usually first presents in infancy. (See "Diagnosis of epidermolysis bullosa".)
EPIDEMIOLOGY EBA is a rare disorder of uncertain incidence. Although

pediatric cases have been reported, adults are most commonly affected [1-5]. Increased risks for
EBA based upon gender, ethnicity, or geographic location have not been definitively established.
PATHOGENESIS Although the inciting factors for EBA are unknown,

evidence indicates that an autoimmune process that involves the production and deposition of
antibodies against type VII collagen, a major component of anchoring fibrils (adhesion structures in
the dermal-epithelial junction [DEJ]) [6,7], likely contributes to the development of clinical disease
(figure 1). This concept is based upon several observations:
●Direct immunofluorescence (DIF) microscopy of perilesional skin from patients with EBA reveals
antibody deposition at the basement membrane zone [8-10].
●Antibodies against type VII collagen can be detected in serum from patients with EBA [11].
●Immunoelectron microscopy demonstrates antibody deposition in the lamina densa area of the
basement membrane zone, a site consistent with the location of anchoring fibrils [11].
●Decreased numbers of normal anchoring fibrils are present in the DEJ in EBA [12,13], a finding
consistent with skin fragility and epidermal blistering.
●Animal models indicate that passive transfer of antibodies against type VII collagen can induce
clinical features consistent with EBA. (See 'Pathogenic mechanism' below.)
●Serum levels of type VII collagen antibodies detected by ELISA correlate with the severity of skin
lesions [14].
●Patients with bullous systemic lupus erythematosus, which is also associated with antibodies
against type VII collagen, develop subepidermal (either sub-lamina lucida or sub-lamina densa)
blistering [15].
2370
The role of type VII collagen in the DEJ and the mechanism through which antibodies against this
protein might contribute to EBA are reviewed in greater detail below.
Type VII collagen — Type VII collagen is composed of three identical alpha
chains, each consisting of a 145 kDa central collagenous triple-helical segment characterized by
repeating Gly-X-Y amino acid sequences. The triple-helical segment is flanked by a large 145 kDa
amino-terminal, noncollagenous domain (NC1) and a 34 kDa carboxyl-terminal noncollagenous
domain (NC2) [6,7,16]. The major antigenic epitopes of type VII collagen are located within the NC1
domain; thus, the type VII collagen antibodies detected in patients with EBA most frequently
recognize epitopes within this site [17]. Less often, antibodies against the triple-helical domain or the
NC2 domain are present [1,18-22].
The NC1 domain may play an important role in maintaining the structural integrity of the DEJ. The
NC1 domain contains subdomains with partial homology to adhesive proteins (cartilage matrix
protein, fibronectin type III domains, and A domains of von Willebrand factor) [23]. This feature may
contribute to the ability of anchoring fibrils to stabilize the attachment of the basement membrane
zone to the underlying dermis.
Additional support for the importance of the NC1 domain in the maintenance of the structural
integrity of the DEJ comes from our study of a recombinant NC1 protein [24]. In the study, we found
that a recombinant NC1 protein was capable of binding to components of the basement membrane
zone and dermal extracellular matrix, including fibronectin, laminin 5, type I collagen, and type IV
collagen.
To date, a definitive link between the epitope specificity of autoantibodies in EBA (ie, NC1 domain,
NC2 domain, or the triple helical domain) and specific clinical subtypes of EBA has not been
identified (see 'Clinical manifestations' below) [25]. The results of a series of five patients with EBA
who were evaluated with immunoelectron microscopy suggested that antibodies to the triple helical
domain may be associated with inflammatory subtypes of EBA; however, additional studies are
necessary to determine whether this conclusion is valid [22].
Pathogenic mechanism — Because it is conceivable that antibody

formation against components of the DEJ could occur as a secondary event following skin injury,
studies have been performed to determine whether the type VII collagen antibodies detected in EBA
are pathogenic. Strong support for the pathogenicity of these antibodies is derived from passive
transfer studies in animals [26-28]. As an example, after intradermal injection of rabbit serum
containing high titers of antibodies against the NC1 domain of human type VII collagen, hairless
immunocompetent mice had deposits of anti-NC1 antibodies and complement at the DEJ and
developed subepithelial blistering and nail dystrophy reminiscent of human EBA [26]. Furthermore,
mice injected with human EBA autoantibodies affinity-purified against an NC1 column have
developed a blistering disease with clinical, immunohistologic, and ultrastructural features akin to
human EBA [28].
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Several theories on the mechanism through which the production and deposition of antibodies
against type VII collagen could lead to mucocutaneous blistering in humans have been proposed.
These include:
●Autoantibody deposition on the NC1 domain of anchoring fibrils may compromise the function of
type VII collagen by disturbing its interactions with other basement membrane or upper dermal
components, such as type IV collagen, laminin 5, and fibronectin [24,29].
●Autoantibodies may interfere with the anti-parallel dimer formation of type VII collagen, thereby
inhibiting anchoring fibril assembly [20]. This could result in defective adherence of the lamina
densa to the dermis.
●Antibody-induced complement fixation may lead to tissue inflammation and damage at the DEJ
and subsequent blister formation. This mechanism is most likely to occur in the inflammatory
bullous pemphigoid-like subtype of EBA [30]. (See 'Clinical manifestations' below.)
Additional study is necessary to confirm the pathogenic mechanism of EBA.
Genetic factors — Genetics may play a role in the risk for EBA. In a study of 29
patients with EBA, the frequency of HLA-DR2 was increased when compared with healthy controls
[31]. In theory, this allele could influence autoimmunity to type VII collagen in anchoring fibrils or
could serve as a marker for another gene that is in linkage disequilibrium with HLA-DR2.
CLINICAL MANIFESTATIONS EBA was initially

described as a subepithelial, noninflammatory mucocutaneous bullous disease associated with skin
fragility, a presentation that is now referred to as classical EBA. However, the subsequent
identification of autoantibodies against type VII collagen as a diagnostic feature led to the
recognition of a broader spectrum of clinical manifestations. In addition to the classical,
noninflammatory presentation of EBA, EBA may manifest as an inflammatory blistering disorder
characterized by features that resemble bullous pemphigoid, mucous membrane (cicatricial)
pemphigoid, linear IgA bullous dermatosis, or Brunsting-Perry pemphigoid. The two most common
presentations of EBA are the classical and bullous pemphigoid-like subtypes. The presence of
antibodies against type VII collagen distinguishes EBA from the true forms of other autoimmune
blistering diseases.
Classical (noninflammatory) EBA — Patients with classical

EBA present with skin fragility and the formation of noninflammatory tense vesicles and bullae that
rupture, leaving erosions (picture 1A-B). The most common locations for lesion development are
sites that are repeatedly subject to minor trauma, such as the hands, feet, elbows, knees, and lower
back. The blisters often heal with scarring and small epidermal inclusion cysts referred to as milia
(picture 2).
2372
Mucosal involvement is common in both classical and inflammatory EBA, and can be subclinical or
may manifest as erosions or adhesions on the oral, nasal, ocular, pharyngeal, laryngeal, esophageal,
or anogenital mucosa [32,33]. In one series of 12 patients with EBA, mucosal involvement was
present in 11 patients (92 percent) [34]. A separate retrospective study of 12 patients with EBA found
mucosal involvement in 9 patients (75 percent) [5].
Alopecia, nail loss, fibrosis of the hands and fingers (leading to a mitten-like deformity), esophageal
stenosis, and esophageal webbing may occur in patients with severe disease reminiscent of
hereditary dystrophic epidermolysis bullosa [19,32,35-38]. (See "Epidemiology, pathogenesis,
classification, and clinical features of epidermolysis bullosa", section on 'Dystrophic epidermolysis
bullosa'.)
Inflammatory EBA — As noted above, the inflammatory subtypes of EBA

resemble other autoimmune subepithelial blistering diseases. In contrast to classical EBA, skin
fragility is not a typical feature.
●Bullous pemphigoid-like EBA –Bullous pemphigoid-like EBA shares clinical features with bullous
pemphigoid, the most common autoimmune subepithelial blistering disease (picture 3). Rather than
the noninflammatory lesions of classic EBA, these patients present with tense bullae that are
surrounded by inflamed or urticarial skin [30,39]. Similar to bullous pemphigoid, the lesions are
widespread with a predilection for the trunk, extremities, and skin folds. Larger areas of skin that
demonstrate only erythema or urticarial plaques without bullae may also be present. Pruritus is
common. Scarring and milia are not prominent findings. (See "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Bullous pemphigoid'.)
●Mucous membrane pemphigoid-like EBA –EBA may present as a mucosal-predominant disorder

with clinical findings that resemble mucous membrane pemphigoid (picture 4). The primary disease
manifestations in these patients are erosions and scarring on the mucosal surfaces of the mouth,
upper esophagus, conjunctiva, anus, or vagina [40]. Our experience with mucous membrane
pemphigoid-like EBA has included a patient who developed scarring and strictures of the urethra and
the larynx that led to impaired urination and vocalization. (See "Clinical features and diagnosis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucous membrane
pemphigoid'.)
●IgA bullous dermatosis-like EBA – IgA bullous dermatosis-like EBA has clinical, histologic, and
direct immunofluorescence (DIF) findings that resemble IgA-mediated bullous dermatoses [2,41,42].
Affected patients may present with the annular arrangement of vesicles and bullae characteristic of
linear IgA bullous dermatosis or with the grouped vesicles characteristic of dermatitis herpetiformis
(picture 5). Concomitant mucosal involvement is common. (See "Linear IgA bullous dermatosis",
●Brunsting-Perry pemphigoid-like EBA – The Brunsting-Perry pemphigoid-like variant of EBA

resembles Brunsting-Perry pemphigoid, a rare subepithelial blistering disorder characterized by
bullae that primarily appear on the head and neck and tend to heal with scarring (picture 6) [43-45].
2373
(See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid",
section on 'Brunsting-Perry pemphigoid'.)
EBA manifesting as generalized erythroderma with inflammatory papules and urticarial plaques
prior to the development of isolated vesicles and bullae has been documented in a case report [46].
Since patients with erythroderma are not routinely evaluated for antibodies against type VII collagen,
it is unclear whether erythroderma is an under-recognized manifestation of EBA. One theory for the
mechanism of erythrodermic EBA involves EBA occurring as a secondary event due to inflammatory
skin disease. Skin injury from inflammation may generate a type VII collagen neoantigen at the
basement membrane zone and lead to autoantibody formation.
Children — EBA rarely occurs in children, but also appears to manifest with various clinical
presentations in this population. One retrospective study found that among 14 children with EBA,
five presented with bullous pemphigoid-like disease, five with linear IgA bullous dermatosis-like
disease, and four with classical EBA [2]. Mucosal involvement was common, occurring in 11
children.
ASSOCIATED DISORDERS The concurrent existence of

EBA and various systemic diseases, such as inflammatory bowel disease (IBD), systemic lupus
erythematosus, amyloidosis, thyroiditis, multiple endocrinopathy syndrome, rheumatoid arthritis,
pulmonary fibrosis, chronic lymphocytic leukemia, thymoma, and diabetes has been anecdotally
reported [47]. Clinical experience with over 60 patients from several academic centers in the United
States suggests that IBD is the systemic disease most frequently seen in association with EBA
[17,48]. The presence of type VII collagen in the human colon and the detection of autoantibodies
against type VII collagen in some patients with IBD support a potential link between these diseases
[49-51]. Additional studies are necessary to confirm and explore the relationship of EBA to IBD and
other diseases.
DIAGNOSIS Since EBA shares clinical, pathologic, and immunohistologic

features with other subepithelial blistering disorders, the diagnosis of this disease can be
challenging. Once an initial evaluation indicates the presence of an autoimmune subepithelial
blistering disease and reveals findings consistent with EBA, additional tests may be used to confirm
the diagnosis. (See 'Differential diagnosis' below.)
Initial evaluation — An evaluation for EBA is triggered by clinical findings that

suggest an autoimmune blistering disease, such as the unexplained onset of multifocal cutaneous
blistering and/or mucosal erosions. As for other subepithelial blistering diseases, the initial
evaluation should include the following:
2374
●A thorough patient history and full skin examination that includes an assessment of the
distribution and morphology of skin lesions – This evaluation helps to narrow the differential
diagnosis. As an example, a diagnosis of classical EBA should be strongly considered in adults who
present with consistent clinical features (eg, skin fragility and trauma-induced tense bullae that
result in milia and scars) and lack a family history of hereditary blistering disease. Due to the various
morphologies of EBA, the possibility of EBA should still be considered when clinical features
suggest another subepithelial blistering disorder. (See 'Clinical manifestations' above and
●Tissue biopsies for routine histopathology and direct immunofluorescence (DIF) microscopy –A
tissue biopsy of lesional skin or mucosa should be obtained for routine histologic examination to
determine the site of blistering within the skin (eg, intraepithelial versus subepithelial). A biopsy of
perilesional skin or mucosa for DIF microscopy should also be performed to evaluate for
autoantibody deposition. A 4 mm punch biopsy is typically utilized to obtain each of the necessary
tissue specimens. The specimen for DIF should not be placed in formalin. Skin biopsy procedures
for the evaluation of blistering diseases are discussed in greater detail separately. (See "Approach to
the patient with cutaneous blisters", section on 'Skin biopsy'.)
●Immunofluorescence on basement membrane zone-split skin –When clinical, histologic, and DIF
findings are consistent with an autoimmune subepithelial blistering disorder, immunofluorescence
on skin artificially split within the basement membrane zone is useful for ruling out bullous
pemphigoid and linear IgA bullous dermatosis, thereby narrowing the differential diagnosis to EBA
and a few other rare diseases. (See 'Immunofluorescence on basement membrane zone-split skin'
below.)
Histopathology — The histopathologic findings in EBA vary with the stage of lesion
development and the clinical subtype. Early lesions typically show vacuolar alteration along the
dermal-epithelial junction (DEJ) with subjacent papillary dermal edema. In more developed lesions,
there is a frank subepithelial blister (picture 7). Dermal fibrosis may be present in older lesions, a
finding that correlates with the clinical development of scarring [52].
The intensity of inflammation in the dermis differs among the clinical subtypes. Classical EBA is
characterized by a sparse lymphocytic infiltrate in the superficial dermis [53]. In contrast,
inflammatory subtypes of EBA develop a heavy perivascular, perifollicular, and/or interstitial infiltrate
in the upper dermis. The infiltrate may be rich in neutrophils or may be a mixed infiltrate that also
includes variable numbers of mononuclear cells and eosinophils. (See 'Clinical manifestations'
above.)
Direct immunofluorescence — DIF shows deposition of immunoreactants

in nearly all cases [33,37,54,55]. The classic DIF findings in EBA are linear deposits of IgG and
complement at the DEJ [53,56]. Deposition of IgA, IgM, Factor B, and properdin may also be
detected.
2375
Because linear deposition of IgG and complement at the DEJ may be seen in multiple autoimmune
subepithelial blistering disorders, the DIF findings do not provide a definitive diagnosis. In addition,
the key DIF finding in linear IgA bullous dermatosis-like EBA, which consists of linear deposition of
IgA along the DEJ, is identical to that in linear IgA bullous dermatosis [41,57]. (See "Linear IgA
bullous dermatosis", section on 'Direct immunofluorescence'.)
The pattern of the antibody deposition at the DEJ may offer additional clues for diagnosis [58-60]. A
study of skin biopsies from 157 patients with subepithelial blistering diseases found that a u-
serrated pattern is most often seen in EBA and bullous systemic lupus erythematosus, whereas an
n-serrated pattern is more typical of bullous pemphigoid, mucous membrane pemphigoid, and linear
IgA bullous dermatosis [58].
Immunofluorescence on basement membrane zone-

split skin — The basement membrane zone-split skin technique involves the artificial
induction of cleavage within the lamina lucida of the basement membrane zone by incubation in 1 M
sodium chloride (salt-split skin) or 20 mM ethylenediaminetetraacetic acid (EDTA). Subsequent
visualization of the location of autoantibody binding in reference to the site of cleavage is utilized to
narrow the differential diagnosis. This technique may be performed utilizing perilesional tissue (DIF
on basement membrane zone-split skin) or serum from the patient and a human skin substrate
(indirect immunofluorescence [IIF] on basement membrane zone-split skin).
Antibody binding to only the dermal side of basement membrane zone-split skin (floor of blister) is
consistent with EBA, which contrasts with bullous pemphigoid, which presents with linear deposits
of IgG on the epidermal side of salt-split skin (roof of blister) or to both the epidermal and dermal
side of the split. Immunofluorescence on basement membrane zone-split skin is also useful for
distinguishing linear IgA bullous dermatosis-like EBA from the more common form of linear IgA
bullous dermatosis, which is characterized by epidermal binding on basement membrane zone-split
skin. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid", section on 'Diagnosis' and "Linear IgA bullous dermatosis", section on 'Diagnosis'.)
A downfall of IIF on basement membrane zone-split skin is that the test may be negative in patients
with low levels of circulating type VII collagen antibodies [35,61]. Although IIF on salt-split skin was
positive and showed dermal staining in all 10 patients with EBA in one series [62], IIF on basement
membrane zone-split skin was negative in around one-third of patients in two other small series
[5,61]. In these patients with low levels of circulating type VII collagen antibodies, the enzyme-linked
immunosorbent assay (ELISA) will also likely be negative. It is also important to note that although
immunofluorescence on salt-split skin that shows antibody binding to only the dermal side of split
skin supports a diagnosis of EBA, it does not rule out the possibility of several rare subepithelial
blistering disorders. (See 'Additional studies' below.)
Additional studies — Additional studies may be useful to support a diagnosis of EBA

in the setting of a negative IIF and may aid in the differentiation of EBA from other subepithelial
blistering disorders. Examples of test options include [17]:
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●Transmission electron microscopy –This test is readily available in many hospitals and can be
used to identify a reduction in anchoring fibrils in the DEJ. It also can demonstrate amorphous
material beneath the lamina densa that may represent immunoglobulin deposits on anchoring fibrils.
●Enzyme-linked immunosorbent assay (ELISA) –ELISA systems based upon the NC1 and NC2
domains of type VII collagen are commercially available tests that can be used to identify, with high
sensitivity and specificity, antibodies that bind to type VII collagen [63-66]. However, when the level
of circulating antibodies against type VII collagen is low (eg, patients in whom IIF on basement
membrane zone-split skin is negative), the ELISA often is negative [67].
●Direct or indirect immunoelectron microscopy (IEM) – These ultrastructural tests are generally
used in the research setting. IEM can identify the location of antibody deposits in perilesional tissue
(direct IEM) or the location where antibodies in patient serum bind within a human skin substrate
(indirect IEM). Antibody deposition in the sublamina densa zone (the site of anchoring fibrils) is
consistent with EBA. IEM is considered the gold standard for diagnosis.
Examples of other studies that have been used in research settings to aid in the diagnosis of EBA
include immunoblotting (demonstrates a 290 kDa band that represents the alpha chain of type VII
collagen ± a 145 kDa band that represents the NC1 domain) [17]; indirect immunofluorescence
utilizing recombinant NC1 domain on the surface of HEK293 cells [65]; and fluorescent overlay
antigen mapping (FOAM) [68,69]. FOAM uses computer analysis to compare the location of
immunoglobulin deposits in perilesional skin to the sites where monoclonal antibodies to various
components of the basement membrane zone bind. In EBA, antibody deposits are localized below
the lamina densa.
Specialized testing is also necessary to distinguish EBA from rare subepithelial blistering diseases
with similar findings on basement membrane zone-split skin immunofluorescence, including bullous
systemic lupus erythematosus, anti-laminin 332 (laminin 5/epiligrin) mucous membrane pemphigoid
[70], anti-p105 pemphigoid [71], and anti-laminin 311 (p200/laminin gamma 1) pemphigoid [72].
Bullous systemic lupus erythematosus occurs in patients with systemic lupus erythematosus, and
therefore can be ruled out when evidence for underlying systemic lupus erythematosus is absent.
ELISA testing for type VII collagen antibodies or IEM can be used to distinguish EBA from the other
rare subepithelial blistering disorders. As noted above, the availability of IEM is primarily limited to
research environments.
DIFFERENTIAL DIAGNOSIS Multiple disorders share

clinical features with EBA. Some of the disorders most commonly mistaken for EBA are reviewed
below:
●Bullous pemphigoid – The inflammatory, urticarial plaques and tense blisters of BP may also occur
in inflammatory EBA (picture 3). Immunofluorescence on basement membrane zone-split skin is
useful for differentiating these diagnoses. (See 'Immunofluorescence on basement membrane zone-
split skin' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid".)
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●Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is a subepithelial blistering disorder
that occurs in children and adults. An annular configuration of blisters is common (picture 5).
Immunofluorescence on basement membrane zone-split skin is useful for distinguishing linear IgA
bullous dermatosis from the linear IgA bullous dermatosis-like form of EBA. (See
'Immunofluorescence on basement membrane zone-split skin' above and "Linear IgA bullous
dermatosis".)
●Porphyria cutanea tarda – Porphyria cutanea tarda is an inherited or acquired metabolic disorder
that presents with photodistributed, noninflammatory vesicles, bullae, crusts, and milia (picture 8A-
B). The dorsal hands and forearms are common sites for involvement. Associated clinical findings
include hyperpigmentation, facial hypertrichosis, and localized sclerodermoid plaques. Porphyria
cutanea tarda is diagnosed through the detection of elevated levels of porphyrins in plasma or urine.
In addition, direct immunofluorescence (DIF) microscopy typically reveals deposition of IgG around
dermal blood vessels [73]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria:
●Bullous systemic lupus erythematosus – Bullous systemic lupus erythematosus is a rare

subepithelial blistering disorder that occurs in the setting of systemic lupus erythematosus (picture
9). As with EBA, antibodies to type VII collagen have been implicated in the pathogenesis of bullous
systemic lupus erythematosus. The presence of an underlying diagnosis of systemic lupus
erythematosus in a patient with immunofluorescence findings similar to those in EBA suggests the
possibility of this diagnosis.
●Recessive dystrophic epidermolysis bullosa – Recessive dystrophic epidermolysis bullosa is a

rare, inherited blistering disorder characterized by the congenital absence of type VII collagen.
Patients first present in infancy. Severe skin fragility and generalized blisters that resolve with
scarring and milia formation are characteristic (picture 10). Fusion of the digits of the hands and
feet (mitten deformity) is common. (See "Epidemiology, pathogenesis, classification, and clinical
features of epidermolysis bullosa" and "Epidemiology, pathogenesis, classification, and clinical
features of epidermolysis bullosa", section on 'Dystrophic epidermolysis bullosa'.)
TREATMENT EBA is notoriously difficult to treat; disease refractory to multiple

interventions is common. Randomized therapeutic trials of this rare disorder are lacking and the
optimal approach to treatment remains unclear [74].
General measures — In addition to pharmacologic therapy, efforts to minimize

disease severity are often beneficial in patients with EBA. These include:
●Avoidance of incidental and iatrogenic trauma to the skin
●Gentle cleansing of skin during bathing and avoidance of vigorous scrubbing and harsh soaps
2378
●Education of patients regarding signs of cutaneous infection to promote early recognition and
treatment
For wound care, we typically use hydrogel or semiocclusive hydrocolloid dressings on new, clean
wounds. For lower extremity wounds, we often apply a silver impregnated dressing that is changed
every 48 hours to minimize the risk for infection. (See "Basic principles of wound management".)
Patients with mucosal involvement usually require multidisciplinary management to minimize

consequences of the disease. Ocular disease may result in conjunctival scarring and blindness.
Thus, patients with ocular involvement should be managed jointly with an ophthalmologist to assist
with following the response to treatment and the use of adjunctive topical therapies. Symptoms of
dysphagia or diarrhea are an indication for a referral to gastroenterology to evaluate for the presence
of esophageal strictures or inflammatory bowel disease, respectively. Last, patients with oral
involvement may benefit from joint management with a dentist who is familiar with the care of
patients with autoimmune blistering diseases [75].
Approach to treatment — The preferred first-line treatments for EBA are

agents that both have appeared to be effective based upon the limited available data and are
generally well tolerated.
Although systemic glucocorticoids are often utilized in EBA, clinical experience suggests that
classical EBA may be less likely to respond to systemic glucocorticoids than inflammatory subtypes
of EBA, and that overall, systemic glucocorticoids are less effective for EBA than for other
subepithelial blistering diseases [17,76]. The long-term side effects of systemic glucocorticoid
therapy are an additional concern. Thus, we prefer a different approach to initial therapy.
In our practice, the initial treatment for most patients consists of colchicine or dapsone, both of
which have been reported to be effective when administered in combination with systemic
glucocorticoids; monotherapy with colchicine has also been reported as effective in several patients
[5,76]. If satisfactory improvement is not attained with colchicine or dapsone monotherapy, we
combine these agents. If this is not effective, we consider treatments for refractory disease, most
often utilizing rituximab (particularly for patients with classical EBA) or a trial of the addition of a
short course of prednisone to colchicine and dapsone therapy. (See 'Refractory disease' below.)
In severe cases in which acute improvement is needed, treatment with prednisone may be initiated
at the start of treatment with colchicine or dapsone to attempt to accelerate improvement of
disease.
Colchicine — Typical doses of colchicine for EBA in adults range from 0.5 to 3 mg per day,
with the maximum dose typically limited by the development of dose-related gastrointestinal
adverse effects. In our experience, tolerance to the drug is improved when the dose is increased
gradually.
2379
In adults, we typically begin colchicine at 0.5 or 0.6 mg per day and increase by 0.5 or 0.6 mg per
week until diarrhea occurs. We then reduce the dose to a level that was tolerated without diarrhea. In
our experience, most adults are able to tolerate up to a daily dose of 2 to 3 mg per day, and higher
doses of colchicine generally are not necessary. Due to the high likelihood of gastrointestinal
adverse effects, we usually avoid the use of colchicine in EBA patients who also have inflammatory
bowel disease [77,78]. (See 'Associated disorders' above.)
Dapsone — Treatment with dapsone and systemic glucocorticoids has been associated with
clinical improvement in adults and children with EBA [5,79,80]. Dapsone is typically given as 1 to 2
mg/kg per day [76], beginning with a low dose (eg, 25 mg in adults) and increasing as tolerated.
Hemolytic anemia is a common side effect of dapsone therapy that occurs to some degree in all
patients, resulting in a mild, typically asymptomatic drop in hemoglobin. Individuals with glucose-6-
phosphate deficiency have an increased risk for severe hemolytic anemia. Thus, we test for G6PD
deficiency prior to initiating therapy with this agent.
Refractory disease — Patients who fail to respond well to colchicine or

dapsone require more aggressive therapy. Treatments that may be of benefit in this population
include immunosuppressants, intravenous immunoglobulin (IVIG), and rituximab. The high costs
and requirements for infusion of IVIG and rituximab limit the use of these agents for some patients.
●Immunosuppressants – Although the efficacy of systemic glucocorticoids for EBA is inconsistent,

a trial of the addition of a short course of prednisone to colchicine and dapsone may be performed
in an attempt to augment improvement. Prednisone is administered in doses of 0.5 to 1.5 mg/kg per
day, with the doses on the lower end of this range used for less severe disease. Prednisone is
subsequently tapered as tolerated, with an ideal goal of limiting the course of systemic
glucocorticoid therapy to six weeks [76].
Case reports and a case series have documented clinical improvement with immunosuppressive
therapy such as cyclosporine, azathioprine, cyclophosphamide, methotrexate, and mycophenolic
acid [76,81]. However, clinical experience suggests the benefit of these agents is particularly limited
in patients with the classical presentation of EBA. Patients with the inflammatory, bullous
pemphigoid-like presentation may be more likely to respond to these therapies.
●Intravenous immunoglobulin – Intravenous immunoglobulin (IVIG) has been utilized for the
treatment of pemphigus vulgaris and other autoimmune diseases. Multiple case reports suggest
that the periodic administration of IVIG alone or in combination with other agents is also effective for
improving the clinical manifestations of EBA [5,82-85]. In a 2011 review of published reports, 14 of
15 patients given IVIG as monotherapy or in conjunction with other therapies achieved clinical
improvement [76]. Multiple cycles of IVIG were typically given; each cycle usually consisted of a total
of 1.5 to 2 g/kg of IVIG given over the course of three to five days.
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Side effects of IVIG are usually mild and transient; however, serious adverse effects occasionally
occur. The adverse effects of IVIG are reviewed separately. (See "Intravenous immune globulin:
Adverse effects".)
●Rituximab – Rituximab, a monoclonal antibody against CD20 that depletes B lymphocytes, has
been given in combination with immunosuppressants, IVIG, or immunoadsorption for refractory EBA
in small numbers of patients with favorable results, including patients with the classical variant of
EBA [5,86-91].
Caution must be used with rituximab as potential side effects include life threatening infections,
pancytopenia, severe mucocutaneous reactions, and bowel obstruction, among others. One EBA
patient treated with rituximab developed a fatal Pseudomonas pneumonia [92]. (See "Rituximab:
Principles of use and adverse effects in rheumatoid arthritis".)
Other therapies — Other treatments that have been reported to be effective in

individual patients with refractory EBA include daclizumab [93], plasmapheresis [94], and
extracorporeal photophoresis [95,96].
PROGNOSIS Although the course of EBA varies, the disease most commonly
has a prolonged course, persisting for years. Mucosal involvement can lead to long-term
consequences, such as blindness and esophageal strictures. Uncontrolled cutaneous involvement
may lead to joint contractures [97].
A cure for EBA does not exist. Thus, the goal of treatment is suppression of disease. In a
retrospective study of 30 patients with EBA, all of whom were initially treated with a combination of
methylprednisolone, dapsone, and colchicine (six who did not respond were subsequently treated
with other immunosuppressants), 8 of 24 patients (33 percent) achieved complete remission and 5
of 24 (21 percent) achieved partial remission within one year [98]. The overall prognosis and
response to treatment may be less favorable in adults than in children [2,99].
SUMMARY AND
RECOMMENDATIONS
●Epidermolysis bullosa acquisita (EBA) is a rare subepithelial blistering disorder that primarily
affects adults. EBA is a disease distinct from hereditary epidermolysis bullosa. (See 'Epidemiology'
above and 'Terminology' above.)
●EBA is an autoimmune disease characterized by the production of antibodies against type VII
collagen, a major component of anchoring fibrils in the dermal-epithelial junction (figure 1). Immune-
mediated disruption of the anchoring fibrils likely contributes to the clinical development of
blistering. (See 'Pathogenesis' above.)
2381
●EBA is characterized by several clinical presentations. The most common presentations are
classical EBA and bullous pemphigoid-like EBA. Classical EBA presents as a mechanobullous
disorder associated with skin fragility and noninflammatory tense bullae, with a predilection for acral
areas (picture 1A-B). Bullae often heal with milia and scarring (picture 2). Bullous pemphigoid-like
EBA is an inflammatory form of EBA that is characterized by urticarial plaques and widespread
inflammatory bullae. (See 'Clinical manifestations' above.)
●Anecdotal reports document the occurrence of EBA in association with multiple other systemic
diseases. The most common disorder seen in association with EBA is inflammatory bowel disease.
(See 'Associated disorders' above.)
●The approach to the diagnosis of EBA resembles that for other autoimmune subepithelial blistering
disorders. The initial evaluation includes a patient history, full skin examination, and skin biopsies for
hematoxylin and eosin staining and direct immunofluorescence. Immunofluorescence on basement
membrane zone-split skin provides valuable clues for further narrowing of the differential diagnosis.
●Although the clinical evaluation, biopsies, and immunofluorescence studies provide evidence to
support a diagnosis of EBA, they do not rule out the possibility of several other rare subepithelial
blistering diseases. (See 'Additional studies' above.)
●Data are limited on the treatment options for EBA. Thus, the optimal approach to treatment has not
been established. For patients with EBA we suggest colchicine or dapsone as initial treatment
(Grade 2C). If treatment is not effective, these agents may be used simultaneously.
●EBA that is refractory to colchicine and dapsone requires more aggressive therapy. Agents that
may have efficacy for refractory EBA include immunosuppressants, intravenous immunoglobulin,
and rituximab. (See 'Refractory disease' above.)
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Friction blisters - UpToDate
uptodate.com/contents/friction-blisters/print
INTRODUCTION Friction blisters are intraepidermal blisters caused by

the skin repeatedly rubbing on another object. This type of blister most commonly occurs on the
hands, fingers, feet, and toes (picture 1A-B).
The causes, clinical features, and management of friction blisters will be reviewed here. An overview
of the approach to the diagnosis of cutaneous blistering is provided separately. (See "Approach to
the patient with cutaneous blisters".)
EPIDEMIOLOGY Friction blisters are a common occurrence in both

children and adults. Populations most at risk include individuals whose recreational or occupational
activities require prolonged walking or running, such as endurance athletes, hikers, and soldiers [1,2].
2383
(See "Heel pain in the active child or skeletally immature adolescent: Overview of causes", section on
'Friction blister' and "Overview of running injuries of the lower extremity", section on 'Friction
blisters'.)
PATHOPHYSIOLOGY Friction blisters result from shearing forces

within the epidermis. The shearing forces produce necrosis and dissociation of keratinocytes,
leading to an intraepidermal split in the stratum spinosum. Hydrostatic pressure causes the area of
separation to fill with fluid similar in composition to plasma but with lower protein levels [3].
The magnitude of the frictional force and the number of passes of an object on the skin determine
the likelihood for blister formation [3]. Moist skin produces higher frictional forces than dry or wet
skin, increasing the risk for blistering [4].
Blisters are most likely to occur in skin areas that have a thick stratum corneum held tightly to
underlying structures, such as the palms of the hands or soles of the feet. On the feet, friction
blisters can occur in the setting of poorly fitting shoes. Vigorous activity and bearing heavy loads
both appear to increase risk for foot blisters [3].
Friction injury in sites of very thin skin (eg, atrophic or sun-damaged skin) is less likely to result in
blistering. Rather, the overlying epithelium may be sloughed, and an erosion may result immediately.
PREDISPOSING DISORDERS Underlying conditions

can increase risk for friction-induced blistering. Epidermolysis bullosa, a group of inherited disorders
characterized by mechanical fragility of epithelial and basement membrane zone tissues, presents
with blister, erosion, or ulcer formation in sites of minor skin trauma. Acquired diseases that cause
skin fragility, such as epidermolysis bullosa acquisita, porphyria cutanea tarda, and
pseudoporphyria, also can predispose to friction-induced blisters [5]. (See "Epidermolysis bullosa
acquisita" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical
manifestations, and diagnosis" and "Pseudoporphyria".)
CLINICAL MANIFESTATIONS Friction blisters are

usually preceded by erythema and a sense of pain or burning at the site of skin trauma.Progression
to vesicles or bullae generally occurs within hours. The vesicles and bullae are often tense and filled
with clear fluid (picture 1A). However, excessive trauma may damage the underlying vasculature
resulting in a hemorrhagic vesicle or bulla (picture 1B) [6]. Pressure associated with the
accumulation of fluid within blisters can cause discomfort.
Friction blisters generally occur in linear or oval configurations. Underlying disorders can influence
sites of predilection. As an example, patients with localized epidermolysis bullosa simplex, the most
common variant of epidermolysis bullosa, primarily develop blisters on the feet or hands (picture 2A-
2384
B). More extensive friction or trauma-induced blistering may occur in other epidermolysis bullosa
variants. (See 'Predisposing disorders' above and 'Additional evaluation' below.)
Friction blisters may rupture soon after formation or persist for hours to several days depending on
the thickness of the overlying stratum corneum. Compared with blisters on skin sites with a thinner
stratum corneum, blisters in sites with a thick stratum corneum, such as the palms or soles, tend to
persist for longer periods. The re-epithelialization occurs in 7 to 10 days, if there is no further trauma
to the area. In the absence of an underlying blistering disorder, blisters generally resolve without
scarring.
HISTOPATHOLOGY The friction blister forms with a split in the

stratum spinosum below the stratum granulosum (figure 1). Midepidermal necrosis is evident. The
blister roof consists of normal and necrotic keratinocytes. The blister floor consists of normal,
edematous, and pale degenerating keratinocytes. The deeper layers of the epidermis appear normal.
Within 24 hours after blister formation, there is evidence of the process of re-epithelialization. High
mitotic activity is present in basal cells. After 48 to 120 hours, a new stratum granulosum and
stratum corneum are present.
Changes in the dermis are minor. Typically, there is only a sparse perivascular infiltrate in the upper
dermis. A significant inflammatory infiltrate is not observed provided secondary infection is absent
[3,6].
The histopathologic appearance of friction-induced blisters varies in patients with disorders that
predispose to blistering. In epidermolysis bullosa simplex, the separation may be suprabasilar or
within basal keratinocytes. Friction-induced blisters in porphyria cutanea tarda and pseudoporphyria
occur at the basement membrane within the lamina lucida. (See 'Predisposing disorders' above.)
DIAGNOSIS The diagnosis of friction blisters can be made based upon the
patient history and physical examination. A skin biopsy is not usually necessary and is typically
reserved for patients in whom the diagnosis is in question or for patients in whom an underlying
disorder is suspected. (See 'Additional evaluation' below.)
The patient history is critical for diagnosis. Patients should be asked about recent rubbing trauma in
the affected area and preceding symptoms. Pain or a burning sensation often precedes friction
blister formation. A supportive history for foot blisters may include new shoes or recent vigorous
physical activity.
The physical examination should involve assessment of the blister site and surrounding skin.
Prominent inflammation (eg, erythematous papules or plaques) is not typical and suggests an
alternative diagnosis or secondary infection. (See 'Differential diagnosis' below.)
2385
If the diagnosis remains uncertain after the patient history and physical examination, a skin biopsy
may help to confirm the diagnosis. Ideally, the biopsy specimen should include the blister edge and
adjacent skin. The differential diagnosis determines whether additional testing is necessary. (See
ADDITIONAL EVALUATION Suspicion for an

underlying disorder that predisposes to blistering should arise when blistering is more frequent or
severe than expected based upon the patient history or exhibits impaired healing. Knowledge of the
duration of the problem and the family history may be helpful. Patients with epidermolysis bullosa
often have onset of blistering in infancy or childhood and a chronic course. Patients with
epidermolysis bullosa simplex, which is most often transmitted in an autosomal dominant fashion,
may report similar blistering in other family members. A drug history is useful for the diagnosis of
pseudoporphyria. (See 'Predisposing disorders' above.)
Patients with presentations concerning for an underlying disorder should also be examined for
suggestive physical signs. Blisters primarily involving the dorsal hands can be a sign of porphyria
cutanea tarda or pseudoporphyria (picture 3A-B). Other physical findings of porphyria cutanea tarda
include hyperpigmentation, hypertrichosis, and localized sclerodermoid plaques. Also, unlike classic
friction blisters, blisters related to porphyria cutanea tarda, pseudoporphyria, and epidermolysis
bullosa acquisita tend to heal with scarring or milia formation (picture 4A-B). Patients with
epidermolysis bullosa may also have mucosal erosions or adhesions.
The diagnosis of epidermolysis bullosa, epidermolysis bullosa acquisita, porphyria cutanea tarda,
and pseudoporphyria is reviewed separately. (See "Diagnosis of epidermolysis bullosa" and
"Epidermolysis bullosa acquisita", section on 'Diagnosis' and "Porphyria cutanea tarda and
hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on
'Diagnostic evaluation' and "Pseudoporphyria", section on 'Diagnosis'.)

of friction blisters includes other causes of localized blisters. In particular, other potential causes of
blistering on the hands and feet, such as acute palmoplantar (dyshidrotic) eczema, bullous tinea
pedis, and allergic contact dermatitis, may be in the differential diagnosis. Attention to the patient
history and additional findings, such as pruritus and erythema, aid with diagnosis. For patients with
a history of rubbing trauma, minimal inflammation at the blister site, and a lack of pruritus, friction
blister is the most likely diagnosis:
●Acute palmoplantar (dyshidrotic) eczema – Acute palmoplantar eczema presents with recurrent,
intensely pruritic vesicles or bullae on the hands or feet (picture 5A-B). Common sites of blistering
are the palms, soles, and sides of the fingers or toes. In contrast, friction blisters are not typically
associated with pruritus. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
2386
●Allergic contact dermatitis – Allergic contact dermatitis is a pruritic eruption following contact with
an allergen. Erythematous papules or plaques in skin areas that come in contact with the allergen
are typical findings. Vesicles and bullae occur in severe cases (picture 6). (See "Clinical features and
diagnosis of allergic contact dermatitis".)
●Vesicobullous tinea pedis – Vesicobullous tinea pedis is a variant of tinea pedis that presents with
vesicles on the feet (picture 7). A potassium hydroxide preparation demonstrating septate hyphae
distinguishes this diagnosis from friction blisters. (See "Dermatophyte (tinea) infections", section on
'Tinea pedis'.)
A broader differential diagnosis of localized skin blisters is provided separately. (See "Approach to
the patient with cutaneous blisters", section on 'Localized distribution'.)
COMPLICATIONS Blisters may become secondarily infected,

manifesting as increasing redness, worsening pain, and purulent drainage. Progression to cellulitis
can occur [7]. Staphylococcus aureus infection of friction blisters resulting in toxic shock syndrome
has been reported [8].
MANAGEMENT Friction blisters can heal spontaneously when the

frictional forces are removed. Interventions are focused on reducing symptoms and minimizing risk
for infection.
Symptomatic blisters — Drainage is suggested for painful blisters and

blisters that cause functional limitations. Clinical experience suggests that a drainage procedure
that maintains the blister roof minimizes discomfort and may also reduce risk for secondary
infection.
Blister drainage is a relatively simple procedure that may be performed by a clinician or the patient
at home. The blister surface should be cleansed with alcohol. A sterile needle is used to puncture
the blister. For large blisters, performing more than one puncture helps to remove blister fluid easily.
Light pressure can be applied to aid with removal of the fluid. The blister roof should be allowed to
collapse over the blister site to serve as a biologic dressing. Topical or oral antibiotic therapy is not
necessary in the absence of infection.
Asymptomatic blisters — Nonpainful, nonexpanding blisters that do not

cause functional limitations may be left intact and allowed to resolve spontaneously. The advantage
of an intact blister is maintenance of a sterile environment during re-epithelialization, minimizing the
risk for infection. A bandage or other protective dressing can help to protect blisters located in sites
where additional trauma cannot be avoided during healing.
2387
Wound care — Ruptured blister sites should be gently cleansed daily and covered with
a clean, dry dressing to protect the healing area from trauma and infection. Blister roofs should only
be debrided if there is sign of infection.
Patients with clinical signs of infection (eg, worsening erythema and purulence) should receive
appropriate topical or systemic antibiotic therapy. A culture can be performed prior to treatment to
identify the causative organism.
When patients must continue physical activity that will irritate the blister site, application of a
hydrocolloid dressing can provide a cushioning effect and may help to reduce discomfort during
activity. In addition, a case report describes use of 2-octyl cyanoacrylate on hand blister wounds for
the successful return to work-related activity [9]. (See "Minor wound repair with tissue adhesives
(cyanoacrylates)".)
PREVENTION Measures that reduce frictional forces on the skin are the
mainstay of prevention. Factors contributing to blister formation should be reviewed to identify
helpful interventions, including the inciting activity, potential exacerbating factors (eg, moisture,
sweating, heat), and the objects that were in contact with the skin. Preventive measures are
particularly important for individuals whose occupations or athletic activities are associated with
high risk for recurrent episodes of friction blisters.
Examples of measures to minimize skin friction include:
●Alter the inciting activity (eg, adjust technique, discontinue activity)
●Ensure proper fit of shoes or other gear that contact skin during the inciting activity (eg, foot does
not slide within the shoe during activity)
●Reduce moisture in the affected area during activity (eg, treatment of hyperhidrosis, use of
absorptive socks or clothing)
Despite the common occurrence of friction blisters, high-quality trials are lacking, and the value of
products to reduce frictional force on the skin and protect from blistering remain uncertain. There is
some support in the literature for interventions such as paper tape, thick-padded acrylic socks,
padded wool socks combined with a synthetic inner liner, antiperspirants, and special insoles that
provide cushioning that reduces shear forces on the skin [3]; however, conclusions on efficacy are
complicated by study methodologic flaws and conflicting data [10]. In addition, antiperspirant use is
associated with high risk for skin irritation.
SUMMARY AND
RECOMMENDATIONS
2388
●The friction blister is a common disorder that occurs when frictional forces repeatedly applied to
the skin lead to separation within the epidermis. Friction blisters are most likely to occur on the
hands and feet. (See 'Epidemiology' above and 'Pathophysiology' above.)
●Friction blisters generally present as vesicles or bullae in linear or oval configurations (picture 1A-
B). The blister cavity typically contains clear fluid. Hemorrhagic vesicles or bullae may also occur.
Discomfort is common. (See 'Clinical manifestations' above.)
●Friction blisters can be diagnosed based upon a history of rubbing trauma in the affected area and
consistent physical examination findings. Skin biopsies usually are not necessary. (See 'Diagnosis'
above.)
●Infrequently, disorders associated with skin fragility are associated with friction blisters. Examples
include epidermolysis bullosa, epidermolysis bullosa acquisita, porphyria cutanea tarda, and
pseudoporphyria. Such disorders should be suspected when blistering is more frequent or severe
than expected or exhibits impaired healing. (See 'Predisposing disorders' above.)
●Friction blisters can heal spontaneously provided the causative frictional force is removed.
Treatment is focused on reducing symptoms and minimizing risk for secondary infection. (See
●Patients with painful blisters or blisters that cause functional limitations often have improvement in
symptoms with blister drainage. A drainage technique that leaves the blister roof may help to reduce
risk for secondary infection after drainage. Ruptured blister sites should be cleansed daily and
covered with a clean, dry dressing. (See 'Symptomatic blisters' above and 'Wound care' above.)
●Asymptomatic blisters can be left intact and allowed to resolve spontaneously. (See 'Asymptomatic
blisters' above.)
●Measures to reduce blister recurrence are aimed at reducing frictional forces on the skin. Factors
contributing to blister formation should be reviewed, including the inciting activity, potential
exacerbating factors (eg, moisture, sweating, heat), and the objects that were in contact with the
skin. (See 'Prevention' above.)
2389
Linear IgA bullous dermatosis - UpToDate
uptodate.com/contents/linear-iga-bullous-dermatosis/print
INTRODUCTION Linear IgA bullous dermatosis (LABD), also known as

linear IgA disease, is a rare, idiopathic or drug-induced autoimmune blistering disease characterized
by the linear deposition of IgA at the dermoepidermal junction. Although the clinical features of this
disorder can be difficult to distinguish from dermatitis herpetiformis (another autoimmune blistering
disease), the distinct immunopathologic findings in LABD and the absence of an associated gluten-
sensitive enteropathy confirm the status of LABD as a distinct disease [1].
LABD occurs in both adults and children, and since the late 1980s, the disorder designated as
chronic bullous disease of childhood has been recognized as the childhood form of LABD [2].
Children classically present with widespread annular blisters that exhibit a predilection for the lower
abdomen, thighs, and groin. In adults, annular lesions are less common and the extensor extremities,
face, and trunk are frequently affected. Mucosal lesions, manifesting as inflammation, erosions, or
scarring, may also occur in patients with LABD.
The clinical features, diagnosis, and management of LABD in adults and children will be reviewed
here. A general approach to the evaluation of patients with blistering skin lesions is reviewed
separately. (See "Approach to the patient with cutaneous blisters".)
2390
EPIDEMIOLOGY Linear IgA bullous dermatosis (LABD) is a rare disorder.
Reports of disease incidence from various countries have ranged from less than 0.5 to 2.3 cases per
million individuals per year [3]. A predilection for LABD based upon ethnicity or sex has not been
definitively established [3,4].
Adults frequently develop LABD in the later stages of life, with many cases occurring after the age of
60 [2,3]. In children, the disease usually presents between the ages of 6 months and 10 years; in a
series of 25 affected children, the average age of onset was 4.5 years [2]. Rarely, neonates are
affected [5,6].
PATHOGENESIS Although the presence of IgA antibodies bound to the

basement membrane zone is accepted as a characteristic feature of linear IgA bullous dermatosis
(LABD), the mechanism of lesion formation in this disorder is not well understood. Both humoral and
cellular immune responses may be involved in the pathogenesis of this disease. In particular, tissue
injury resulting from an antibody-induced local inflammatory response and the release of proteolytic
enzymes by neutrophils and other inflammatory cells may contribute to the development of skin and
mucosal lesions [3].
Most patients with LABD have IgA1 antibodies that target a 97 kDa antigen and a 120 kDa antigen
within the basement membrane zone. Both of these antigens are fragments of the extracellular
portion of bullous pemphigoid antigen 2 (BP180/type XVII collagen), a transmembrane protein that
plays a key role in epidermal-dermal adhesion [7,8]. Authors have detailed the process by which the
cleavage of the BP180 antigen results in exposure of neoepitopes on the 15th collagenous domain
that react with IgA autoantibodies [9]. Less frequently, the NC16a epitope on BP180 has been
associated with LABD [10-12]. Some patients with LABD have IgA antibodies that are directed
against other basement membrane antigens, including type VII collagen (COL7), laminin-332, or
laminin gamma 1. These antigenic targets are relevant when IgA antibody binding localizes to the
dermal side of salt-split skin (sublamina densa) [13]. Type VII collagen appears to be the target
antigen in some patients with vancomycin-induced LABD. In one study, 10 of 14 sera from patients
with vancomycin-induced LABD demonstrated enhancement of reactivity to the recombinant
noncollagenous (NC1) domain of type VII collagen when exposed to vancomycin [14]. (See 'Indirect
immunofluorescence' below and "Approach to the patient with cutaneous blisters", section on
'Indirect immunofluorescence' and 'Risk factors' below.)
In addition, the presence of both IgA and IgG antibodies against basement membrane zone
components has been detected in a subset of patients with features consistent with LABD. A
Japanese review of 213 reported cases found that such findings were present in approximately 20
percent of patients [15]. Additional study is necessary to determine whether this presentation
represents a distinct disorder or a variant of LABD.
2391
RISK FACTORS In most patients with linear IgA bullous dermatosis (LABD),
the inciting factor for the disease is unknown.
Although multiple case reports have documented drug exposure as a precipitating factor [16], formal
studies validating the existence of drug-induced LABD are lacking. Vancomycin is the
pharmacologic agent most frequently reported as a potential inciting factor [16]. Examples of other
drugs that may be linked to LABD include a variety of antibiotics, nonsteroidal anti-inflammatory
agents (eg, diclofenac, naproxen, piroxicam), lithium, captopril, amiodarone, phenytoin, cyclosporine,
furosemide, interferon alfa, and somatostatin (table 1) [3,17-19]. (See "Vancomycin
hypersensitivity".)
Genetic factors also may contribute to the development of LABD. Associations of LABD with human
leukocyte antigen (HLA) B8, HLA Cw7, HLA DR3, HLA DQ2, and the tumor necrosis factor-2 allele
have been reported [20]. Further study is necessary to determine the role of both drugs and genetics
in LABD.
CLINICAL MANIFESTATIONS Linear IgA bullous

dermatosis (LABD) may present with lesions on the skin, on the mucous membranes, or in both
locations. Although both children and adults develop LABD, differences in the clinical characteristics
of the disease are observed among these populations.
Cutaneous lesions — Since blister formation in LABD occurs subepidermally,

the vesicles and bullae that form on the skin of affected patients typically have a tense, rather than
flaccid, pemphigus-like quality. (See "Approach to the patient with cutaneous blisters", section on
'Blister quality'.)
A summary of the clinical characteristics of adult and childhood LABD is provided below:
●Children –LABD of childhood, also known as chronic bullous disease of childhood, most often
presents with the acute development of vesicles or bullae on sites of inflamed or noninflamed skin
(picture 1A-D). New blisters often form at the periphery of resolving lesions, resulting in an arciform
or annular appearance (picture 2). Such lesions are frequently described as resembling strings of
pearls, crowns of jewels, or rosettes [21].
The distribution of skin lesions usually is widespread, involving the trunk, face (particularly perioral
area), genitalia, hands, feet, and other sites. The most intensely involved areas are often the
perineum, lower abdomen, and inner thighs [2,4,22].
Affected children may be asymptomatic, but pruritus is common and may be severe. In some
patients, intense pruritus heralds recurrences of the disease [7,8].
2392
●Adults – Adult patients with LABD typically experience an abrupt onset of skin lesions; less
frequently, the disease develops more slowly [23]. The tense vesicles and bullae may arise on
normal skin or within inflammatory plaques (picture 3A-D). Annular lesions demonstrating peripheral
vesiculation develop less frequently in adults than in children [23].
The trunk, extensor extremities, buttocks, and face (particularly the perioral area) are common sites
for lesion development [3]. This distribution can make it difficult to distinguish LABD from dermatitis
herpetiformis, which affects similar sites. Localized variants of LABD presenting as limited blistering
eruptions or annular inflammatory plaques have also been reported [24-30]. Pruritus may be intense,
and can result in the development of excoriated papules or prurigo nodularis-like lesions [31,32].
Mucosal involvement — Mucous membrane involvement can occur in both

adults and children. Mucosal disease occurs in up to 80 percent of adult patients [2]. Estimates of
the incidence of mucosal LABD in childhood disease vary widely. In a series of 25 children with
LABD in the United Kingdom, mucosal involvement was present in 64 percent [2]. In contrast,
similarly sized Japanese and Tunisian retrospective studies found mucosal disease in only 3 and 8
percent of children, respectively [15,33].
Mucosal lesions primarily present as erosions or ulcers; the detection of intact vesicles or bullae is
uncommon. Any mucosal surface may be affected, including the oral cavity, conjunctiva, nose,
genitalia, pharynx, larynx, anus, and esophagus [2,3,5,23].
The oral and ocular mucosa are the most commonly affected mucosal sites [2,3]. In patients with
oral disease, lesions are frequently located on the palate, palatine arches, or buccal mucosa [3].
Erosive gingivitis and erosive cheilitis may also occur as manifestations of oral LABD [2,34,35].
Ocular disease may present with conjunctival redness, ocular discharge, ocular pain, or a foreign-
body sensation [2].
Mucosal scarring may occur, and similar to patients with ocular cicatricial pemphigoid, patients with
ocular LABD can develop symblepharon and ectropion [36] (see "Ocular cicatricial pemphigoid").
Examples of serious adverse consequences of cicatrizing mucosal disease include corneal damage
leading to blindness, airway obstruction, and esophageal strictures [36-38].
Rarely, the mucosa is the initial or only site of LABD [34,39-41]. Mucosal-predominant LABD is
considered a form of mucous membrane pemphigoid [42]. (See "Epidemiology and pathogenesis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Classification'.)
Drug-induced linear IgA — The clinical findings in drug-induced LABD

usually do not differ significantly from those of idiopathic disease [16,43]. Occasionally, lesions are
localized rather than widespread or resemble morbilliform drug eruptions, erythema multiforme, or
toxic epidermal necrolysis (TEN) (picture 4) [44-50]. The presence of mucosal involvement varies
[16].
2393
The shared clinical features of idiopathic LABD and drug-induced LABD were demonstrated in a
retrospective study of 16 patients considered to have spontaneous LABD and 12 patients
considered to have drug-induced LABD that found similar frequencies of erythematous plaques,
string of pearls-like configurations, target or target-like lesions, and mucosal involvement in the two
groups [50]. Only the atypical features of large erosions and a positive Nikolsky sign were
significantly more frequent in the drug-induced group.
Most reported cases of drug-induced LABD have occurred in adults, but LABD in association with
drug exposure has also been observed in children [2,16,17]. The disease usually begins within one
month of drug initiation, and often resolves within several weeks following drug cessation [17,51,52].
However, the eruption persists for longer in some patients. In addition, reexposure to an inciting
agent can result in the rapid recurrence of blistering [53].
The culprit medication is typically identified by the history. Use of established adverse drug
algorithms to support causality is encouraged [54]. Drug-induced lymphocyte stimulation testing
may provide additional information when multiple medications are temporally related to the onset of
skin disease [55].
Patients with vancomycin-induced disease may have increased risk for TEN-like presentations. In a
retrospective study of 69 patients with drug-induced LABD (including 39 with suspected
vancomycin-induced disease), vancomycin was the suspected cause in 11 of 14 patients (79
percent) with TEN-like features [43].
Rarely, patients with LABD also develop IgA nephropathy. Resolution of drug-induced IgA
nephropathy following drug withdrawal has been reported [56].
ASSOCIATED DISORDERS Linear IgA bullous

dermatosis (LABD) has occurred in the setting of ulcerative colitis, hematologic or solid organ
malignancies, and other disorders.
●Ulcerative colitis – Ulcerative colitis is the most common benign disorder reported in association
with LABD [15,57-61]. In a retrospective study of 70 patients with LABD referred to two dermatology
departments in the United Kingdom, five patients (7 percent) had ulcerative colitis, and ulcerative
colitis preceded the diagnosis of LABD by an average of six years [58]. Moreover, a Japanese review
of 213 reported cases of LABD identified four patients with this disease [15].
The reason for an association between LABD and ulcerative colitis is unclear. Some authors have
suggested that abnormal IgA1 production by the inflamed bowel may contribute to the development
of LABD [58]. Although improvement in skin disease following surgical intervention for bowel
disease has been reported [59-61], in other patients skin disease has persisted after surgery [58].
Limited data from case reports suggest that persistence of LABD may be more common after
colectomy with sparing of the rectal mucosa than after proctocolectomy [62].
2394
●Malignancy – The occurrence of LABD in association with lymphoproliferative and solid organ
malignancies has been reported in multiple case reports [29,63-80]. However, further studies are
necessary to confirm an association between LABD and malignancy. Thus, in the absence of signs
or symptoms suggestive of a malignancy, screening beyond age-appropriate investigation is not
warranted in patients with LABD.
Other disorders reported to occur in association with LABD in a few patients include a variety of
infections [26,81-85], psoriasis [84,86], and systemic lupus erythematosus [15,87]. The development
of LABD has also been reported following exposure to ultraviolet light [26,88,89]. Unlike dermatitis
herpetiformis, which may clinically and histologically resemble LABD, gluten sensitivity is not a
feature of this disorder and gluten-free diets do not improve LABD [3,90].
DIAGNOSIS The clinical signs and symptoms of linear IgA bullous dermatosis
(LABD) may resemble multiple mucocutaneous diseases. Thus, when available, laboratory studies
are typically utilized to confirm the diagnosis. Although the findings of routine histopathologic
examination of affected tissue may suggest LABD, the demonstration of linear deposits of IgA along
the basement membrane zone via direct immunofluorescence (DIF) is the gold standard for
diagnosis [7]. In addition, a medication history should always be reviewed to assess for the
possibility of drug-induced disease. (See 'Drug-induced linear IgA' above.)
Light microscopy — The histopathologic findings of linear IgA bullous

dermatosis are nonspecific and often closely resemble dermatitis herpetiformis. A subepidermal
blister with an underlying neutrophil-predominant dermal infiltrate is characteristic (picture 5) [3].
Lymphocytes, eosinophils, and papillary microabscesses similar to those seen in dermatitis
herpetiformis also may be present [7]. (See "Approach to the patient with cutaneous blisters", section
on 'Skin biopsy'.)
Direct immunofluorescence — In order to perform direct

immunofluorescence, a small biopsy (eg, 4 mm punch) is taken from perilesional skin (clinically
normal appearing skin immediately adjacent to a lesion) and sent to an immunopathology laboratory
in a preservative such as Michel's or Zeus medium or as a flash-frozen specimen. In situations in
which the specimen can be delivered to the laboratory within minutes, transport on saline-moistened
gauze is an alternative. Specimens for direct immunofluorescence should not be placed in formalin.
(See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
The diagnostic finding of LABD via direct immunofluorescence is a linear band of IgA at the
dermoepidermal junction (picture 6) [7]. Utilization of the salt-split skin technique is not particularly
useful for diagnosis since testing reveals variable results [15,91]. Antibody binding to the epidermal
side of the induced cleavage zone is most common; binding to the dermal side may be more likely to
occur in patients who are older or who have both IgA and IgG deposits at the epidermal basement
2395
membrane zone [15]. Binding to both epidermal and dermal sides of the plane of cleavage may also
occur. (See "Approach to the patient with cutaneous blisters", section on 'Basement membrane zone-
split skin technique'.)
Indirect immunofluorescence — Indirect immunofluorescence

can be used to detect circulating IgA antibodies against basement membrane zone components and
may aid in diagnosis when a skin biopsy is not possible. This test is less likely to be positive in
adults than in children (30 versus ≥75 percent of patients) [4,23]. For best results, indirect
immunofluorescence should be performed on a substrate of salt-split human skin [8,91]. In the vast
majority of cases, indirect immunofluorescence studies reveal antibody bound to the epidermal side
of salt-split skin, a finding that is consistent with the locations of the 97 kDa antigen, 120 kDa
antigen, laminin-332, and BP180 (NC16a domain) [92-94]. Type VII collagen (COL7), laminin-332, or
laminin gamma 1 may be the target antigens when antibody binding localizes to the dermal side of
salt-split skin (sublamina densa) [13]. (See 'Pathogenesis' above and "Approach to the patient with
cutaneous blisters", section on 'Indirect immunofluorescence'.)
Other tests — Other tests such as immunoelectron microscopy and immunoblotting

can also be used to confirm the diagnosis [3]. However, the cost and limited availability of these
tests limit their value in the clinical setting. We do not routinely utilize these studies for diagnosis.
DIFFERENTIAL DIAGNOSIS The acute onset of

widespread annular or arcuate blisters strongly suggests the possibility of linear IgA bullous
dermatosis (LABD) (picture 2). However, annular lesions are not always present, and multiple other
disorders share clinical features with LABD. Examples of conditions to consider in the differential
diagnosis are provided below:
●Dermatitis herpetiformis – Dermatitis herpetiformis is an autoimmune subepidermal blistering

disorder with clinical and histopathologic features that can closely resemble LABD. Patients typically
present with grouped vesicles or bullae on the scalp, extensor extremities, or buttocks (picture 7).
Direct immunofluorescence microscopy is useful for distinguishing these disorders. (See "Dermatitis
herpetiformis".)
●Bullous impetigo – Bullous impetigo is a Staphylococcus aureus infection that most commonly
occurs in young children. Multiple, easily-ruptured bullae with clear or yellow fluid are typically
present on the face, trunk, or extremities (picture 8). A collarette of scale often remains at the site of
ruptured lesions. A culture of the fluid from an intact blister can be used to detect S. aureus. (See
"Impetigo", section on 'Bullous impetigo'.)
●Bullous pemphigoid – Bullous pemphigoid is an autoimmune subepidermal blistering disorder that

typically affects older adults and manifests as pruritic inflammatory plaques and bullae that are
primarily distributed on the trunk and extremities (picture 9A-C). Histopathologic examination
usually reveals a higher proportion of eosinophils than are present in LABD. Direct
2396
immunofluorescence in bullous pemphigoid usually reveals linear IgG and C3 deposits at the
basement membrane zone. (See "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Bullous pemphigoid'.)
●Pemphigoid gestationis –Pemphigoid gestationis is an autoimmune subepidermal blistering

disorder that occurs in pregnant women. The pruritic eruption frequently begins around the
umbilicus and subsequently spreads elsewhere (picture 10A-C). Direct immunofluorescence
microscopy reveals the deposition of C3 in a linear pattern at the basement membrane zone. (See
"Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)
●Bullous lupus erythematosus – Bullous lupus erythematosus is a rare subepidermal blistering

disorder. The presence of a bullous disorder in a patient with systemic lupus erythematosus
suggests the possibility of this disease. (See "Overview of cutaneous lupus erythematosus", section
on 'Bullous cutaneous lupus erythematosus'.)
●Epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare acquired subepidermal

blistering disorder of the skin and mucous membranes (picture 11). Scarring and milia are common
associated features. On direct immunofluorescence, deposits of IgG are most commonly detected at
the basement membrane zone; however, less commonly, other immunoglobulins (including IgA) may
be present. (See "Epidermolysis bullosa acquisita".)
●Mucous membrane pemphigoid – Mucous membrane pemphigoid consists of a group of

subepidermal blistering disorders in which mucosal surfaces are the primary site of involvement.
Mucosal-predominant LABD may be considered a form of mucous membrane pemphigoid. The
immunofluorescence findings distinguish this subtype from other disorders. (See "Clinical features
and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucous
membrane pemphigoid'.)
Infrequently, LABD may resemble prurigo nodularis [31], morbilliform drug eruptions [46], erythema
multiforme [47], or toxic epidermal necrolysis (TEN) [44,45]. In addition, LABD in children may be
mistaken for child abuse. (See 'Cutaneous lesions' above and 'Drug-induced linear IgA' above.)
THERAPY Data on the treatment options for linear IgA bullous dermatosis (LABD)
are limited. The approach to treatment is primarily based upon case reports and case series.
First-line therapy — Dapsone, an immunomodulatory sulfone that has been

successfully utilized for the treatment of multiple dermatologic disorders characterized by
neutrophilic infiltrates, is considered first-line treatment for LABD [3,4,7,8,95]. Dapsone has a long
history of successful use in LABD and dermatitis herpetiformis, and is well tolerated by most
patients.
2397
Dapsone — Although no controlled trials have evaluated the efficacy of dapsone in children
and adults with LABD, based upon case series, case reports, and clinical observations, the drug
appears to be effective in many patients [15,31,33,96-100]. As an example, in a retrospective study in
which 19 children received dapsone (1 to 2 mg/kg per day) as monotherapy, 11 patients (61 percent)
attained lesion regression within 8 to 15 days [33].
Dapsone is started at a low dose (eg, <0.5 mg/kg per day in children or 25 or 50 mg per day in
adults) that is titrated upward over several weeks as tolerated and in accordance with treatment
response [101]. In LABD, the response to treatment can be dramatic, with signs of improvement
noted within the first few days of therapy.
Typical dose ranges for dapsone therapy for LABD are listed below:
●Children –0.5 to 2 mg/kg per day [21,33,102]
●Adults –50 to 150 mg per day [8,95]
Although most patients tolerate the drug well, dapsone must be administered with caution, since
potential serious adverse effects, such as hemolysis, methemoglobinemia, agranulocytosis,
hypersensitivity syndrome, and peripheral motor neuropathy may occur as a result of therapy.
Hemolysis occurs to some degree in all patients, and frequent hematologic monitoring during the
early stages of treatment is recommended.
A complete blood count (CBC) with differential, liver function tests and glucose-6-phosphate
dehydrogenase (G6PD) level should be obtained prior to the initiation of dapsone. We typically follow
the CBC with differential weekly for one month, and then decrease the frequency to every two weeks
for an additional eight weeks. Liver function tests should be monitored monthly for first three
months. For long-term monitoring we recommend obtaining a CBC with differential, renal function
tests, and liver function tests every three to four months.
Screening for glucose-6-phosphate (G6PD) deficiency should be performed prior to the initiation of
dapsone therapy. The administration of dapsone should be avoided in patients with G6PD deficiency
since this disorder is associated with an elevated risk for the development of severe hemolytic
anemia. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD)
deficiency", section on 'Acute hemolytic anemia' and "Diagnosis and management of glucose-6-
phosphate dehydrogenase (G6PD) deficiency", section on 'Screening tests'.)
Topical corticosteroids — Although some authors have suggested that topical

corticosteroids may be sufficient for disease control in patients with mild or localized LABD [95,103],
most patients require systemic therapy to adequately control the disease. Thus, topical
corticosteroids are primarily used as adjunctive therapy.
High potency or superpotent topical corticosteroids applied to individual lesions once or twice daily
for up to two weeks may be utilized to accelerate improvement in lesions on the trunk or extremities.
Low potency agents are preferred for lesions on the face, genital, or intertriginous regions due to an
2398
increased risk for corticosteroid-induced cutaneous atrophy in these areas. (See "Topical
Second-line therapy — Patients who cannot tolerate dapsone may benefit

from treatment with sulfapyridine or sulfamethoxypyridazine, sulfonamide agents that have
structural similarities with dapsone [7]. Colchicine is an additional therapeutic option.
Sulfonamides — Evidence for the efficacy of sulfapyridine and sulfamethoxypyridazine

are primarily limited to reports of expert clinical experience [3,7,8,101,104]. Formal therapeutic trials
of these agents to confirm efficacy in LABD have not been performed. In one series,
sulfamethoxypyridazine monotherapy (1000 mg per day) was associated with the attainment of
disease control in three patients with LABD who discontinued dapsone due to a failure to tolerate
therapy [104]. None of these patients were young children.
Adults with LABD may be treated with 1000 to 1500 mg per day of sulfapyridine or
sulfamethoxypyridazine [8]. Children have been treated with 15 to 60 mg/kg per day of sulfapyridine
[3,7]. An appropriate dose range has not been established for sulfamethoxypyridazine treatment in
children [3]. These agents have also been used in combination with dapsone in patients with LABD
[7,104,105].
The availability of these agents is limited in some countries. In the United States, sulfapyridine can
be obtained through compounding pharmacies, and sulfamethoxypyridazine is not available. The
side effect profile of sulfapyridine is similar to dapsone, but the toxicity is less, a feature that makes
use of this agent possible in patients with dapsone intolerance [106]. Alveolitis is an additional side
effect that has been reported in patients treated with sulfamethoxypyridazine [104,107].
Monitoring guidelines for sulfapyridine and sulfamethoxypyridazine have not been established.
During treatment with sulfapyridine, we typically obtain a CBC every three to six months to evaluate
for leukopenia.
Colchicine — Successful treatment of childhood LABD with colchicine has been

documented in case reports and small case series and this agent may be another reasonable option
for children who cannot tolerate dapsone [97,108-111]. In a series of eight children with systemic
glucocorticoid-refractory LABD, the addition of colchicine to glucocorticoid therapy led to dramatic
responses to therapy in five patients within four to six weeks. In addition, these patients tolerated
tapering and discontinuation of glucocorticoid therapy.
Colchicine has also been reported to be effective in a few adults with generalized or localized LABD
[27,112]. However, the clinical experiences of some authors with adult patients have been less
favorable [8].
The typical dosage for colchicine is 0.6 mg twice daily in children and 0.6 to 1 mg two to three times
daily in adults [3,4,108,109].
2399
Severe and refractory disease — Immunosuppressive agents
may be beneficial in patients with severe clinical manifestations or refractory disease.
Immunosuppressants — Systemic glucocorticoids (eg, 0.5 to 1 mg/kg per day of

prednisone) may be used during the initial few weeks of treatment to accelerate improvement in
patients with severe involvement while awaiting the response to dapsone [8,33,95,97].
Patients who fail to respond sufficiently to dapsone may also derive benefit from the addition of
systemic glucocorticoids to dapsone therapy [8,98-101,113]. However, due to the potential adverse
effects of systemic glucocorticoids, these agents are not recommended for long-term use.
Glucocorticoid-sparing agents, such as mycophenolate mofetil [114-118], cyclophosphamide, and
cyclosporine [119], have been reported to be effective in small numbers of patients and can be
utilized. Cyclophosphamide may be considered in patients with severe mucosal involvement [120].
Other interventions — Intravenous immunoglobulin [24,121-126] and

immunoadsorption [127] have been reported to be effective in a few patients with LABD. Rituximab
and anti-tumor necrosis factor (TNF)-alpha inhibitors have been used for patients with recalcitrant
disease unresponsive to standard treatment [120]. Further studies are necessary to evaluate the
efficacy of these interventions prior to a recommendation for their routine use in severe or refractory
LABD.
Additional therapeutic options — Antibiotic therapy, tetracycline

in combination with nicotinamide, and topical tacrolimus are utilized less frequently than dapsone
for the treatment of LABD, but have been reported to be effective in small numbers of patients.
Additional studies are necessary to confirm the efficacy of these therapies.
Systemic antibiotics — Case reports and small case series suggest that systemic
antibiotics may be of benefit for childhood LABD. Whether anti-inflammatory, antibacterial, or other
properties of these agents contribute to treatment efficacy is unknown.
In a series of seven children with LABD treated with flucloxacillin, disease clearance was achieved in
all patients, but only four patients who received treatment early in the course of the disease (within
one month of disease onset) had long-lasting remission off of therapy [81]. Oxacillin [33],
dicloxacillin [128], erythromycin [98], and miocamycin [129], all given at doses of 50 mg/kg per day,
have additionally been reported to be of benefit in individual children [130]. Erythromycin may also
have been effective in an adult [131]. Trimethoprim-sulfamethoxazole has been associated with both
the induction and remission of LABD [18,132-134].
2400
Tetracycline and nicotinamide — Tetracycline (1000 to 1500 mg per day)
plus nicotinamide (900 to 2000 mg per day), a drug combination that has been used for the
treatment of bullous pemphigoid, was reported to induce disease clearance within a few weeks in
three adult patients with LABD [135-137]. Of note, tetracycline cannot be utilized in children under
the age of nine due to the drug's adverse effects on developing teeth.
Topical tacrolimus — Treatment with tacrolimus ointment, a topical calcineurin

inhibitor, has been attempted in LABD. Disease resolution was observed in a child on dapsone
therapy two weeks after her adjunctive topical therapy was changed from betamethasone
dipropionate 0.05% to tacrolimus 0.03% ointment applied twice daily [138]. However, spontaneous
resolution may also have accounted for the resolution of the disease.
Drug-induced disease — Drug-induced LABD typically resolves with

withdrawal of the offending agent (see 'Prognosis and cessation of therapy' below). In severe or
persistent cases, treatment with prednisone and/or dapsone may be beneficial. Therapy should be
tapered or discontinued early in the course of treatment (eg, within the first four to six weeks) to
confirm the presence of active disease that necessitates the continuation of systemic treatment.
Prolonged systemic treatment is rarely needed. A report describes a patient with severe drug-
induced LABD with toxic epidermal necrolysis (TEN)-like presentation who improved with cessation
of the offending medication and initiation of etanercept, an anti-TNF agent [139].
PROGNOSIS AND CESSATION OF

THERAPY Idiopathic linear IgA bullous dermatosis (LABD) typically persists for
months to several years prior to spontaneous resolution, and resolves in most children prior to
puberty [2,4,113]. However, disease may persist for a decade or longer, and relapses after long
periods of remission may occur [113]. A review of 72 adults with LABD found that older patients (>70
years) without mucosal involvement were most likely to experience a complete remission [120]. Even
within this group relapses are common, and a chronic course was seen in 64 percent of all LABD
patients [120]. In contrast, in drug-induced LABD, cessation of new lesion formation typically occurs
within three days of removal of the inciting agent and disease resolution usually occurs within
several weeks [52].
The duration of treatment required for idiopathic LABD is variable. It is important to recognize
patients at high risk for a chronic, recalcitrant course (those with mucosal involvement and less than
70 years of age) when selecting treatment and determining treatment duration. Treatment with an
effective agent is usually continued for several weeks after complete remission is attained. A
negative direct immunofluorescence in areas of prior involvement may provide further support that a
gradual tapering towards treatment cessation is reasonable [8,113,120]. If relapse occurs after
treatment cessation, treatment should be reinitiated [113].
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Although cutaneous lesions usually heal without permanent scars, patients with mucosal
involvement may experience morbidity and functional limitations due to stricture formation or
conjunctival and corneal scarring. Consequences related to poor oral hygiene and alimentation may
also occur in patients with oral disease. (See 'Mucosal involvement' above.)
INDICATIONS FOR REFERRAL A dermatologist

or another clinician familiar with the management of LABD should be involved in the care of these
patients. Patients with signs or symptoms of ocular disease should be referred to an
ophthalmologist. In addition, consultation with an otolaryngologist or gastroenterologist is
appropriate for patients with symptoms suggestive of pharyngeal, laryngeal, or esophageal disease.
SUMMARY AND
RECOMMENDATIONS
●Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder that usually
presents with the abrupt onset of tense bullae and inflammatory lesions on the skin. Both children
and adults may be affected. (See 'Epidemiology' above.)
●Most cases of LABD are idiopathic. However, LABD has also been reported in association with drug
exposure. Vancomycin is the pharmacologic agent most frequently associated with LABD. (See 'Risk
factors' above and 'Drug-induced linear IgA' above.)
●Children with LABD frequently develop widespread annular or arciform blisters that are often most
abundant on the groin, lower abdomen, and medial thighs. In adults, the annular lesions are less
commonly detected, and the trunk and extremities are typical sites of involvement. Pruritus is a
common symptom of LABD. (See 'Cutaneous lesions' above.)
●Mucosal involvement in LABD may affect any mucosal site. Examples of potential serious
consequences of mucosal involvement include blindness, airway obstruction, and esophageal
strictures. (See 'Mucosal involvement' above.)
●The gold standard for the diagnosis of LABD is the detection of linear deposits of IgA with direct
immunofluorescence microscopy. The tissue specimen for direct immunofluorescence should be
taken from perilesional skin. The specimen must not be placed in formalin. (See 'Diagnosis' above
and "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
●Data on the treatment options for LABD are primarily limited to case reports and case series. For
children and adults with LABD, we suggest the use of dapsone as first-line therapy (Grade 2C). The
response to therapy is usually evident within days. Sulfapyridine, sulfamethoxypyridazine, and
colchicine are additional options for patients who cannot tolerate dapsone therapy. (See 'Therapy'
above.)
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●Immunosuppressive therapy may be employed for patients with LABD that is refractory to dapsone
or sulfonamide therapy. Use of a glucocorticoid-sparing agent such as mycophenolate mofetil is
recommended when long-term immunosuppression is required. (See 'Severe and refractory disease'
above.)
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Evaluation and diagnosis of hair loss
uptodate.com/contents/evaluation-and-diagnosis-of-hair-loss/print
INTRODUCTION "Hair loss" is a common clinical complaint that is a

manifestation of a wide variety of disorders. Although the cause of hair loss is easily diagnosed in
some cases, such as in patients who present with classic male pattern hair loss or patchy hair loss
due to alopecia areata, the diagnosis of hair loss also can be challenging.
An overview of the basic principles of hair biology, potential causes of hair loss, and the assessment
of patients who present with a complaint of hair loss is provided here. Specific types of hair
disorders are reviewed in greater detail separately.
●(See "Acne keloidalis nuchae".)
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●(See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis".)
●(See "Central centrifugal cicatricial alopecia".)
●(See "Alopecia related to systemic cancer therapy".)
●(See "Alopecia areata: Clinical manifestations and diagnosis".)
●(See "Dissecting cellulitis of the scalp".)
and diagnosis".)
●(See "Folliculitis decalvans".)
●(See "Lichen planopilaris".)
●(See "Telogen effluvium".)
●(See "Tinea capitis".)
●(See "Traction alopecia".)
HAIR BIOLOGY
Anatomy — The human scalp contains approximately 100,000 to 150,000 hair follicles [1].
Each hair follicle sits above a dermal papilla, a collection of mesenchymal tissue with inductive
properties (figure 1). The dermal papilla induces the development of hair follicles in the fetus and
appears to play an important role in follicular cycling and hair growth [2]. (See 'Hair cycle' below.)
Hair follicles consist of four segments: the bulb, suprabulbar region, isthmus, and infundibulum
(figure 1) [3]. The bulb, the lowest portion of the hair follicle, is the site of the hair matrix, a group of
rapidly proliferating keratinocytes responsible for the production of hair [2]. The suprabulbar region
of the follicle extends from the bulb to the isthmus, which is the portion of the follicle between the
insertion of the arrector pili muscle and the insertion of the sebaceous gland. The uppermost portion
of the follicle, the infundibulum, extends from the insertion of the sebaceous gland to the
interfollicular epithelium.
The hair shaft is a layered structure that consists of three major components. The medulla, the
innermost layer, is surrounded by the cortex and cuticle. Between the hair bulb and the isthmus, the
hair shaft is surrounded by the inner root sheath, a structure that is composed of the cuticle of the
inner root sheath, Huxley layer, Henle layer, and companion layer. The inner root sheath plays an
important role in the shaping of the hair shaft [2]. The outer root sheath surrounds both the inner
root sheath and the hair shaft and extends from the hair bulb to the epidermis. The outer root sheath
and each of the components of the hair shaft and inner root sheath have distinct keratin profiles [4].
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A region near the insertion of the arrector pili muscle, referred to as the bulge region of the hair
follicle, has been identified as a site that harbors hair follicle stem cells that are essential for
follicular cycling and hair growth [5]. The loss of the hair follicle stem cells in the bulge is postulated
to contribute to permanent loss of hair in cicatricial alopecias (see 'Cicatricial alopecia' below) [5,6].
Mouse studies have demonstrated that hair follicle stem cells may also support wound healing by
contributing to repopulation of interfollicular epithelial cells [7].
Hair types — The two major types of hair follicles on the human body are terminal hair
follicles and vellus hair follicles. Terminal hair follicles are larger than vellus hair follicles and extend
into the subcutaneous fat (2 to 5 mm from the skin surface) during hair growth. In contrast, the
lowest portions of vellus hair follicles generally extend only into the reticular dermis. Hairs produced
by terminal hair follicles are usually at least 0.06 mm in diameter while vellus hairs are short, fine,
and usually less than 0.03 mm in diameter [8]. The term "intermediate hairs" has been used to
describe hairs with characteristics that are between vellus and terminal hairs (0.03 to 0.06 mm)
[9,10].
At birth, terminal hairs are found on the scalp, eyebrows, and eyelashes, and vellus hairs populate
the remaining hair-bearing areas. During puberty, vellus hairs in certain areas, such as the genital
area and axilla, are stimulated to become terminal hairs. Transitioning between terminal and vellus
hair follicles may also occur in pathologic states. Abnormal transitioning of vellus hairs to terminal
hairs occurs in hirsutism in women, and transitioning of terminal hairs to vellus hairs (follicular
miniaturization) is a classic feature of androgenetic alopecia. (See "Pathophysiology and causes of
hirsutism" and "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis" and
diagnosis".)
Hair cycle — Once formed, hair follicles undergo lifelong cycling characterized by periods
of growth (anagen), transformation (catagen), and rest (telogen). In humans, hair cycling is not
synchronous, meaning that individual follicles cycle independently, preventing en mass shedding of
hair. Although the lower portion of the hair follicle undergoes growth and regression during cycling,
the isthmus and infundibulum remain stable.
●Anagen – At any given time, approximately 90 percent of scalp hair follicles are in the anagen
phase [11]. The rate of hair growth and the duration of anagen vary with the type of hair and location.
On the scalp, the growth rate of terminal hair is approximately 0.3 mm per day and the duration of
anagen ranges from two to six years [9,11]. In contrast, eyebrow hair grows only at a rate of 0.1 mm
per day and has an anagen phase of two to three months [2,9]. The abbreviated anagen phase
accounts for the relatively short maximum length of eyebrow hair. Similarly, a short anagen phase is
responsible for the short maximum length of vellus hairs (typically less than 20 mm) [8].
●Catagen –During catagen, the lower portion of the hair follicle regresses and hair production
ceases. The deepest part of the hair follicle tracts upward toward the isthmus, and the dermal papilla
migrates from within the subcutaneous fat into the reticular dermis. The duration of catagen on the
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scalp is usually around three weeks [9]. Less than 1 percent of follicles on the scalp are in catagen
[11].
●Telogen – The telogen phase, also known as the resting phase, follows catagen and lasts for two
to three months on the scalp [11]. Normally, up to 10 percent of scalp follicles are in telogen [11].
Telogen is characterized by the presence of a club hair (a fully keratinized hair with a club-shaped
proximal end) that is ready for shedding from the hair follicle (figure 2) [2]. The term "exogen" has
been used to describe the exact time point at which the hair is shed. Normally, between 50 and 150
telogen hairs are shed per day [2].
Anagen follows the telogen phase, resulting in the production of a new hair. Prolongation of the
telogen phase, as may occur in telogen effluvium, can result in a reduction in hair density due to a
failure of follicles to reenter anagen following shedding. The term "kenogen" has been used to
describe a delay in the entry into anagen following shedding of a telogen hair [12].
CLASSIFICATION Hair loss disorders are a large, heterogenous group

of conditions that have various clinical features, pathologic findings, and etiologies. Hair loss may
occur due to disorders of hair cycling, inflammatory conditions that damage hair follicles, or
inherited or acquired abnormalities in hair shafts.
The major dividing lines for the various forms of hair loss are the distinction between cicatricial
(scarring) alopecia, nonscarring alopecia, and structural hair disorders. Cicatricial alopecias are
conditions that lead to the irreversible cessation of hair cycling and permanent hair loss. As noted
above, the loss of hair follicle stem cells in the bulge region of the hair follicle is thought to
contribute to the development of cicatricial alopecia (see 'Anatomy' above). In nonscarring
alopecias, the hair follicle is not permanently damaged, making spontaneous or treatment-induced
regrowth a possibility. Structural hair disorders that lead to hair loss demonstrate abnormalities
within the hair shafts that result in hair fragility. (See 'Scalp and hair examination' below.)
Cicatricial alopecia — Primary cicatricial alopecias are inflammatory disorders

of the scalp that lead to permanent hair loss. The primary cicatricial alopecias are subdivided by the
type of inflammation detected on histologic examination. The three major classes are lymphocytic
primary cicatricial alopecias, neutrophilic primary cicatricial alopecias, and mixed primary cicatricial
alopecias [13].
Examples of the primary cicatricial alopecias are provided below. A summary of the clinical and
histologic features of the cicatricial alopecias is provided in a table (table 1A).
●Lymphocytic primary cicatricial alopecia
•Alopecia mucinosa –Alopecia mucinosa (also known as follicular mucinosis) may result in scarring
or nonscarring alopecia. Permanent hair loss results from the replacement of hair follicles by mucin,
rather than from fibrosis. Patients usually present with erythematous or skin-colored indurated
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plaques of alopecia on the face or scalp (picture 1). Follicular papules may also be present.
Two types of alopecia mucinosa have been described, idiopathic alopecia mucinosa and alopecia
mucinosa that occurs as a manifestation of mycosis fungoides or cutaneous T cell lymphoma.
However, some authors believe that these disorders may represent aspects of a single disease
spectrum [14]. Whether all cases designated as idiopathic alopecia mucinosa are actually indolent
forms of mycosis fungoides remains uncertain [15]. (See "Clinical manifestations, pathologic
features, and diagnosis of mycosis fungoides".)
•Central centrifugal cicatricial alopecia – Central centrifugal cicatricial alopecia is a form of

cicatricial alopecia that primarily affects women of African descent. Alopecia occurs on the crown of
the scalp and gradually progresses in a centrifugal manner to the parietal areas (picture 2).
Perifollicular hyperpigmentation and the emergence of multiple hairs from a single follicle may be
present. Symptoms may include itching, tenderness, or prickling sensations [14]. (See "Central
•Discoid lupus erythematosus – Discoid lupus erythematosus (also known as a form of chronic
cutaneous lupus erythematosus) may occur in the absence of systemic disease but may also occur
in the setting of systemic lupus erythematosus. Patients typically present with well-demarcated
inflammatory plaques that develop into atrophic scars (picture 3A-B). Follicular hyperkeratosis
(follicular plugging, aka patulous follicles), telangiectasias, hypopigmentation, and
hyperpigmentation are common clinical features [16]. When the scalp seems to be the primary site
of involvement, examination of the conchal bowls for patulous follicles can aid in differentiating
discoid lupus erythematosus from other forms of scarring alopecia. (See "Overview of cutaneous
lupus erythematosus", section on 'Discoid lupus erythematosus'.)
•Keratosis follicularis spinulosa decalvans (KFSD) –Keratosis follicularis spinulosa decalvans is a

rare genetic disorder that commonly is associated with a mutation in the membrane-bound
transcription factor protease site 2 (MBTPS2) gene on the X-chromosome (MIM #308800) [17].
Familial cases of KFSD that demonstrate an autosomal dominant inheritance pattern have also been
reported (MIM #612843) [18,19]. Patients first present in infancy with follicular papules with
keratotic spines on the scalp. Eyebrow, eyelash, and other involvement of hair-bearing skin may
develop (picture 4A-B). Photophobia is common [18]. Progression of the disease improves during
puberty, leaving atrophic scars. (See "Keratosis pilaris atrophicans", section on 'Keratosis follicularis
spinulosa decalvans'.)
•Lichen planopilaris – Lichen planopilaris is a follicular variant of lichen planus that typically
manifests with perifollicular erythema and follicular hyperkeratosis (picture 5A-B) [20]. The areas of
alopecia may be discrete or confluent, especially on the crown. Itching, burning, pain, or skin
sensitivity are often present. (See "Lichen planopilaris".)
•Frontal fibrosing alopecia – In this disorder, patients present with band-like alopecia affecting the
frontal scalp. Follicular hyperkeratosis and perifollicular erythema may be seen. Concomitant
eyebrow involvement is common and may precede the hair loss [21]. Facial involvement may
2408
manifest as small rough follicular papules that have a predilection for the temporal area [22]. (See
"Lichen planopilaris", section on 'Frontal fibrosing alopecia'.)
•Pseudopelade of Brocq –Pseudopelade of Brocq is an idiopathic cicatricial alopecia that presents

with small, skin-colored patches of alopecia on the scalp [16]. The pattern of the disorder has been
described as "footprints in the snow" [23]. Follicular hyperkeratosis and erythema are minimal or
absent. Some clinicians believe pseudopelade of Brocq is a late stage of lichen planopilaris.
●Neutrophilic primary cicatricial alopecia
•Dissecting cellulitis of the scalp – Dissecting cellulitis of the scalp (also known as perifolliculitis
capitis abscedens et suffodiens of Hoffman or dissecting folliculitis) is a form of cicatricial alopecia
that may occur independently or in association with acne conglobata and hidradenitis suppurativa
as part of the "follicular occlusion triad." The condition most commonly occurs in young black men
[24]. Patients develop follicular papules, pustules, fluctuant nodules, and abscesses on the scalp
(picture 6A-B). Purulent drainage is common. Over time, hypertrophic or keloidal scars may develop.
•Folliculitis decalvans – Folliculitis decalvans often begins on the vertex of the scalp. Patches of
alopecia, inflamed papules, pustules, and follicular hyperkeratosis are common features (picture 7A-
B) [25]. Tufted folliculitis (multiple hairs emerging from a single inflamed follicle) is a characteristic
feature, but is not exclusive to this disorder. Pain, itching, and burning are common. Staphylococcus
aureus colonization and a defect in host cell-mediated immunity may be contributing factors [25].
(See "Folliculitis decalvans".)
●Mixed
•Acne keloidalis nuchae – Acne keloidalis nuchae primarily occurs in young black men [26]. Affected
patients present with dome-shaped follicular papules, pustules, and plaques on the occipital scalp
(picture 8). Keloid-like plaques also may develop. (See "Acne keloidalis nuchae".)
•Acne necrotica –Acne necrotica is a rare form of cicatricial alopecia that is characterized by the
development of umbilicated papules on the scalp that undergo central necrosis. Patients usually
experience pruritus or pain. Individual lesions resolve with small varioliform or pox-like scars [27,28].
•Erosive pustular dermatosis of the scalp –Erosive pustular dermatosis of the scalp is a rare
disorder that primarily occurs in older adults. The condition often develops after trauma or surgery
on the scalp [29,30]. It may also develop after treatment of actinic keratoses with topical agents or
photodynamic therapy [31]. Patients develop sterile pustules, erosions, and crusted plaques on the
scalp that lead to scarring (picture 9) [29,30].
A wide variety of conditions or events may cause secondary cicatricial alopecia. Inflammation from
a condition that is not a primary scalp disease and physical trauma are potential causes. Examples
include tinea capitis, neoplasms, radiation therapy, and surgical scars. (See "Tinea capitis".)
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Nonscarring alopecia — In nonscarring alopecias, clinical signs of
inflammation are usually mild or absent and destruction of the hair follicle does not occur.
Recognition of the distribution of nonscarring alopecia is useful for narrowing the differential
diagnosis (table 1B).
●Focal hair loss
•Alopecia areata – Alopecia areata is a relatively common form of nonscarring alopecia in which an
autoimmune process contributes to the loss of hair on the scalp or other areas. Most frequently, hair
loss occurs in patches (picture 10A-B). Another common pattern is loss at the occipital scalp
margin, called ophiasis. Occasionally, alopecia areata progresses to loss of all scalp or body hair. A
diffuse variant of alopecia areata that manifests with diffuse hair thinning also occurs. (See
•Alopecia syphilitica – Secondary syphilis can present with patchy hair loss on the scalp, which has
been described as "moth-eaten" alopecia (picture 11). Hair loss may also occur in other sites. (See
•Pressure-induced (postoperative) alopecia –Pressure-induced alopecia describes transient hair

loss that occurs in areas of prolonged pressure on the scalp, as may occur during general
anesthesia for long operative procedures [32,33]. Hair loss usually develops a few weeks after the
event. Regrowth occurs in most patients.
•Temporal triangular alopecia –Temporal triangular alopecia (also known as congenital triangular
alopecia) is a lifelong condition that is usually first noted in infancy or childhood as a triangular or
oval patch of alopecia in the temporal area (picture 12) [34,35]. The area of involvement is usually
only a few centimeters in diameter. Most cases are unilateral, though bilateral involvement may also
occur. Fine vellus hairs are visible in the affected area with close inspection. Hair transplantation is
an effective treatment [36,37].
•Traction alopecia – Traction alopecia results from prolonged pull or tension on the hair follicle,
usually due to hairstyles such as tight ponytails or braids. Traction alopecia from braids or hair
weaves is most commonly detected along the frontal and temporal hair lines (picture 13).
Longstanding traction can result in a transition to cicatricial alopecia with permanent hair loss. (See
"Traction alopecia".)
●Patterned
•Androgenetic alopecia in men (male pattern hair loss) – Androgenetic alopecia in men is
characterized by the slow, progressive loss of hair in a characteristic distribution (picture 14A-C).
The condition is mediated by the action of androgens on androgen-sensitive hair follicles in
genetically susceptible males. (See "Androgenetic alopecia in men: Pathogenesis, clinical features,
and diagnosis".)
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•Female pattern hair loss – Female pattern hair loss most frequently presents as hair thinning on the
frontal and crown areas of the scalp with relative sparing of the occipital scalp (picture 15A-B). The
frequency of this condition increases with age. (See "Female pattern hair loss (androgenetic
alopecia in women): Pathogenesis, clinical features, and diagnosis".)
•Trichotillomania –Trichotillomania is a disorder in which individuals repeatedly pluck hairs from the
scalp or other hair-bearing areas (picture 16A-C) [38]. The areas of alopecia may have irregular,
bizarre shapes.
●Diffuse
•Anagen effluvium –Anagen effluvium occurs as a result of an acute interruption of the anagen
phase and leads to extensive hair loss without transition of follicles into the catagen or telogen
phase. Hair loss typically occurs within two weeks of an inciting event. Chemotherapeutic agents are
a major cause of anagen effluvium. (See "Alopecia related to systemic cancer therapy".)
•Loose anagen syndrome –Loose anagen syndrome usually presents in young children (ages two to
five years) as slowly growing hair that can easily be pulled out without pain [39]. The hair density
may appear normal or reduced (picture 17). Affected children are often females with blond hair.
Loose anagen syndrome is characterized by the light microscopic finding of anagen hairs with a
ruffled cuticle and an absent inner root sheath (picture 18). The condition often improves with age
and may be sporadic or familial.
•Telogen effluvium –Telogen effluvium is a common cause of diffuse hair loss that usually presents
with acute or chronic loss of hair due to an abrupt shift of numerous hair follicles in anagen to the
telogen phase (picture 19A-B). Chronic telogen effluvium may also occur. Examples of factors that
may stimulate acute telogen effluvium include major physical or psychologic stressors, childbirth,
dietary restriction, and medications. Hair loss usually occurs two to three months after the inciting
event. Arsenic, thallium, or mercury poisoning can also result in telogen effluvium [40]. (See 'Medical
and family history' below.)
•Other –Alopecia areata and female pattern hair loss may present with diffuse hair thinning.
Additional rare causes of diffuse nonscarring hair loss include atrichia with papular lesions (MIM
#209500), a condition caused by a mutation in the hairless gene that results in hair loss within the
first year of life (picture 20) [41], and hypotrichosis simplex. Hypotrichosis simplex consists of a
group of hereditary alopecias in which diffuse hair loss usually begins in early childhood and
progresses until adulthood [42]. Multiple gene mutations have been linked to this condition [42].
Nonscarring alopecia may also occur as a direct consequence of scalp involvement with acute or
chronic inflammatory skin diseases. As examples, psoriasis, atopic dermatitis, seborrheic dermatitis,
and contact dermatitis may result in focal or diffuse hair loss. In addition, patients with systemic
lupus erythematosus may develop "lupus hair," which is described by dry, coarse hair along the
frontal hair line that usually occurs in association with disease flares [43]. Patients with systemic
lupus erythematosus may also develop telogen effluvium as a consequence of disease
exacerbations or medical treatments [43].
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Inherited and acquired structural hair
disorders — Structural hair abnormalities that result in brittle or fragile hair can lead to
hair breakage or the appearance of a failure of hair to grow. The hair fragility may result from
abnormal hair formation or external insults that damage the hair shaft. The most common structural
hair abnormalities are acquired trichorrhexis nodosa and trichoptilosis, both of which may occur as
a result of harmful hair care practices, such as chemical processing, excessive brushing or teasing
of hair, or the application of excessive heat. Trichorrhexis nodosa is characterized by disruption of
the protective cuticle and fraying of the hair shaft (picture 21A). Trichoptilosis is a term that
describes splitting and fraying of the distal end of the hair shaft, which is commonly referred to as
"split ends." Bubble hair (bubble-like structures within the hair shaft) is another microscopic finding
that may be seen in heat-damaged hair.
Examples of genetic conditions that cause hair fragility and excessive hair breakage include:
●Menkes disease –Patients with Menkes disease (MIM #309400), an X-linked disorder associated
with a defect in copper transport, develop hair fragility that is most prominent during childhood. The
mutation is in the gene encoding a copper transporting ATPase (ATP7A) [44]. Sparse, short, and
brittle hair with a kinky or steel wool-like quality is present (picture 22). Microscopic examination of
the hair shaft reveals pili torti (flattened, twisted hair) (picture 21C). Pili torti may also be seen as an
isolated congenital disorder or a manifestation of other genetic conditions.(See "Overview of dietary
trace elements", section on 'Menkes disease'.)
●Monilethrix –Monilethrix (MIM #158000) is a genetic condition that is usually associated with an
autosomal dominant pattern of inheritance. Most cases occur due to mutations in the hair cortex
keratin genes, KRT81, KRT83, or KRT86 [45]. Patients present with short, brittle hair (picture 23).
Microscopic examination of the hair shaft reveals elliptical nodes, resulting in a beaded appearance
(picture 21D). Examples of other potential findings in monilethrix include brittle nails, keratosis
pilaris, cataracts, and tooth abnormalities.
●Trichothiodystrophy –Trichothiodystrophy (MIM #601675) is an autosomal recessive disorder that

manifests with sulfur-deficient, short, brittle hair (picture 24). Microscopic examination of the hair
reveals trichoschisis (transverse fractures of hair) (picture 21B). Examination of the hair shaft under
polarized light demonstrates alternating light and dark bands that resemble a "tiger tail" pattern.
Patients may have accompanying features such as photosensitivity, ichthyosis, intellectual
impairment, decreased fertility, and short stature. Mutations in the XPD, XPB, and p8/TTDA subunits
of the transcription/repair factor TFIIH have been linked to trichothiodystrophy with photosensitivity
[46].
●Trichorrhexis invaginata –Trichorrhexis invaginata (also known as "bamboo hair" or "ball and
socket" deformity) is a hair shaft disorder that results from intussusception within the hair shaft
(picture 21E). Trichorrhexis invaginata is a pathognomonic finding of Netherton syndrome (OMIM
#256500), but may also occur as a sporadic disorder or in combination with other hair shaft
disorders. (See "Netherton syndrome".)
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Individuals with Netherton syndrome (OMIM #256500), an autosomal recessive disorder, develop
atopy, ichthyosis (ichthyosis linearis circumflexa), and short, sparse hair (picture 25A-B). Mutations
in the SPINK5 gene encoding the serine protease inhibitor lymphoepithelial Kazal-type related
inhibitor (LEKTI) lead to this disorder [47]. Clinicians should be aware that trichorrhexis invaginata is
not evident in every hair. Multiple hairs may need to be examined before trichorrhexis invaginata is
detected.
Examples of other rare inherited conditions that may result in hair fragility include inherited
trichorrhexis nodosa, Björnstad syndrome, ectodermal dysplasias, and argininosuccinic aciduria.
Structural hair disorders may also occur without associated hair fragility. Examples include pili
annulati, uncombable hair syndrome (picture 26), and woolly hair.
PATIENT INTERVIEW The patient interview, if performed

carefully, can provide valuable clues for diagnosis. In general, the interview should include an
assessment of the nature of hair loss, the patient's medical history (including medication and
supplement use), the patient's hair care practices, and the patient's family history as it relates to hair
loss and potential causes of hair loss.
Description of hair loss — Questioning about the nature of hair loss

consists of an assessment of the course and pattern of hair loss, as well as associated symptoms.
This can be particularly helpful for narrowing the differential diagnosis in patients with physical
findings that suggest nonscarring alopecia.
●Duration and rate of progression of hair loss – Knowledge of the duration and progression of hair
loss is useful for differentiating between congenital and acquired disorders, and between acute,
chronic, or transient conditions.
●Location and pattern of hair loss –In conjunction with the physical examination, the patient's
description of the distribution of hair loss may help to distinguish focal, patterned, and diffuse hair
loss (see 'Nonscarring alopecia' above). Since some disorders characterized by scalp hair loss may
involve other hair-bearing areas, patients should also be asked about the presence of additional sites
of hair loss.
●Extent of hair loss –When evaluating patients with a complaint of diffuse hair loss, the knowledge
that normal hair loss ranges from 50 to 150 hairs per day is useful for comprehending the magnitude
of the patient's complaint [2]. Of note, for patients who shampoo hair infrequently, marked increases
in hair loss may be noted on shampoo days due to the manual dislodging of telogen hairs that would
have been progressively shed with more frequent manipulation of the hair.
Patient descriptions of physical changes noted (eg, a thinning ponytail or increased visibility of the
scalp through hair) and review of prior photographs also may be useful for assessing the degree of
hair loss. On average, a 30 percent decrease in hair density occurs before hair loss is easily
2413
appreciated by individuals other than the affected patients [43]. In particular, patients with thick,
coarse hair at baseline may not appear to have clinically concerning hair loss until a major reduction
in hair density has occurred.
●Associated symptoms –Although symptoms such as pain, tenderness, pruritus, or burning

sensations are not always consistently detected in specific types of hair loss, the recognition of
associated symptoms can be useful for supporting a diagnosis. In addition, in patients who appear
to have a form of hair loss that is typically asymptomatic, the presence of symptoms may indicate
the presence of an additional disorder (eg, pruritus from seborrheic dermatitis in a patient with
androgenetic alopecia).
●Differentiation of hair shedding from hair breakage –Patients who are focused on their hair loss
may be able to communicate information that helps to distinguish hair shed from the follicle from
hair breakage. Patients with disorders associated with shedding of telogen hairs from follicles may
describe the hair loss as occurring from "the roots," meaning that they have noticed a small white
bulb at the proximal end of lost hairs (figure 2). In contrast, the follicular portion of the hair shaft is
absent in broken hairs.
●Hair care practices – Questions about hair care practices are particularly relevant in patients with
features suggestive of hair breakage or traction alopecia. Hair care practices that damage the hair
shaft are a common cause of hair breakage and prolonged traction of hair by tight braids, ponytails,
or other means can lead to traction alopecia.
Medical and family history — Questions about the patient's medical

and family history may be useful for diagnosis. As an example, for women with clinical features
suggestive of patterned hair loss, questions about irregular menses, hirsutism, infertility, and signs
of virilization may provide clues about an underlying hormonal disorder as a contributor to the
condition. (See "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical
features, and diagnosis", section on 'Diagnosis' and "Evaluation of premenopausal women with
hirsutism" and "Diagnosis of polycystic ovary syndrome in adults".)
In addition, telogen effluvium, one of the most common causes of nonscarring hair loss, may be
induced by factors that can be detected via a medical history (see "Telogen effluvium"). Potential
contributing factors include [40]:
●Drugs(table 2)
●Poor diet (caloric or protein restriction)
●Medical disorders and medical events
•Major illness or surgeries
•Major psychologic stress
2414
•Significant weight loss
•Chronic iron deficiency
•Thyroid disorders
•Childbirth
•Poisoning from arsenic, mercury, or thallium
The clinical history may also be useful when a diagnosis that may present with associated clinical
findings is being considered. Examples of questions that may be useful include inquiries about a
history of lichen planus in a patient with lichen planopilaris and questions about a history of
hidradenitis suppurativa or severe acne in a patient with folliculitis decalvans. (See "Lichen planus",
section on 'Clinical features' and "Hidradenitis suppurativa: Pathogenesis, clinical features, and
diagnosis".)
Obtaining a family history of similar hair loss can be useful because genetics play a role in
susceptibility to multiple hair diseases. Sometimes patients will deny a family history of hair loss
because their parents were not fully bald. Asking about both hair thinning and balding is helpful for
identifying a family history of alopecia.

the patient with a complaint of scalp hair loss involves the examination of the scalp, hair, and other
body sites.
Scalp and hair examination — Ideally, the scalp and hair

examination should be performed with the patient in a position that allows the clinician to examine
the scalp from above comfortably, such as the clinician in a standing position and the patient seated
in a chair. Good lighting is essential. Examination techniques such as trichoscopy and the hair pull
test may be helpful.
Visual inspection — The first step of the physical examination consists of inspection
of the entire scalp for physical clues that may aid with diagnosis, such as erythema, scales, papules,
pustules, erosions, or excoriations. The presence or absence of follicular ostia (the pinpoint
openings from which hair emerges from the scalp) within affected areas also should be noted; a lack
of follicular ostia suggests a scarring alopecia. Among the primary cicatricial alopecias, pustules
are most likely to be seen in neutrophilic or mixed cicatricial alopecias.
The examination of the hair should include an assessment of the distribution and density of hair on
the scalp to identify the pattern and degree of hair loss. Hair density is best assessed by parting the
hair and noting the amount of space between the parts [48]. Comparing the frontal hair density to the
occipital hair density is particularly useful for female pattern hair loss. In female pattern hair loss,
2415
hair density on the frontal and vertex scalp is reduced, while hair on the occipital scalp is relatively
spared. A Christmas-tree-like pattern of hair loss (with a wider part at the frontal hairline) is often
evident in the involved area (picture 15A-B). (See "Female pattern hair loss (androgenetic alopecia in
women): Pathogenesis, clinical features, and diagnosis", section on 'Physical examination'.)
The hair shafts are then evaluated for caliber, length, shape, fragility, and texture. Distinguishing
between terminal and vellus hairs is particularly helpful for the diagnosis of male and female pattern
hair loss, disorders in which terminal hairs transition to vellus hairs. Broken hairs, which suggest a
structural hair disorder, may also be noted during this step. Hair fragility can be further assessed by
grasping a cluster of hair fibers in two places and tugging in opposite directions [48].
Features associated with certain forms of hair loss may also be detected during examination of the
hair and may aid in diagnosis. Examples include exclamation point hairs in alopecia areata (picture
27), tufted folliculitis in folliculitis decalvans and other cicatricial alopecias (picture 7B), follicular
plugging in discoid lupus erythematosus (picture 3A), and keratotic follicular papules in lichen
planopilaris (picture 5B).
A tool that can be helpful during the hair examination is a small piece of white or black paper. The
color should contrast with the color of the patient's hair (eg, white paper for a patient with dark hair).
Placing the paper behind the hairs being examined facilitates visualization of the hairs [48]. This
procedure also is helpful for differentiating the tapered tips of regrowing hairs from the blunt tips of
broken or cut hairs.
Trichoscopy — Dermoscopy, a technique in which a handheld magnifier is used to

visualize skin structures, can aid in the examination of patients with hair loss. Some devices are
equipped for photography. (See "Overview of dermoscopy".)
Dermoscopy of the hair and scalp (trichoscopy) facilitates the examination of the epidermis,
follicular ostia, hair shafts, perifollicular scale and erythema, and blood vessels [49]. Certain
dermoscopic findings have been linked to particular forms of hair loss [49-54]. (See "Overview of
Examples of trichoscopic features of follicular ostia that may aid in diagnosis include [49]:
●Absence of follicular ostia (suggests cicatricial alopecia)
●Black dots (indicates hairs broken or destroyed at the level of the scalp as may occur in alopecia
areata, dissecting cellulitis, tinea capitis, and some other disorders)
●Yellow dots (indicates accumulation of keratotic material or sebum, as may occur in alopecia
areata, discoid lupus erythematosus, male or female pattern hair loss, and some other disorders)
●Fibrotic white dots (indicates fibrosis as may occur in primary cicatricial alopecias)
Examples of hair shaft abnormalities that may be detected with trichoscopy include [49]:
2416
●Exclamation point hairs (as may occur in alopecia areata, trichotillomania, or chemotherapy-
induced alopecia) (picture 27)
●Comma or corkscrew hairs (as may occur in tinea capitis) (picture 28)
●Pohl-Pinkus constrictions (thinning of the hair shaft), as may occur in alopecia areata;
chemotherapy-induced alopecia; blood loss; malnutrition; or chronic intoxication
●Increased proportion of vellus hairs (as may occur in male or female pattern hair loss or alopecia
areata)
●Hair shaft changes correlating with genetic hair shaft disorders
Hair pull test — A hair pull test identifies active hair loss and should be performed on
every patient who presents with a complaint of hair loss. It is important to consider that patients
with hair loss may have concerns about pulling out additional hair; therefore, good communication is
essential.
To perform the test, 50 to 60 hair fibers are grasped close to the skin surface and tugged from the
proximal to the distal end. The easy extraction of more than six hair fibers suggests the presence of
active hair loss. The proximal ends of hairs obtained by the hair pull test can be microscopically
examined to determine the type of hairs removed (eg, telogen, anagen, dystrophic, or broken hairs)
(figure 2).
Examination of other sites — Some hair loss disorders are associated

with abnormalities in areas other than the scalp. Depending on the disorder, additional hair, nail, skin,
tooth, or other abnormalities may be seen. Examining the entire skin surface, nails, and teeth at the
time of the initial evaluation is useful for identifying additional sites of involvement and associated
features.
DIAGNOSTIC TECHNIQUES If the cause of hair loss

remains uncertain following the patient history and physical examination, additional tests may
assist with diagnosis. Microscopic examination of hair shafts and scalp biopsies are commonly
performed in clinical practice.
Microscopic examination — When patients present with diffuse hair

shedding, microscopic evaluation of the proximal ends of shed hairs is useful for determining the
type of hairs that are being shed (eg, telogen, anagen, or dystrophic anagen hairs). For patients with
hair breakage, microscopic examination of the hair shaft may identify structural abnormalities that
contribute to hair fragility (picture 21A-E); this is done by cutting hairs close to the scalp surface.
2417
The use of 1 to 2 drops of a mounting medium (eg, Permount) when placing the hair shafts between
a glass slide and a coverslip optimizes the examination [48]. Examinations for pili torti are an
exception; the shadows and twists of pili torti are best visualized when the hair is examined dry,
without a mounting medium [48].
Of note, microscopic examination under polarized light is necessary for visualization of the "tiger-
tail" pattern seen in patients with trichothiodystrophy. (See 'Inherited and acquired structural hair
disorders' above.)
Scalp biopsies — Scalp biopsies can be a useful tool for the evaluation of hair loss
when the diagnosis is uncertain. Scalp biopsies can distinguish scarring from nonscarring alopecia,
and can provide information that further narrows the differential diagnosis. We perform scalp
biopsies to confirm the diagnosis in all patients with cicatricial alopecia. Scalp biopsies are not
usually performed for the diagnosis of hair shaft disorders due to the ability to diagnose these
disorders with light microscopic examination of the hair shaft. However, in genetic structural hair
disorders, abnormalities also may be evident when the intrafollicular portion of the hair shaft is seen
on histologic examination.
Cicatricial alopecia — In patients with suspected cicatricial alopecia, scalp biopsies

for diagnosis should be performed in sites of active disease. Features that suggest sites of active
disease include the presence of primary lesions, symptoms, or a positive pull test [14]. The
peripheral margin of an area of alopecia usually is the preferred site for a biopsy. Some hair should
remain in the biopsy site; areas of end-stage, complete balding should be avoided.
Many dermatopathologists prefer to receive two punch biopsy specimens, since this allows for
evaluation of the tissue in both vertical and transverse sections [14]. We usually perform two 4 mm
punch biopsies. If only one biopsy can be performed, transverse sections are preferred [13,14]. The
punch biopsies should be performed at an angle that mimics the direction of hair growth. (See "Skin
biopsy techniques", section on 'Punch biopsy'.)
The vascular nature of the scalp can lead to significant bleeding during surgical procedures. To
decrease bleeding, we inject 1% lidocaine with epinephrine for anesthesia and wait up to 10 minutes
prior to performing the biopsy.
Nonscarring alopecia — Scalp biopsies are less frequently performed in patients

with nonscarring alopecias, since the clinical picture and patient history often provide the diagnosis.
However, when the diagnosis remains uncertain, scalp biopsies can be useful for ruling in or ruling
out certain diagnoses (table 1A-B). Pathologic assessment of the proportion of anagen, catagen, and
telogen follicles; the proportion of terminal and vellus hairs; the follicular structure; and the degree of
inflammation can aid in distinguishing among the different types of nonscarring alopecia and can
provide important information for treatment selection and setting patient expectations. Scalp
biopsies are particularly useful for distinguishing among the diffuse presentations of alopecia
areata, telogen effluvium, and female pattern hair loss.
2418
A single scalp biopsy processed with transverse sections usually is sufficient for the evaluation of
patients with clinical features suggestive of nonscarring alopecia [40].
Trichograms and phototrichograms — Trichograms and

phototrichograms are techniques for the evaluation of nonscarring hair loss that are primarily used
in research studies and specialized hair centers. Trichograms and phototrichograms can be used to
assist with diagnosis and following the response to treatment.
To perform a trichogram, approximately 25 to 50 hairs are grasped close to the scalp with a needle
holder. The hairs are then sharply plucked from the scalp. Following this, the proximal ends of the
hairs are microscopically examined to evaluate the proportion of hairs in each stage of the hair cycle
and to determine whether dystrophic hairs are present.
A phototrichogram is a less traumatic procedure in which hairs in a defined area are clipped to a
length of approximately 1 mm and photographed. This baseline photograph can be used to assess
hair density and the proportion of vellus, intermediate, and terminal hairs [55]. The same site is
photographed two to three days after the initial photograph to assess hair growth. Since only anagen
hairs grow substantially, catagen hairs elongate only slightly, and telogen hairs remain stable, the
proportion of anagen, catagen, and telogen (resting) hairs can be estimated by comparing the two
photographs [56].
Phototrichogram technology has evolved to include contrast-enhanced phototrichograms. Contrast-

enhanced phototrichograms involve the use of high-resolution photography and hair dye that
augments the contrast between hair color and skin color [56]. In addition, a software-based system
for performing phototrichograms (TrichoScan) has been developed [57].
Laboratory studies — Depending on the type of hair loss suspected, serologic

and microbiologic studies may also be useful for obtaining information to support the diagnosis and
to detect associated disorders. For patients with new-onset diffuse, nonscarring hair loss without a
clear cause, an initial laboratory evaluation focused on identifying potential causes can be
performed. Suggested initial laboratory tests for the primary care setting include thyroid stimulating
hormone to assess for thyroid disease as well as serum iron and ferritin to assess for iron
deficiency. In addition, a rapid plasma reagin test to rule out syphilitic alopecia is appropriate for
patients with patchy hair loss without visible inflammation or scarring.
Laboratory evaluation for hyperandrogenism can be beneficial for women presenting with both
pattern hair loss and other signs of hyperandrogenism, and testing for thyroid stimulating hormone
is typically performed for patients with alopecia areata, based upon an association of alopecia
areata with thyroid disease. The suggested laboratory work up for specific forms of alopecia is
discussed in detail in dedicated topic reviews in UpToDate. (See "Telogen effluvium", section on
'Laboratory tests' and "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis,
clinical features, and diagnosis", section on 'Laboratory tests' and "Alopecia areata: Clinical
manifestations and diagnosis", section on 'Additional evaluation'.)
2419
INDICATIONS FOR REFERRAL Patients with
signs of cicatricial alopecia (eg, hair loss with absent follicular ostia) should be referred to a
dermatologist for evaluation and management. Referral to a dermatologist is also indicated if the
cause of hair loss is unclear. Patients with extensive alopecia areata or chronic telogen effluvium
may also benefit from referral.
PATIENT SUPPORT Due to the cosmetic value placed upon hair in

many societies, hair loss can be a highly distressing condition. In addition to diagnosis and
treatment of the hair loss disorder, the clinician must also address the emotional and psychologic
well-being of the patient. Organizations such as the National Alopecia Areata Foundation
(www.naaf.org) and the Cicatricial Alopecia Research Foundation (www.carfintl.org) can provide
information and support for patients with hair loss. The North American Hair Research Society
(www.nahrs.org) is an additional source for information.

SUMMARY AND
RECOMMENDATIONS
●Throughout life, hair follicles undergo cycling characterized by periods of growth (anagen),
involution (catagen), and rest (telogen). At any given time, 90 percent of hair follicles on the scalp are
in anagen. The duration of the anagen phase determines maximum length of hair growth. (See 'Hair
cycle' above.)
●Hair loss disorders can be divided into cicatricial (scarring) alopecias, nonscarring alopecias, and
structural hair disorders. When not treated early, cicatricial alopecias are characterized by
irreversible damage to the hair follicle that results in permanent hair loss. The primary cicatricial
alopecias are subdivided into lymphocytic, neutrophilic, and mixed inflammatory disorders (table
1A). (See 'Classification' above and 'Cicatricial alopecia' above.)
●Nonscarring alopecias are conditions in which the hair follicle is not destroyed; in many cases of
alopecia areata or telogen effluvium hair loss, spontaneous or treatment-induced hair regrowth can
occur. Recognition of the distribution of hair loss is useful for the diagnosis of nonscarring alopecias
(table 1B). (See 'Nonscarring alopecia' above.)
2420
●Structural hair disorders result in fragile hair and may be inherited or acquired. Damaging hair care
techniques are a common cause of hair fragility. (See 'Inherited and acquired structural hair
disorders' above.)
●Assessment of the patient with hair loss begins with obtaining a description of hair loss from the
patient as well a medical history and family history. The physical examination incorporates
inspection of the scalp, hair, and other body sites. (See 'Patient interview' above and 'Physical
examination' above.)
●When the diagnosis remains uncertain after the patient history and clinical examination have been
performed, diagnostic techniques such as microscopic examination of cut or plucked hair fibers and
scalp biopsies may provide additional information that is helpful for diagnosis. Depending on the
differential diagnosis, additional laboratory studies may be performed. (See 'Diagnostic techniques'
above.)

2421
Overview of dermoscopy of the hair and scalp
uptodate.com/contents/overview-of-dermoscopy-of-the-hair-and-scalp/print
INTRODUCTION Hair and scalp dermoscopy, also known as trichoscopy,

is a useful, noninvasive, adjunctive tool for the diagnosis of alopecia and other scalp and hair
disorders. The utility of dermoscopy resides in improved visualization of abnormalities of follicular
ostia, perifollicular skin, cutaneous blood vessels, and hair shafts. In addition, dermoscopy may aid
in the selection of a biopsy site when pathologic examination of a scalp disorder is warranted.
The dermoscopic evaluation of scalp and scalp hair disorders will be reviewed here. The
dermoscopic features observed in select hair disorders are reviewed in a table and discussed in
topics dedicated to specific hair diseases (table 1).
2422
●Androgenetic alopecia (see "Androgenetic alopecia in men: Pathogenesis, clinical features, and
diagnosis", section on 'Physical examination' and "Female pattern hair loss (androgenetic alopecia in
women): Pathogenesis, clinical features, and diagnosis", section on 'Dermoscopy')
●Alopecia areata (see "Alopecia areata: Clinical manifestations and diagnosis", section on 'Physical
examination')
●Central centrifugal cicatricial alopecia (see "Central centrifugal cicatricial alopecia", section on
'Dermoscopy')
●Dissecting cellulitis of the scalp (see "Dissecting cellulitis of the scalp", section on 'Dermoscopy')
●Folliculitis decalvans (see "Folliculitis decalvans", section on 'Dermoscopy')
●Lichen planopilaris (see "Lichen planopilaris", section on 'Dermoscopy')
●Tinea capitis (see "Tinea capitis", section on 'Dermoscopy')
●Traction alopecia (see "Traction alopecia", section on 'Physical examination')
Overviews of dermoscopy and the evaluation and diagnosis of patients with hair loss are provided
separately.
TECHNIQUE Dermoscopic examination of the hair and scalp provides improved

visualization of epidermal and dermal structures through magnification and reduction of the skin
surface reflection of light. Most handheld dermatoscopes provide 10-fold magnification; digital
dermatoscopes can provide up to 50-fold magnification [1].
Dermoscopic examination can be performed using instruments that emit polarized light or
nonpolarized light. Examination with polarized light reduces skin surface reflection through the use
of two orthogonally placed filters in a process called cross-polarization. Examination with
nonpolarized light requires use of an immersion fluid (eg, alcohol or water) to reduce skin surface
reflection. (See "Overview of dermoscopy", section on 'Dermoscopy physics' and "Overview of
dermoscopy", section on 'Types of dermatoscopes'.)
Dry dermoscopy (polarized or nonpolarized dermoscopy without use of an immersion fluid) is

particularly useful for the evaluation of cicatricial (scarring) alopecias because it allows for
evaluation of scales and other features that are associated with disease activity, such as peripilar
casts and keratotic plugs. These features are not seen when an immersion fluid is utilized. Thus,
2423
when examining patients with patchy alopecia, scalp itching, or possible hairline recession, all of
which are features that may occur in both cicatricial and noncicatricial alopecia, examination with
dry dermoscopy prior to the application of an immersion fluid is prudent.
Use of an immersion fluid, either alcohol or water, facilitates visualization of vascular patterns in
inflammatory scalp diseases, such as psoriasis and seborrheic dermatitis [2-5].
NORMAL DERMOSCOPIC
PATTERNS Familiarity with normal features aids in the recognition of
abnormalities of the follicular ostia, perifollicular skin, cutaneous blood vessels, and hair shafts. (See
'Abnormal dermoscopic patterns' below.)
Follicular ostia — Normal follicular ostia appear as small, circular, regularly spaced
structures that are commonly referred to as "dots." Most normal follicular units contain two or three
hair shafts emerging from the same follicular ostium [6]. Follicular units composed of only one hair
shaft are also present but become more prevalent with aging and certain hair disorders, such as
androgenetic alopecia and central centrifugal cicatricial alopecia (picture 1).
Perifollicular skin — The examination of normal perifollicular skin is fairly

unremarkable. Mild diffuse scaling is a common finding that may be incidental or associated with
use of hair products, such as gels [1]. In moderately to highly pigmented skin (eg, tanned skin or skin
phototypes IV to VI (table 2)), the normal scalp shows a honeycomb-like pigment network
characterized by pigmented lines surrounding round, hypochromic areas that resemble pinpoint
white dots (picture 2) [7]. These dots are 0.2 to 0.3 mm in diameter and are regularly distributed
between follicular units. The dots correspond to sweat gland ostia and empty follicular ostia. The
presence of pinpoint white dots makes the loss of follicular ostia in cicatricial alopecia difficult to
appreciate. (See 'Utility' below.)
Blood vessels — Normal scalp vessels appear as interfollicular simple red loops and
arborizing red lines. The simple red loops correspond to vessels of the dermal papilla, and arborizing
red lines correspond to the subpapillary vascular plexus.
Hair shafts — Dermoscopic examination of scalp hair will reveal both terminal and
vellus hairs (picture 3). Normal terminal hairs have a consistent diameter and color along the length
of the hairs. Vellus hairs are shorter and narrower than terminal hairs. In the normal scalp, vellus
hairs account for less than 20 percent of all scalp hairs [4]. (See "Evaluation and diagnosis of hair
loss", section on 'Hair types'.)
2424
ABNORMAL DERMOSCOPIC
PATTERNS The abnormal dermoscopic features detected in scalp and hair
disorders can correlate with pathologic features and aid in narrowing the differential diagnosis.
Abnormal dermoscopic patterns of the follicular ostia, perifollicular skin, blood vessels, and hair
shafts and potential associated disorders are reviewed below (table 1).
Follicular ostia — A variety of abnormal features can occur within follicular ostia.
Examples and associated pathologic findings and disorders include [3]:
●Absence/reduction of follicular ostia
•Dermoscopic findings – Loss of follicular ostia (picture 4A-B)
•Pathologic correlation – Fibrosis
•Associated disorders – Cicatricial alopecias
●Black dots
•Dermoscopic findings – Round, black dots within ostia (picture 5A-B)
•Pathologic correlation – Broken hair shafts
•Associated disorders – Alopecia areata, dissecting cellulitis, tinea capitis, trichotillomania
●Blue-gray dots
•Dermoscopic findings – Blue-gray dots in speckled or target pattern within ostia (picture 6)
•Pathologic correlation – Melanophages in papillary dermis
•Associated disorders – Discoid lupus erythematosus (speckled pattern), lichen planopilaris (target
pattern)
●Empty follicles
•Dermoscopic findings – Small depressions without hairs
•Pathologic correlation – Absence of hair within follicular infundibula
•Associated disorders – Androgenetic alopecia, telogen effluvium
●Follicular keratotic plugging
•Dermoscopic findings – Keratin within follicular ostia (picture 5B-D)
2425
•Pathologic correlation – Hyperkeratosis resulting in keratin plugs within follicular ostia
•Associated disorders – Discoid lupus erythematosus, dissecting cellulitis of the scalp
●Hair tufting
•Dermoscopic findings – More than five hairs emerging from a single ostium (picture 7)
•Pathologic correlation – Fusion of outer root sheaths of adjacent follicles
•Associated disorder – Acne keloidalis, folliculitis decalvans
●Red dots
•Dermoscopic findings – Erythematous, polygonal or concentric structures within or around

follicular ostia (picture 8)
•Pathologic correlation – Dilated infundibula with peripheral dilated vessels and red blood cell
extravasation
•Associated disorder – Discoid lupus erythematosus
●Yellow dots
•Dermoscopic findings – Round or polycyclic, yellow to yellow-pink dots (often not visible in patients
with moderately to highly pigmented skin) (picture 9)
•Pathologic correlation – Dilated infundibula filled with sebum and keratin
•Associated disorders – Alopecia areata, androgenetic alopecia, congenital hypotrichosis, dissecting

cellulitis of the scalp, trichotillomania
Perifollicular skin — Abnormalities of perifollicular skin that may aid in

diagnosis include the peripilar sign, peripilar white halo, scale, and white patches [3]:
●Peripilar sign
•Dermoscopic findings – Brown halo around follicular ostia
•Pathologic correlation – Inflammation around the upper follicle
•Associated disorder – Androgenetic alopecia
●Peripilar white halo
•Dermoscopic findings – Gray-white halo around follicular ostia (picture 10)
•Pathologic correlation – Concentric fibrosis
2426
•Associated disorder – Central centrifugal cicatricial alopecia
●Scale
•Dermoscopic findings – Diffuse or perifollicular scale (picture 5D)
•Pathologic correlation – Hyperkeratosis
•Associated disorders – Normal scalp (mild, diffuse scale), psoriasis (white scale and twisted
capillaries (picture 11)), seborrheic dermatitis (yellow and white scale and arborizing vessels (picture
12)), lichen planopilaris (peripilar scale (picture 4A-B)), folliculitis decalvans (peripilar and
interfollicular scale (picture 7)) (see 'Hair shafts' below)
●White patches
•Dermoscopic findings – Irregularly distributed white patches of different sizes and shapes
interspersed with pinpoint white dots (picture 13), mostly seen in highly pigmented skin (phototypes
IV to VI (table 2))
•Pathologic correlation – Fibrosis
•Associated disorder – Cicatricial alopecias
Blood vessels — Dermoscopic features of scalp blood vessels that may aid in
diagnosis include:
●Enlarged branching vessels
•Dermoscopic finding – Enlarged, tortuous, and dilated vessels
•Pathologic correlation – Dilated capillaries in papillary dermis
•Associated disorders – Connective tissue disorders (discoid lupus erythematosus,

dermatomyositis)
●Increased number of arborizing vessels
•Dermoscopic finding – Branching vessels (picture 5C).
•Pathologic correlation – Proliferation of vessels in the subpapillary vascular plexus.
•Associated disorder – Arborizing vessels are a feature of a normal scalp but are increased in
number in seborrheic dermatitis and contact dermatitis.
●Twisted red loops
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•Dermoscopic finding – Seen at magnification ≥40x as twisted glomerular vessels (picture 14), these
appear as red dots at low magnification.
•Pathologic correlation – Enlarged and dilated capillaries in papillary dermis.
•Associated disorders – Folliculitis decalvans, psoriasis.
Hair shafts — Examples of hair shaft abnormalities associated with scalp disease
include [3]:
●Broken hairs
•Dermoscopic findings – Broken hairs of different lengths (picture 15)
•Associated disorders – Alopecia areata, hair fragility disorders, tinea capitis, trichotillomania, woolly
hair
●Circle hairs
•Dermoscopic findings – Short, thin hairs forming a circle (picture 16)
•Associated disorders – Alopecia areata (numerous circle hairs), androgenetic alopecia
●Coiled hairs
•Dermoscopic findings – Curled, broken hairs
•Associated disorder – Trichotillomania
●Comma hairs
•Dermoscopic findings – Short, C-shaped hairs (picture 17A-B)
•Associated disorder – Tinea capitis
●Corkscrew hairs
•Dermoscopic findings – Short, spiral-shaped hairs (picture 17B)
•Associated disorder – Tinea capitis
●Exclamation point hairs
•Dermoscopic findings – Short, tapered hairs (narrower proximal end) (picture 5A)
•Associated disorders – Alopecia areata
●Hair diameter variability
2428
•Dermoscopic findings – Terminal hair shafts of varying diameter (picture 18A-B)
•Associated disorder – Androgenetic alopecia
Examples of other acquired hair shaft abnormalities include [8]:
●Bubble hair
•Dermoscopic findings – Clear, oval spaces within hair shaft
•Associated disorder – Exposure of hair shaft to excessive heat (eg, hair dryer, curling iron)
●Nits
•Dermoscopic findings – Viable eggs (brown, ovoid structures with a convex end) and empty egg
cases (translucent structures with flat end) attached to one side of hair shaft (picture 19A-C) [9]
•Associated disorder – Pediculosis capitis
●Peripilar casts
•Dermoscopic findings – White to brown, cylindric structures with spindled edges around proximal
hair shafts (traction alopecia (picture 20)), white to yellow scale loosely adherent to hair shafts
(psoriasis, seborrheic dermatitis), tightly adherent scale to the proximal hair shaft (lichen
planopilaris (picture 4A-B), folliculitis decalvans (picture 7))
•Associated disorders – Folliculitis decalvans, lichen planopilaris, psoriasis, seborrheic dermatitis,

traction alopecia
●Pseudocasts
•Dermoscopic findings – Irregularly shaped concretions with variable length and thickness (hair
product residue) (picture 21) [10], yellow or beige nodules or sheaths (white piedra), dark nodules
(black piedra), yellow concretions (trichomycosis capitis (picture 22))
•Associated disorder – Hair product residue (eg, hair spray, dry shampoo), piedra, trichomycosis
capitis
●Trichoptilosis (split ends)
•Dermoscopic findings – Longitudinal splitting of distal hair shaft (picture 23)
•Associated disorder – Weathering of hair shaft
●Trichorrhexis nodosa
•Dermoscopic findings – White nodules and fractured or frayed ends of hair (picture 24)
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•Associated disorder – Mechanical, chemical, or thermal damage to hair shaft
Examples of abnormalities seen in congenital hair disorders associated with hair fragility include [8]:
●Monilethrix
•Dermoscopic findings – Regularly spaced beading of hair shaft caused by nodes (medulla present)
and internodes (medulla absent) (picture 25)
•Associated disorder – Monilethrix
●Pili torti
•Dermoscopic findings – Sharp bending of hair shaft at irregular intervals visible at low
magnification (20x), twisting of hair shaft at irregular intervals visible at higher magnification (picture
26)
•Associated disorders – Various causes (rare genetic disorders, occasional occurrence in cicatricial
alopecia)
●"Tiger-tail" pattern
•Dermoscopic findings – Pattern of alternating light and dark bands within hair shaft not visible with
standard dermoscopy; however, use of a polarized transilluminating dermoscopy technique that
involves either two dermatoscopes plus a light-emitting diode from a cellular phone or a single
dermatoscope and a mirror may allow for recognition of this characteristic finding [11].
•Associated disorder – Trichothiodystrophy.
●Trichorrhexis invaginata
•Dermoscopic findings – Bamboo hairs (knots in hair shaft demonstrating ball and cup-like
morphology), broken hairs with cupped ends ("golf-tee hairs") or ball-shaped ends ("matchstick
hairs")
•Associated disorder – Netherton syndrome
Examples of hair shaft abnormalities in hair disorders not associated with hair fragility include [8]:
●Pili annulati
•Dermoscopic finding – Alternating white bands within hair shaft (air-filled cavities) (picture 27)
•Associated disorder – Pili annulati
●Pili trianguli and canaliculi
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•Dermoscopic findings – Triangular or kidney-shaped hair shaft with longitudinal groove or
flattening
•Associated disorder – Uncombable hair syndrome
●Woolly hair
•Dermoscopic finding – Hair shafts with crawling snake configuration with short wave cycles,
broken hairs
•Associated disorder – Hereditary woolly hair, familial woolly hair, woolly hair nevus
APPROACH TO EXAMINATION Dermoscopic

examination is a useful, adjunctive diagnostic tool (table 1). Dermoscopic findings may narrow the
differential diagnosis, support or confirm a suspected diagnosis, or support the need for further
pathologic, microbiologic, or other testing.
Utility — Dermoscopy can be useful for differentiating cicatricial and noncicatricial forms of
alopecia. The loss of follicular ostia is a characteristic finding of cicatricial alopecia (picture 4A-B).
Although loss of follicular ostia may not be prominent in early-stage disease that lacks patches of
alopecia, dermoscopy can identify other supportive findings of cicatricial alopecia, such as peripilar
casts or absence of vellus hairs. In addition, loss of follicular ostia is difficult to appreciate in
patients with moderately to highly pigmented skin (eg, skin phototypes IV to VI (table 2)) due to the
presence of numerous pinpoint white dots representative of both follicular openings and sweat
gland ostia (picture 10). However, features such as an irregular distribution of pinpoint white dots
and presence of white patches support the diagnosis of cicatricial alopecia. (See 'Abnormal
dermoscopic patterns' above.)
Dermoscopy can also aid in differentiating common hair shedding disorders (eg, telogen effluvium,
androgenetic alopecia) from each other and from hair breakage secondary to hair fragility. Hair
diameter variability is a characteristic finding of androgenetic alopecia that is absent in telogen
effluvium (picture 18A-C). Empty follicles support hair shedding, whereas hair shaft abnormalities
associated with increased hair fragility (eg, trichorrhexis nodosa) are supportive of hair breakage.
(See 'Hair shafts' above and 'Follicular ostia' above.)
Many cicatricial and inflammatory disorders of the scalp are associated with erythema or scale.
Dermoscopy can aid in visualizing these features and may identify signs that are helpful for
diagnosis, such as particular vascular patterns and the distribution of scale (eg, peripilar versus
diffuse scale). (See 'Perifollicular skin' above and 'Blood vessels' above and 'Hair shafts' above.)
In the past, assessment of many congenital or acquired hair shaft disorders required plucking or
clipping of hairs and light microscopic or electron microscopic examination of hair shafts.
Dermoscopy facilitates rapid identification of multiple congenital and acquired hair shaft disorders.
(See 'Hair shafts' above and 'Examination of hair shafts' below.)
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Dermoscopy also can help to identify structures adherent to the hair shaft. The magnified view
facilitates differentiation of structures such as nits (picture 19A), peripilar casts (picture 20), and hair
concretions (picture 22), as may be seen in disorders such as pediculosis capitis, traction alopecia,
and trichomycosis capitis, respectively. Pseudocasts, which result from hair spray or dry shampoo
residue, may also be identified with dermoscopy (picture 21) [10]. (See 'Hair shafts' above.)
Examination of the scalp — Dermoscopic examination of the scalp is

facilitated by parting of the hair. The ideal site(s) for examination are determined by the suspected
disorder(s). In patients with suspected cicatricial alopecia, examination of the center of an alopecic
patch is often useful for assessing for loss of follicular ostia, whereas examination of the periphery
of a patch of alopecia is often the best for assessing for features of active disease (eg, erythema,
peripilar casts, follicular plugging, etc). Examination of the frontal hairline is helpful for diagnosis of
frontal fibrosing alopecia (picture 28).
Examination of hair shafts — Dermoscopic examination of hair

shafts can be performed on hairs that remain lodged in the scalp or hairs that have been pulled out,
plucked, or cut. In patients in whom the color contrast between scalp and hair is low (eg, dark brown
skin and black hair) or with markedly curly hair (eg, Afro-textured hair), examination of plucked hairs
may allow for better visualization of hair shafts than in vivo examination of hairs [8]. Pulling hairs
also allows for examination of hair roots, a feature that can be useful for determining the type of
hairs being shed (eg, telogen versus anagen). Placement of hair shafts on a piece of paper with a
color that contrasts with the patient's hair color facilitates examination of pulled, plucked, or cut
hairs.
If androgenetic alopecia is suspected, it is helpful to compare findings in characteristically affected

and unaffected areas. For example, in females, the hair should be parted and examined at the vertex,
mid scalp, and frontal scalp (2 cm from hairline). The degree of hair diameter diversity detected in
these areas can be compared with a typically unaffected site, such as the occipital scalp. (See
diagnosis" and "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis".)
DERMOSCOPY-GUIDED BIOPSY When a

biopsy is necessary to confirm the diagnosis, dermoscopy can help with identifying the most
appropriate site for biopsy. Dermoscopy allows for more accurate assessment of sites of disease
activity, which can be particularly helpful for pathologic diagnosis of cicatricial alopecias. As
examples, follicular units exhibiting peripilar casts, a gray-white halo, hair tufts, or follicular red dots
may be preferred biopsy sites for the diagnosis of lichen planopilaris, central centrifugal cicatricial
alopecia, folliculitis decalvans, and discoid lupus erythematosus, respectively [12].
2432
FEATURES OF SPECIFIC
DIAGNOSES Dermoscopic features associated with specific hair and scalp
disorders are reviewed in a table (table 1).

SUMMARY AND
RECOMMENDATIONS
●Dermoscopy of the hair and scalp (also known as trichoscopy) is a noninvasive adjunctive tool for
the diagnosis of a variety of hair and scalp disorders (table 1). Dermoscopy magnifies structures in
the epidermis and dermis and allows for better visualization of follicular ostia, perifollicular skin,
cutaneous blood vessels, and hair shafts. (See 'Introduction' above and 'Technique' above and
"Overview of dermoscopy".)
●Clinicians utilizing dermoscopy should be familiar with the normal dermoscopic patterns of the
scalp and hair. Abnormalities in dermoscopic patterns often correlate with pathologic features and
can narrow the differential diagnosis for hair and scalp diseases. (See 'Normal dermoscopic
patterns' above and 'Abnormal dermoscopic patterns' above.)
●Dermoscopic examination can be helpful for distinguishing cicatricial from noncicatricial alopecia
and androgenetic alopecia from telogen effluvium. Dermoscopy is also helpful for identifying
particular features of cicatricial and inflammatory disorders of the scalp that aid in diagnosis, such
as the appearance of follicular ostia, vascular patterns, and the distribution of scale. (See 'Abnormal
dermoscopic patterns' above and 'Utility' above.)
●In the past, the diagnosis of many congenital and acquired hair shaft disorders required plucking or
clipping of hairs and light microscopy or electron microscopy of the hair shafts. Dermoscopy allows
for rapid identification of these disorders and often can be performed without plucking or clipping
hair shafts. (See 'Utility' above and 'Hair shafts' above and 'Examination of hair shafts' above.)
●The optimal sites for the examination of scalp disorders are dependent upon the disorders in the
differential diagnosis. In the evaluation of androgenetic alopecia, comparing involved and uninvolved
areas of the scalp is helpful for confirming the diagnosis. (See 'Examination of the scalp' above.)
●Dermoscopy may aid in the selection of a biopsy site in the evaluation of cicatricial alopecia. (See
'Dermoscopy-guided biopsy' above.)
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Alopecia areata: Clinical manifestations and diagnosis
uptodate.com/contents/alopecia-areata-clinical-manifestations-and-diagnosis/print
INTRODUCTION Alopecia areata is a chronic, immune-mediated disorder

that targets anagen hair follicles and causes nonscarring hair loss. The condition most commonly
presents with discrete, smooth patches of alopecia on the scalp but may also occur in other hair-
bearing areas, such as the eyebrows, eyelashes, beard, and extremities (picture 1A-H). In severe
alopecia areata, patients may experience loss of all scalp hair (alopecia totalis) or all hair (alopecia
universalis) (picture 2A-B).
The clinical manifestations and diagnosis of alopecia areata will be discussed here. The treatment
of alopecia areata and the general approach to the evaluation and diagnosis of hair loss are
reviewed separately.
●(See "Alopecia areata: Management".)
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EPIDEMIOLOGY Alopecia areata occurs worldwide. The estimated

prevalence is approximately 1 in 1000 people, with a lifetime risk of approximately 2 percent [1,2].
Both children and adults may develop alopecia areata, and the disorder occurs at similar rates in
males and females [1]. An analysis of clinical data collected from the population of Olmsted County,
Minnesota between 1990 and 2009 revealed a mean age for diagnosis of alopecia areata of 32 years
in males and 36 years in females [3].
Whether there is a seasonal pattern for flares of alopecia areata is unclear. A retrospective study of
approximately 450 children with alopecia areata suggested a predilection for disease flares during
cold months of the year [4]. Additional study is necessary to confirm this finding.
PATHOGENESIS Alopecia areata is an autoimmune disease in which hair

follicles in the growth phase (anagen) prematurely transition to the nonproliferative involution
(catagen) and resting (telogen) phases, leading to sudden hair shedding and inhibition of hair
regrowth (figure 1). Unlike cicatricial alopecias, the inflammatory process in alopecia areata does
not lead to permanent destruction of the hair follicle. (See "Evaluation and diagnosis of hair loss",
section on 'Hair cycle' and "Evaluation and diagnosis of hair loss", section on 'Cicatricial alopecia'.)
The mechanisms leading to alopecia areata are not fully understood. Key events may include the
loss of follicular immune privilege and the development of an associated T cell-mediated immune
attack on cells within the hair bulb. Genetic susceptibility to alopecia areata also plays a role.
●Loss of immune privilege and immune dysregulation –The combination of loss of immune
privilege at the hair follicle and other immunologic events is likely necessary for the development of
alopecia areata [5]. The loss of immune privilege is postulated to involve unknown local stressors or
events that inhibit the expression of hair follicle immune privilege "guardians" (eg, transforming
growth factor [TGF]-beta and alpha-melanocyte-stimulating hormone [MSH]) and stimulate the
expression of major histocompatibility complex class I polypeptide-related sequence A (MICA) on
hair follicle cells. These events can lead to activation of natural killer cells and local secretion of
interferon (IFN)-gamma and interleukin (IL)-15. IFN-gamma stimulates the expression of major
histocompatibility complex (MHC)-I protein on hair follicle cells, which may allow the presentation of
previously hidden antigens to T cells. IL-15 inhibits suppressive function of regulatory T cells and
promotes proliferation of natural killer cells and T cells.
IFN-gamma and IL-15 activate target immune cells via the Janus kinase-signal transducer and
activator of transcription (JAK-STAT) signaling pathway. The importance of this pathway is
illustrated by the efficacy of Janus kinase (JAK) inhibitors for alopecia areata [6-8]. (See "Alopecia
areata: Management", section on 'Janus kinase inhibitors'.)
A mouse study suggests that a defect in hair follicle immune privilege may not always be necessary,
supporting a role for broader immune system dysfunction in the pathogenesis [9].
2436
●Genetic predisposition – Familial and twin studies support a genetic predisposition to alopecia
areata [10-12]. In one study of 206 patients with alopecia areata, 20 percent had a first-degree
relative with the disease [10]. In a twin study, among 19 pairs of monozygotic twins, both twins had
alopecia areata in 42 percent of twin pairs [12]. In contrast, among 31 pairs of dizygotic twins, both
twins had alopecia areata in only 10 percent of twin pairs.
Genome-wide association studies have confirmed associations of alopecia areata with human
leukocyte antigen (HLA) genes [13-19]. The HLA-DQB1*03 allele, among others, may be an important
marker for susceptibility to alopecia areata [18,20]. Several susceptibility loci that have been
associated with other autoimmune diseases (eg, cytotoxic T lymphocyte-associated antigen 4
[CTLA-4], IL-2/IL-21, interleukin-2 receptor-alpha [IL-2RA]) have also been identified, indicating that
alopecia areata may share a common pathway with other autoimmune diseases, such as type 1
diabetes mellitus and rheumatoid arthritis. (See "Pathogenesis of type 1 diabetes mellitus", section
on 'Genetic susceptibility' and "HLA and other susceptibility genes in rheumatoid arthritis".)
Other factors, such as infections, drugs, and vaccinations, have been proposed as contributors to
episodes of alopecia areata. Some patients report severe stress, especially emotional stress, as a
precipitating event, although many patients have no such history. Remote events, such as childhood
trauma, have also been associated with the development of alopecia areata in adults [21].
A role for vitamin D has been proposed based upon a study that found significantly lower serum
levels of 25-hydroxyvitamin D in patients with alopecia areata compared with healthy controls and
an inverse correlation between serum vitamin D levels and alopecia areata severity [22]. Additional
studies are necessary to determine the relevance of this finding.
CLINICAL FEATURES Key clinical features of alopecia areata

include the pattern and speed of hair loss, exclamation point hairs, and associated nail dystrophy.
Hair loss — Alopecia areata most commonly occurs on the scalp but may occur on any
hair-bearing area, such as the eyelashes, eyebrows, beard, extremities, or other areas (picture 1A-D,
1F-H). Patchy alopecia, which manifests as smooth, circular, discrete areas of complete hair loss
that develop over a period of a few weeks, is the most common clinical variant. The patches may
remain discrete or enlarge and coalesce into bizarre patterns.
Hair loss is typically asymptomatic. Occasionally, pruritus or a burning sensation precedes the loss
of hair.
In a subset of patients, patchy alopecia progresses to alopecia totalis (total loss of scalp hair) or
alopecia universalis (loss of all hair over the entire skin surface). In our experience, alopecia totalis
or universalis also occasionally develop rapidly after the onset of diffuse hair loss. (See 'Disease
course' below.)
2437
Less common patterns of hair loss include the ophiasis pattern, the rare sisaipho pattern, and the
diffuse alopecia areata variants:
●Ophiasis pattern – a band-like area of alopecia extending across the occipital scalp (picture 1E)
[23]
●Sisaipho (ophiasis inversus) pattern – alopecia involving the frontal, temporal, and parietal scalp
but sparing hair along the scalp periphery (picture 3), resembling male pattern hair loss [24]
●Diffuse alopecia areata – rapidly progressive, generalized thinning of scalp hair that has also been
reported to occur as a rare variant characterized by acute, extensive hair loss that is followed by
regrowth of hair within several months (acute diffuse and total alopecia) (picture 4) [25,26]
In men, involvement of the beard may be the initial or only manifestation (picture 1F). In a
retrospective study of 55 men with new-onset alopecia areata limited to the beard and a mean
follow-up period of 29 months (range 12 to 144 months), 46 percent developed scalp involvement,
usually within 12 months [27].
White hairs initially may be spared in alopecia areata, leading to the appearance of rapid graying of
the hair in adults with multiple new lesions.
Exclamation point hairs — Exclamation point hairs, short broken hairs

for which the proximal end of the hair is narrower than the distal end, are a common and
pathognomonic finding in alopecia areata (picture 5A-B) [1]. Exclamation point hairs are typically
found at the edges of expanding patches and can be extracted with minimal traction. (See
'Diagnosis' below.)
Nail abnormalities — Nail involvement is estimated to occur in 10 to 20 percent

of patients with alopecia areata, with the potential for more frequent nail involvement in patients with
severe disease [1]. Nail disease may precede, follow, or coexist with active hair loss.
Pitting of the nail plate is most common; however, a variety of other disorders, including
trachyonychia (roughening of the nail plate), onychorrhexis (longitudinal fissuring of the nail plate),
red spotting on the lunulae, onycholysis (separation of the distal nail plate from the nail bed), and
onychomadesis (detachment of the proximal nail plate from the nail bed), may also accompany
alopecia areata (picture 6A-B) [28]. Nail involvement has been associated with greater severity of
disease [28]. (See "Overview of nail disorders".)
DISEASE COURSE Spontaneous hair regrowth is common. Around 50

percent of patients with limited patchy hair loss will recover within a year, although almost all will
experience more than one episode of the disease [29-31]. Patients may also exhibit persistent areas
of alopecia and patches with regrowth of hair simultaneously. Regrowth sometimes begins with the
appearance of fine, white vellus hairs (picture 7).
2438
Alternatively, alopecia areata may persist for several years or indefinitely. Approximately 10 percent
of patients with patchy disease progress to alopecia totalis or alopecia universalis (picture 2A-B) [2].
The following factors have been associated with increased risk for a poor prognosis or high
likelihood of relapse [29]:
●Onset in childhood
●Severe disease, especially alopecia totalis or alopecia universalis
●Duration of more than one year
●Band-like involvement of the peripheral temporal and occipital scalp (ophiasis pattern)
●Nail disease
●Atopy
●Family history of alopecia areata
Long-term outcomes were assessed in a study of 191 patients with alopecia areata who presented
to a university dermatology clinic in Italy between 1983 and 1990 and who were contacted by phone
in 2005 to give self-reports of their clinical status [32]. Patients with less severe disease at
presentation were more likely to report being free of disease at follow-up (68 percent with less than
25 percent hair loss initially, 32 percent with 25 to 50 percent hair loss initially, 8 percent with more
than 50 percent hair loss initially). Patients with more severe disease at the time of presentation
were also more likely to report worsening patterns of alopecia, such as alopecia totalis and alopecia
universalis.
ASSOCIATED DISORDERS Alopecia areata has been

associated with other dermatologic and nondermatologic disorders.
Dermatologic and systemic disorders — One of the

largest disease association studies, a nationwide study from Taiwan that included 4334 patients
with alopecia areata, found associations with vitiligo (odds ratio [OR] 5.23, 95% CI 3.06-9.00), lupus
erythematosus (OR 3.95, 95% CI 3.05-5.11), psoriasis (OR 2.80, 95% CI 2.24-3.50), atopic dermatitis
(OR 2.24, 95% CI 1.95-2.58), thyroid disease (OR 1.89, 95% CI 1.68-2.13), and allergic rhinitis (OR
1.29, 95% CI 1.18-1.41) among all patients compared with control subjects and differences in
disease associations based upon the age of onset of alopecia areata. Another large study supports
an association between alopecia areata and atopic dermatitis. In a case-control study of 2055
patients with alopecia areata and 588 nonalopecic controls, a history of atopic disease was more
common in the alopecia group (31 percent) than in controls (21 percent) and was associated with an
increased risk of developing alopecia areata (OR 2.00, 95% CI 1.50-2.54) [33].
2439
An increased risk for type 1 diabetes mellitus has been reported in relatives of individuals with
alopecia areata [34]. However, there does not appear to be an increased risk for diabetes among
those with the disease.
Genetic disorders associated with an increased risk for alopecia areata include Down syndrome
(trisomy 21, MIM #190685) and polyglandular autoimmune syndrome type 1 (MIM #240300) [35-38].
The latter is a rare autosomal recessive disorder that results from a mutation in the autoimmune
regulator (AIRE) gene on chromosome 21. In a study of 1000 institutionalized patients with Down
syndrome, the prevalence of alopecia areata was approximately 6 percent [35]. Approximately one-
third of patients with polyglandular autoimmune syndrome type 1 have alopecia areata [38,39]. (See
"Down syndrome: Clinical features and diagnosis" and "Causes of primary adrenal insufficiency
(Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'.)
Psychosocial disorders — Hair loss can be distressing for many patients

with alopecia areata, leading to reduced quality of life [40,41]. An increased prevalence of anxiety
and mood disorders has also been reported in this population [42-44].
HISTOPATHOLOGY The pathologic findings in alopecia areata vary

with the acuity of hair loss in the biopsied area [45]. In sites of acute disease with active hair
shedding, the presence of intense, peribulbar, lymphocytic, inflammatory infiltrates surrounding
anagen follicles is characteristic. These infiltrates are often described as resembling swarms of
bees. In addition, signs of follicular insult may be seen, such as follicular edema, cellular necrosis,
microvesiculation, and pigment incontinence.
Follicular miniaturization characterizes the findings in sites of chronic alopecia. The inflammatory
infiltrate is variable and usually less pronounced than in early lesions. In addition, because of the
transition of anagen follicles to the catagen and telogen stages in alopecia areata, biopsy specimens
from areas of chronic involvement reveal high proportions of follicles in catagen or telogen. (See
DIAGNOSIS The patient history and physical examination are usually sufficient
for diagnosis. Clinical features that should raise suspicion for alopecia areata include smooth,
discrete areas of rapid hair loss with absent or minimal erythema. (See 'Clinical features' above.)
History — The patient history should include assessment of the onset and duration of hair
loss as well as associated symptoms. In most patients, alopecia areata presents as sudden,
asymptomatic hair loss. Given the potential for spontaneous resolution and relapse, patients may
report a history of previous hair loss.
The general approach to the patient interview for hair loss is discussed in detail separately. (See
"Evaluation and diagnosis of hair loss", section on 'Patient interview'.)
2440
Physical examination — The physical examination should include careful
examination of the hair, scalp, and other hair-bearing areas to assess the distribution and extent of
hair loss and to detect findings suggestive of other hair or scalp diseases. Smooth, round, or
irregular areas of nonscarring hair loss are typical of alopecia areata. (See "Evaluation and diagnosis
of hair loss", section on 'Physical examination'.)
Close visual inspection may reveal exclamation point hairs, a pathognomonic finding of alopecia
areata (picture 5A). However, exclamation point hairs are sometimes difficult to detect, and their
absence does not exclude the diagnosis. The examination of the scalp should also include
assessment for follicular orifices within patches of alopecia, as the absence of these suggests
cicatricial (scarring) alopecia. (See "Evaluation and diagnosis of hair loss", section on 'Visual
inspection'.)
Performance of a hair pull test can be useful for confirming active hair loss. (See "Evaluation and
diagnosis of hair loss", section on 'Hair pull test'.)
Dermoscopic examination of the hair and scalp (also known as trichoscopy) can be helpful for
visualizing findings consistent with alopecia areata [46-49]. Dermoscopic findings include yellow
dots, short vellus hairs, black dots, tapering hairs, and broken hairs (table 1 and picture 8A-C).
Dystrophic hair fibers with monilethrix-like constrictions also may be seen [50]. (See "Overview of
Examination of the nails may yield nail abnormalities that support the diagnosis. (See 'Nail
abnormalities' above.)
Biopsy — Biopsies are typically reserved for patients in whom the diagnosis is uncertain
despite a careful history and physical examination. Ideally, biopsies are to be taken from the edge of
a patch of active hair loss and positioned to include at least a few remaining hairs.
We typically perform two 4 mm punch biopsies that extend into the subcutaneous fat on the scalp.
This allows for routine vertical sectioning of one specimen and horizontal sectioning of the other
specimen. If only a single specimen is obtained, horizontal sections will give a better representation
of the histopathology. (See 'Histopathology' above.)
ADDITIONAL EVALUATION Patients with alopecia

areata may benefit from an assessment for thyroid disease and signs or symptoms of other
associated disorders. (See 'Associated disorders' above.)
Thyroid studies — Because of the association between alopecia areata and

autoimmune thyroid disease and the relatively high frequency of thyroid disease in the general
population, we screen adults and children with alopecia areata for this disorder [51]. Thyroid
disorders may be present at the time of diagnosis or develop later in the course of disease. Thus, the
2441
subsequent development of symptoms of thyroid disease should prompt re-evaluation. (See
'Associated disorders' above and "Laboratory assessment of thyroid function", section on 'Evaluating
for thyroid dysfunction'.)
However, a retrospective study suggests that limiting screening for thyroid dysfunction in children
with alopecia areata to certain populations may be reasonable [52]. Among 298 children (ages 10
months to 19 years) with alopecia areata who had thyroid function studies performed, 59 (20
percent) had abnormal results. Factors associated with increased risk for abnormalities included a
personal history of Down syndrome or atopy and a family history of thyroid disease. Age, disease
duration, pattern of alopecia, and a diagnosis of autoimmune disease were not associated with
abnormal thyroid studies.
Pending additional data to support reduced screening for thyroid disease in children with alopecia
areata, we continue to screen all affected children for thyroid disease.
Other — Adults and children with clinical signs or symptoms suggestive of other autoimmune
diseases should be evaluated for those disorders. In the absence of such features, routine testing for
other autoimmune diseases (eg, celiac disease) is not advised [53]. (See 'Associated disorders'
above.)

of alopecia areata primarily includes other causes of nondiffuse hair loss, such as androgenetic
alopecia, cicatricial alopecias, secondary syphilis, tinea capitis, triangular alopecia, and
trichotillomania. (See "Evaluation and diagnosis of hair loss".)
●Androgenetic alopecia – Androgenetic alopecia occurs in characteristic male and female patterns
and characteristically manifests with slow, progressive hair thinning, rather than the rapid
development of areas of complete hair loss that is typical of alopecia areata (picture 9A-B). The rare
sisaipho pattern of alopecia areata can resemble male pattern androgenetic alopecia (picture 3). A
biopsy can distinguish androgenetic alopecia from alopecia areata in challenging cases. (See
"Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis" and "Female pattern
hair loss (androgenetic alopecia in women): Pathogenesis, clinical features, and diagnosis".)
●Cicatricial (scarring) alopecia – Cicatricial alopecia may be the result of diverse pathologies, such
as lichen planopilaris, discoid lupus erythematosus (picture 10), and folliculitis decalvans. All are
characterized by permanent destruction of hair follicles. Hair loss is usually patchy, and there is loss
of follicular orifices in sites of alopecia, a finding indicative of scarring. Additional features vary
depending on the primary pathology and may include erythema, scaling, follicular plugging, and
pustulation. Skin biopsies are often indicated to confirm a diagnosis of cicatricial alopecia. (See
"Evaluation and diagnosis of hair loss", section on 'Cicatricial alopecia'.)
2442
●Secondary syphilis – Areas of patchy hair loss may appear in secondary syphilis. The patches are
often described to have a "moth-eaten" appearance rather than the smooth and discrete areas
characteristic of alopecia areata (picture 11). Serologic testing for syphilis can confirm the
diagnosis. (See "Syphilis: Screening and diagnostic testing".)
●Tinea capitis – Tinea capitis typically presents with scaly patches of hair loss on the scalp and is
most common in children (picture 12A-B). Inflammation and cervical lymphadenopathy may also be
present. Tinea capitis should always be considered in children presenting with patchy hair loss. In
contrast, alopecia areata produces smooth areas of hair loss that lack scale. A potassium hydroxide
(KOH) or fungal culture can confirm a diagnosis of tinea capitis. (See "Tinea capitis".)
●Trichotillomania – Trichotillomania is a disorder in which individuals compulsively pull hair from

the scalp or other body areas. The disorder produces unusual patterns of broken hairs of varying
length, which leads to a characteristic "wire brush" feel as compared with the smooth hair loss of
alopecia areata (picture 13A-B). The history and physical examination are usually sufficient for
diagnosis. However, a biopsy in the area of alopecia can help to differentiate alopecia areata from
trichotillomania disorders when necessary. (See "Skin picking (excoriation) disorder and related
disorders", section on 'Trichotillomania'.)
●Triangular alopecia – Triangular alopecia is a developmental abnormality of hair follicles that

presents in infancy or childhood as a triangular or round patch of hair loss near the frontotemporal
hair line (picture 14). The disorder may be unilateral or bilateral, and persists throughout life. Close
examination and biopsy specimens reveal vellus hairs.
The diffuse variant of alopecia areata may be difficult to distinguish clinically from telogen effluvium
when hair loss is not severe. A biopsy can be used to differentiate between the two disorders. In
addition, more pronounced hair thinning in the bitemporal region is more consistent with telogen
effluvium than alopecia areata, and a positive hair pull test in alopecia areata may reveal both
dystrophic anagen and telogen hairs in contrast to the isolated telogen hairs in telogen effluvium
[25]. (See "Telogen effluvium".)


2443
●Basics topics (see "Patient education: Hair loss in men and women (The Basics)")
●Beyond the Basics topics (see "Patient education: Alopecia areata (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Alopecia areata is a chronic, relapsing disorder characterized by nonscarring hair loss (picture 1A-
H). The disorder can affect individuals of any age. (See 'Epidemiology' above.)
●The pathogenesis of alopecia areata is thought to involve autoimmune-mediated disruption of the

normal hair cycle, leading to the inhibition of normal hair growth. A loss of the immune-privileged
status of the hair follicle is considered a key pathogenic event. Genetic predisposition also
contributes to the development of the disorder. (See 'Pathogenesis' above.)
●Patients with alopecia areata most often present with smooth, circular, discrete areas of complete
hair loss that develop over a period of a few weeks. Exclamation point hairs, short broken hairs for
which the proximal end of the hair is narrower than the distal end, are a common finding (picture 5A).
Patients may also have associated nail abnormalities. (See 'Clinical features' above.)
●The course of alopecia areata is unpredictable. Many patients with limited patchy hair loss
experience regrowth within one year, but recurrence is common. A minority of patients may progress
to total loss of scalp hair (alopecia totalis) or loss of all hair (alopecia universalis) (picture 2A-B).
Poor prognostic factors for alopecia areata include young age of onset, severe disease, long
duration of disease, ophiasis pattern, nail disease, and an atopic history. (See 'Disease course'
above.)
●Alopecia areata has been associated with a variety of autoimmune diseases and other disorders.
(See 'Associated disorders' above.)
●The diagnosis of alopecia is often made via the patient history and physical examination. Biopsies
can be performed in cases in which the diagnosis is uncertain. (See 'Diagnosis' above.)
2444
Alopecia areata: Management - UpToDate
uptodate.com/contents/alopecia-areata-management/print
INTRODUCTION Alopecia areata is a chronic, relapsing, immune-

mediated inflammatory disorder affecting hair follicles resulting in nonscarring hair loss. The
severity of the disorder ranges from small patches of alopecia on any hair-bearing area to the
complete loss of scalp, eyebrow, eyelash, and body hair.
Although up to 50 percent of patients who present with patchy alopecia areata experience
spontaneous hair regrowth within one year, most will relapse months or years after remission [1].
The unpredictable course of the disease and the psychologic distress associated with hair loss
prompt many patients to seek therapy. (See "Alopecia areata: Clinical manifestations and diagnosis",
section on 'Disease course'.)
The management of alopecia areata involves both addressing the psychologic needs of the patient
and offering treatment to patients who desire intervention. A variety of topical, intralesional, and
systemic agents, as well as devices, have been used for alopecia areata, but the response to
treatment varies widely; few well-designed clinical trials have evaluated these therapies [2].
Options for the management of alopecia areata will be discussed here. The clinical manifestations
and diagnosis of the disorder are reviewed separately. (See "Alopecia areata: Clinical manifestations
and diagnosis".)
2445
COUNSELING Educating patients about alopecia areata, discussing realistic
expectations for treatment, and offering resources for psychologic support are important
components of therapy [1].
Psychosocial support — For the majority of patients, alopecia areata is a

cosmetic concern, although it can occasionally cause physical disability, such as when there is
eyelash involvement, loss of nasal hairs, or marked nail dystrophy. Nevertheless, the cosmetic
importance of hair is such that alopecia areata can cause severe emotional problems, particularly in
children, adolescents, and young women, though by no means restricted to these groups. Studies of
adolescents suffering from alopecia areata have found increased rates of psychiatric symptoms
[3,4].
In view of the variable efficacy of current forms of treatment, the clinician has an important role in
helping patients adapt to hair loss. Input from other health professionals, such as a clinical
psychologist, may be needed. Many patients are helped by involvement in patient support groups [5].
With children, it is often the parents whose reactions must be addressed for the child to adjust to the
hair loss.
The National Alopecia Areata Foundation (NAAF) is a useful resource for support for children and
adults with alopecia areata and their family members. NAAF maintains an informative website,
publishes a newsletter, and provides names of local support groups. (See 'Information for patients'
below.)
Decision to treat — Treatment of alopecia areata is not mandatory. The decision

to treat is a shared decision with the patient that involves careful consideration of the patient's
preferences and the risks and benefits of treatment.
The discussion with the patient should involve a review of the course of the disease and the various
treatment options and their respective side effects. The following general principles should be
reviewed:
●The course of alopecia areata varies, including spontaneous resolution, persistence, recurrence,
and progression. (See "Alopecia areata: Clinical manifestations and diagnosis", section on 'Disease
course'.)
●Responses to treatment vary, and there is no curative treatment.
●Even if a treatment is effective, the disease often recurs once the treatment is discontinued.
Cosmetic options — Some patients who elect to forgo treatment or who have
incomplete responses desire products or techniques to address persistent scalp, eyebrow, or
eyelash hair loss. Wigs, hairpieces, shaving of the scalp, and protein powders, sprays, or lotions
2446
designed to make hair appear more full may be helpful for scalp hair loss. Eyebrow tattooing can be
helpful for loss of eyebrows. Patients with alopecia of the eyelashes may choose to apply false
eyelashes. False eyelashes are widely available in pharmacies and beauty supply stores. (See
'Eyelash loss' below.)
FIRST-LINE THERAPIES The treatment approach for

patients who desire medical intervention differs based upon the clinical presentation. Initial
interventions for patients with limited (not strictly defined, but generally less than 50 percent) patchy
scalp hair loss and extensive (generally more than 50 percent) scalp hair loss are reviewed below.
(See 'Limited patchy hair loss' below and 'Extensive hair loss' below.)
Limited patchy hair loss — Intralesional and topical corticosteroids are

the preferred initial treatment for patients with limited patchy alopecia areata. This is based upon
relative safety and the available, although limited, evidence for efficacy [1]. Often, patients with <25
percent scalp hair loss are the best candidates because of difficulty tolerating the high number of
injections required to treat larger areas. Children and other patients who cannot tolerate injections
can be treated with topical corticosteroids. (See 'Potent topical corticosteroids' below.)
Intralesional corticosteroids — We suggest intralesional corticosteroids as

the preferred therapy for adults with isolated patches of hair loss.
Efficacy — There are no randomized trials of intralesional corticosteroids for alopecia areata.
One nonrandomized comparative study found regrowth of tufts of hair at 33 of 34 sites injected with
triamcinolone hexacetonide in 11 patients and at 16 of 25 sites injected with triamcinolone
acetonide in 17 patients [6]. Another study reported complete regrowth of hair after four months in
40 of 62 patients (63 percent) treated with monthly injections of triamcinolone acetonide [7].
Administration — Intralesional injections should be performed on both existing and newly

forming patches of alopecia. The goals of treatment are to promote regrowth and limit hair loss.
(See "Intralesional corticosteroid injection".)
●The affected area may be pretreated with a topical anesthetic cream (eg, lidocaine 2.5% and
prilocaine 2.5% cream). The cream is applied generously and is placed under occlusion with a tightly
fitting shower cap or plastic wrap 1.5 to 2 hours before treatment. The cream is removed
immediately before injection.
●Triamcinolone 2.5 to 5 mg/mL is injected into the upper subcutis on the face for eyebrow or beard
involvement; concentrations of 5 to 10 mg/mL are injected into the upper subcutis on the scalp.
Small volumes (0.1 mL or less) are injected into multiple sites 1 cm apart (picture 1). The dose per
visit is largely determined by the extent of disease and patient tolerance but is usually around 20 mg
or less on the scalp. The dose of triamcinolone administered should not exceed 40 mg per treatment
session.
2447
●New growth is usually visible within six to eight weeks. The treatment may be repeated as
necessary every four to six weeks and is stopped once regrowth is complete. If there is no response
after six months, treatment should be discontinued [8] and alternative treatments may be attempted.
Adverse effects — Local skin atrophy is a consistent side effect but usually resolves within
a few months. Other cutaneous side effects include telangiectasias and hypopigmentation. Facial
injection should be approached cautiously, particularly in patients with pigmented skin, in whom
hypopigmentation can be prominent. Nondermatologists should consider referring patients who
need facial injections to a dermatologist. The risk for adrenal suppression in patients treated with
intralesional corticosteroid injections into the skin has not been formally studied [9-11]. (See
"Intralesional corticosteroid injection", section on 'Side effects, complications, and pitfalls' and
Potent topical corticosteroids — While potent topical corticosteroids are

frequently used to treat alopecia areata, evidence for their effectiveness is limited. We usually
reserve first-line therapy with topical corticosteroids for children and adults who cannot tolerate
intralesional injections [12-14].
Efficacy — Examples of studies investigating the efficacy of topical corticosteroids for alopecia
areata include the following:
●A trial in 70 patients with patchy alopecia areata randomly assigned patients to apply either 0.25%
desoximetasone cream or placebo twice daily [15]. After 12 weeks of therapy, a larger number of
patients treated with desoximetasone experienced complete regrowth of hair (58 versus 39 percent,
relative risk 1.5, 95% CI 0.83-2.59); however, the difference was not statistically significant. More
patients treated with the corticosteroid experienced at least mild improvement, and this result did
achieve statistical significance.
●A 12-week randomized trial in which 105 patients with localized alopecia areata were randomized
to treatment with betamethasone valerate 0.1% foam applied twice daily, intralesional triamcinolone
acetonide (10 mg/mL) administered every three weeks, or topical tacrolimus 0.1% ointment applied
twice daily found >75 percent hair regrowth in 54, 60, and 0 percent of patients, respectively [16]. Of
note, 27 patients dropped out of the study prior to completion and were not included in the analysis
of data.
Preferential use of a potent topical corticosteroid over lower-potency corticosteroids is supported by

the findings of a 24-week randomized trial performed in 41 children with alopecia areata involving at
least 10 percent of the scalp surface area. The trial found that twice-daily treatment with clobetasol
propionate 0.05% cream (a high-potency topical corticosteroid) for two six-week cycles separated by
six weeks was more effective for decreasing the area of scalp hair loss than hydrocortisone 1%
cream (a low-potency topical corticosteroid) administered via the same regimen [12]. After 24 weeks,
85 percent of children treated with clobetasol propionate had at least a 50 percent reduction in the
surface area with hair loss, compared with only 33 percent of children treated with hydrocortisone.
2448
Administration — We typically treat scalp involvement with a high-potency topical
corticosteroid, such as betamethasone dipropionate 0.05% (cream, lotion, ointment), applied to
affected areas and 1 cm beyond once daily (table 1). The entire scalp is treated if a large area is
involved.
The response to treatment should be evaluated after three months of use. We discontinue the topical
corticosteroid and consider alternative therapies at this point if patients do not have hair regrowth.
For patients who have hair regrowth, we continue the topical corticosteroid and gradually taper the
frequency of application.
The best regimen for tapering and discontinuing topical corticosteroids in patients who respond is
unclear. We tend to individualize our approach and taper more quickly for patients with robust hair
regrowth than for patients with slower, less dramatic improvement. In general, we are able to taper
and discontinue topical corticosteroid therapy over the course of three to six months.
Application under occlusion increases the potency of topical corticosteroids. Given the potential for
increasing side effects, we do not recommend this method of application in the absence of
additional studies demonstrating safety and long-term efficacy. (See 'Adverse effects' below.)
Long-term treatment with high-potency topical corticosteroids is usually avoided for beard and
eyebrow involvement because of the potential for corticosteroid-induced skin atrophy in this area
[17]. When utilizing topical corticosteroid therapy in these areas, we typically opt for a medium-
potency topical corticosteroid initially and assess for a response after approximately six weeks,
rather than three months (table 1). If there is no response, a high-potency topical corticosteroid can
be tried, with reassessment for signs of response after six weeks. Topical corticosteroid therapy is
subsequently discontinued if hair regrowth is absent. (See "Topical corticosteroids: Use and adverse
effects", section on 'Adverse effects'.)
Adverse effects — Similar to intralesional corticosteroids, side effects of topical therapy

include local skin atrophy, telangiectasias, hypopigmentation, and adrenal suppression. (See
Extensive hair loss — Topical immunotherapy is the preferred first-line

treatment for patients with extensive disease. We typically reserve intralesional and topical
corticosteroid therapy for treatment of strategic sites (eg, frontal hairline, eyebrows) in these
patients. Systemic glucocorticoids are occasionally used for temporarily slowing rapid, extensive
hair loss, but side effects limit use of this therapy. (See 'Systemic glucocorticoids' below.)
Topical immunotherapy — Topical immunotherapy is probably the most

effective treatment for patients with extensive or recurrent scalp involvement [1,18]. The procedure
is usually performed by dermatologists.
2449
A potent contact allergen is applied weekly to the scalp to precipitate hair regrowth [19,20]. The
reason for this response remains unknown, but an immunomodulatory effect on the inflammatory
infiltrate surrounding affected hair follicles is thought to play a role. Theories for the mechanism of
action have focused on the inhibition of the pathologic immune response via antigenic competition
[21], the induction of lymphocyte apoptosis [22], or an effect on the type or function of lymphocytes
in the inflammatory infiltrate [23-25].
Efficacy — Randomized trials evaluating topical immunotherapy are lacking, and uncontrolled
studies have found variable rates of response. A systematic review and meta-analysis of studies
evaluating contact immunotherapy with diphenylcyclopropenone (DPCP) or squaric acid dibutyl
ester (SADBE) for patchy alopecia areata, alopecia totalis, and/or alopecia universalis found an
overall rate of complete (90 to 100 percent) hair regrowth of 32.3 percent (95% CI 25.3-40.2) [26].
Patients with patchy alopecia areata had better response rates than patients with either alopecia
totalis or universalis (25 versus 43 percent for complete regrowth). Factors associated with poorer
hair regrowth outcomes included a Severity of Alopecia Tool (SALT) score ≥50 (odds ratio [OR] 3.05,
95% CI 2.26-4.11), atopic disease (OR 1.61, 95% CI 1.03-2.50), and nail involvement (OR 2.06, 95% CI
1.26-3.36). Although longer disease duration is often considered a negative prognostic factor,
disease duration ≥1 year was not a statistically significant prognostic factor in this study (OR 1.56,
95% CI 0.95-2.55). Relapse after treatment was common. Analysis of studies reporting treatment
status at the time of relapse revealed recurrence rates among patients not receiving and receiving
maintenance treatment of 38 and 49 percent, respectively.
Administration — Topical immunotherapy can be performed with DPCP or SADBE. The

agents for topical immunotherapy are typically purchased from a chemical distributor. The solutions
are subsequently prepared by a pharmacy or the clinician. Careful handling during preparation and
treatment is essential to avoid inadvertent contact with the skin that results in sensitization of
pharmacists or clinicians.
When both agents are available, DPCP is often favored over SADBE because it is less expensive and
more stable in solution. SADBE must be refrigerated. DPCP is degraded by light and should be
stored in an amber glass bottle or another protective container.
●Topical immunotherapy with DPCP begins with the application of a 2% solution to a small (eg, 4x4
cm) area, usually on the scalp, to sensitize the patient [1]. One to two weeks later, treatment is
initiated with the application of a 0.001% concentration of the allergen to the affected areas.
●Patients should be instructed to wash off DPCP after 24 to 48 hours. While the product is on the
skin, the treated areas should be protected from sun exposure with an opaque scarf or hat.
●For patients who exhibit a severe eczematous response to sensitization, an additional week should
pass before starting treatment and an even lower initial concentration of DPCP should be used.
●Treatments are usually repeated once weekly with slowly increasing concentrations of DPCP to a
maximum concentration of 2%. Typically, the concentration that induces a mild dermatitis is utilized
for all subsequent treatments. A retrospective study suggests that the development of clinically
2450
evident dermatitis may not be necessary for efficacy of DPCP; however, additional study is
necessary to confirm this finding [27].
Signs of hair growth are expected by approximately three months, and the frequency of treatment is
reduced once maximal hair growth is attained [6,28]. Most clinicians discontinue therapy if there is
no response after six months [29]; however, improvement requiring longer courses of DPCP therapy
has been reported [28]. Further study is necessary to confirm the results of a retrospective study that
suggest that combination therapy with DPCP and anthralin is more effective than DPCP
monotherapy [30]. (See 'Anthralin' below.)
The procedure for sensitization and treatment with SADBE is similar. Sensitization is performed with
a 2% solution and is followed by weekly 24-hour applications of the agent. Treatment begins with a
low concentration solution (such as 0.0001%) that is increased until mild dermatitis is elicited.
Further study is necessary to confirm the findings of a small retrospective study that suggest an
initial eczematous reaction to sensitization is not always necessary for successful treatment [31].
Opinions vary on whether patients should be allowed to apply SADBE or DPCP at home [1]. Limited
data suggest that treatment can be safe and effective; however, additional study is necessary to
clarify which patients are the best candidates for home treatment [32].
Adverse effects — Severe dermatitis is a potential side effect of topical immunotherapy. If

a vesicular or bullous reaction occurs, the contact allergen should be washed from the skin and
treatment with a topical corticosteroid should be initiated. Other potential side effects include
lymphadenopathy, urticaria, vitiligo, and dyschromia [8]. Use in pregnant women is not
recommended [8].
Local corticosteroids — We typically reserve intralesional and topical

corticosteroid therapy for treatment of strategic sites (eg, frontal hairline, eyebrows) in patients with
extensive disease. Although a minority of patients with extensive alopecia areata may have
significant regrowth with local corticosteroid therapy, these interventions are less frequently used
alone due to concern for lower efficacy in this subgroup [33-35]. One retrospective study reported
superior efficacy of topical immunotherapy over intralesional corticosteroids for patients with
patches of hair loss exceeding 50 cm2 in size [18]. An additional concern for intralesional
corticosteroid therapy is the large number of injections required. (See 'Intralesional corticosteroids'
above and 'Potent topical corticosteroids' above.)
Systemic glucocorticoids — Most patients with extensive hair loss are most
appropriately treated with topical immunotherapy and local corticosteroids as initial treatment;
however, systemic glucocorticoids are occasionally prescribed as a temporary measure to slow hair
loss in patients with rapidly progressing, extensive hair loss. These patients may be subsequently
transferred to topical immunotherapy or an alternative therapy, if available.
2451
Although systemic glucocorticoids appear to stimulate hair growth, the adverse effects associated
with these agents limit the duration of therapy, and recurrence of hair loss frequently occurs after
the discontinuation of treatment [36,37]. Various regimens involving daily dosing or pulsed dosing
have been utilized. A common daily treatment regimen is 40 to 60 mg per day in adults or 1 mg/kg
per day in children tapered over four to six weeks. Evidence of hair regrowth is expected within this
period. Regimens that involve pulsed oral glucocorticoids may also induce hair regrowth [38,39].
The efficacy of a prednisone taper (from 40 mg to 0 mg over the course of six weeks in patients
weighing at least 40 kg) was investigated in a prospective study of 32 children and adults with
alopecia areata, including 16 patients with alopecia totalis or universalis [40]. After six weeks, 13
patients achieved at least 50 percent hair regrowth, including four patients with 75 to 99 percent hair
loss at baseline and four patients with alopecia universalis. Two patients worsened during
prednisone therapy.
SECOND-LINE THERAPY Patients with limited disease

who do not respond to local corticosteroid therapy can be treated with topical immunotherapy. The
treatment regimen is identical to patients with more extensive disease. (See 'Topical immunotherapy'
above.)
Topical anthralin is an additional second-line treatment option for limited or extensive alopecia
areata. Anthralin may be used alone or in combination with first-line interventions. (See 'First-line
therapies' above.)
Anthralin — Anthralin is an irritant agent that is mainly used to treat patients with
psoriasis. Evidence of its effectiveness for alopecia areata is limited to case series without adequate
controls [1,41]. Compared with intralesional corticosteroids and topical immunotherapy, anthralin
appears to be less effective. Children may also have difficultly tolerating the irritation caused by
anthralin.
Short-contact therapy with anthralin is performed by applying anthralin 0.5 or 1% cream to the
affected areas for 20 to 30 minutes daily, followed by rinsing the cream off with cool to lukewarm
water, and washing the treated area with any shampoo [8]. The time of contact is increased by 10
minutes every two weeks up to one hour or to the time required to elicit a mild dermatitis. Therapy is
then continued at that exposure time.
Alternatively, treatment can be initiated with application of a 0.1% concentration of anthralin to the
scalp for 10 to 20 minutes. Tolerance to irritation is built up by gradually increasing (over a period of
days) the time that the anthralin is left on the affected area, eventually reaching tolerance for leaving
anthralin on overnight. The concentration of anthralin can be increased up to 2% as tolerated.
An irritant reaction with erythema and scaling is desired but should not be allowed to become
frankly vesicular. Mild irritation is expected and preferred over severe irritation. Anthralin should be
used for at least three months before re-evaluating for treatment effectiveness.
2452
Anthralin will stain hair, skin, and clothing brown. Patients should wash their hands with cool to
lukewarm water immediately after application.
REFRACTORY DISEASE Systemic therapies are

occasionally used for severe alopecia areata. A high likelihood of relapse, limited efficacy data, and
the potential adverse effects of these drugs limit their use to refractory cases.
Azathioprine — Data from small, uncontrolled studies suggest that azathioprine

induces hair regrowth in some patients with moderate to severe alopecia areata [42,43]. In a
prospective study of 14 adult patients with alopecia universalis, six patients regrew hair during
treatment with azathioprine (2.5 mg/kg per day adjusted according to thiopurine methyltransferase
[TMPT] levels), all achieving regrowth on 75 percent or more of the scalp [42]. Responses occurred
four to six months after the start of treatment, and four of the six responders had persistent
improvement after the discontinuation of treatment. Adverse effects (diarrhea, liver enzyme
elevation, pancreatitis, or bone marrow suppression) occurred in 5 of the 14 treated patients,
resulting in treatment cessation in four patients.
Additional study is necessary to confirm the efficacy of azathioprine therapy. (See "Overview of
pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
Janus kinase inhibitors — Janus kinase (JAK) inhibitors appear to induce

hair growth in alopecia areata; however, further study is necessary prior to conclusions about
efficacy and safety. Oral tofacitinib is the JAK inhibitor that has been most studied for the treatment
of alopecia areata:
●Oral tofacitinib – Regrowth of hair during treatment with tofacitinib (a small molecule selective JAK
1/3 inhibitor) has been documented in patients with alopecia areata [44-50]. Patients are typically
treated with 5 to 10 mg twice daily.
A retrospective study of 90 adults with severe alopecia areata (at least 40 percent scalp hair loss,
alopecia totalis, or alopecia universalis) who had stable or worsening disease for at least six months
and received oral tofacitinib (5 to 10 mg twice daily) for at least four months (with or without
adjuvant prednisone) supports benefit [44]. Of the 65 patients with a duration of the current disease
episode of 10 years or less, 77 percent had a clinical response (at least 6 percent improvement in the
Severity of Alopecia Tool [SALT] score) and 58 percent achieved greater than 50 percent
improvement in the SALT score over 4 to 18 months of treatment. Patients with a disease episode
longer than 10 years appeared less likely to respond to treatment; the clinical response rate in this
population was 32 percent (8 of 25 patients). No serious adverse effects occurred during treatment.
Data on oral tofacitinib use in children are limited [51,52]. In a series of four children (ages 8 to 10
years) with refractory alopecia totalis or alopecia universalis treated with tofacitinib, two had
complete regrowth of scalp hair, one had partial regrowth, and one failed to respond [52]. Responses
2453
occurred within three to six months. The three responders received 5 mg twice daily, and the child
who failed treatment received 5 mg once daily, which was subsequently increased to 5 mg twice
daily after three months. In another series, partial hair regrowth occurred in all of eight adolescents
with alopecia universalis treated with tofacitinib 5 mg twice daily for 5 to 18 months [51]. Initial signs
of regrowth occurred within the first three months. No adverse events occurred in either series.
A beneficial effect of tofacitinib on alopecia areata may result from inhibition of T lymphocyte
activation. Further study is necessary to confirm the efficacy of this treatment. Tofacitinib therapy is
associated with increased risk for infection, including serious infections [53,54]. The development of
malignancy and laboratory abnormalities has also been reported in patients receiving tofacitinib
therapy for other diseases [55].
●Oral ruxolitinib – Further support for a potential role for JAK inhibitors in the treatment of alopecia
areata stems from an open-label pilot study, case series, and case reports describing the use of oral
ruxolitinib [56-60]. In the open-label study, 9 of 12 patients (75 percent) with moderate to severe
alopecia areata treated with 20 mg of ruxolitinib twice daily for three to six months achieved at least
50 percent hair regrowth by the end of treatment [60].
●Topical JAK inhibitors – In addition, limited data suggest topical formulations of ruxolitinib and
tofacitinib may be beneficial, although these are not yet commercially available [61-65]. A 28-week
phase 1 trial in which 16 adults with alopecia universalis applied tofacitinib 2% ointment, ruxolitinib
1% ointment, clobetasol dipropionate 0.05% ointment, or vehicle to one of four randomly assigned
areas of the scalp and eyebrows twice daily found hair regrowth in the treated area in 6, 5, 10, and 0
patients, respectively [61]. In addition, in a 24-week, open-label study, hair regrowth occurred in 3 of
10 adults with alopecia areata or alopecia totalis during use of tofacitinib 2% ointment [62].
Case series support potential benefit of topical JAK inhibitors in children [63,66]. In the larger series,
tofacitinib 2% ointment therapy in 11 children with alopecia areata, alopecia totalis, or alopecia
universalis refractory to oral and topical corticosteroids was associated with improvement in the
SALT score in 8 children, including 3 children who had sufficient hair regrowth to cover the scalp or
conceal residual areas of hair loss [63].
Methotrexate — A systematic review and meta-analysis of primarily retrospective

observational studies suggests there may be benefit of methotrexate, particularly when used in
adults or in conjunction with systemic glucocorticoids [67]. Patients were generally treated with
doses between 7.5 and 25 mg per week. The pooled rate of good or complete response (at least 50
percent hair regrowth) was 63 percent. Initial hair regrowth with methotrexate may be evident after
approximately three months, and 6 to 12 months of therapy may be necessary for complete
regrowth. However, recurrence appears common upon tapering of methotrexate.
Additional study is necessary to confirm efficacy of methotrexate. In addition, methotrexate therapy

requires close laboratory monitoring and has important toxicities. (See "Major side effects of low-
dose methotrexate".)
2454
Sulfasalazine — Sulfasalazine is a drug with immunosuppressive and
immunomodulatory properties. Uncontrolled studies and a retrospective chart review have reported
successful therapy in approximately one-quarter of patients with alopecia areata [68-70]. However,
relapse rates of up to 45 percent have been reported [69]. Side effects of sulfasalazine may include
gastrointestinal distress, headache, fever, rash, and, less frequently, hematologic disorders and
hepatotoxicity.
Starting therapy with a low dose may decrease gastrointestinal symptoms. Patients can be treated
with 0.5 g twice daily for one month, followed by 1 g twice daily for one month and 1.5 g twice daily
for at least three months [68,69]. Complete blood cell counts and liver function tests should be
closely monitored during the first three months of therapy and every three to six months thereafter
[68].
EYELASH LOSS There are no established local treatments for eyelash

disease. False eyelashes are a cosmetic option for patients. (See 'Cosmetic options' above.)
Topical prostaglandin analogues have been studied for eyelash involvement, but their efficacy
remains uncertain and use cannot be recommended. The majority of studies of topical
prostaglandin analogues, including a 16-week randomized trial of 11 patients, have shown no benefit
[71-73]. However, a nonrandomized, prospective study reported benefit with a longer course of
therapy. Of 44 patients with eyelash alopecia treated with latanoprost ophthalmic solution for two
years, complete or moderate regrowth occurred in 17.5 and 27.5 percent, respectively [74]. None of
the 10 patients in the control group attained similar levels of response.
OTHER THERAPIES Improvement following treatment with a

variety of additional local and systemic therapies has been reported. However, further studies are
necessary before any of these agents can be routinely recommended.
Local therapies
●Bexarotene – In a phase I/II, randomized, single-blind trial, patients with alopecia areata applied
topical bexarotene, a retinoid, to one side of the scalp [75]. After 24 weeks, 5 out of 42 patients (12
percent) exhibited at least 50 percent hair regrowth on the treated side of the scalp. An additional six
patients (14 percent) had regrowth on both sides of the scalp. The reason for the bilateral hair
growth is unclear.
●Excimer laser – The excimer laser emits monochromatic ultraviolet B (UVB) light at a wavelength
of 308 nm. Its mechanism of action in alopecia areata is thought to involve the induction of T cell
apoptosis [76,77]. In a few small studies and case reports, treatment with the excimer laser was
associated with improvement in patchy alopecia areata of the scalp [76,78-81]. Patients with lesions
on the extremities, alopecia totalis, or alopecia universalis have not responded to therapy [76,78,81].
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●Minoxidil – Randomized trials of minoxidil have been small, and some, but not all, trials have found
evidence of benefit, at least for patients with limited alopecia areata [82-84]. Minoxidil does not
appear to be effective in patients with total loss of scalp hair [84].
Topical minoxidil is used twice daily alone or in combination with intralesional or topical
corticosteroids. While there may be a dose response effect with the 5% solution being more effective
than the 2% solution [85], few patients achieve cosmetically significant regrowth, and continued
application is required to maintain growth. If used, minoxidil should be tried for three months before
evaluating effectiveness.
Topical minoxidil is generally well tolerated but can lead to unwanted growth of facial hair in
approximately 3 percent of women [86]. Pruritus or dermatitis is an occasional adverse event [87]; a
foam formulation is less likely to induce these symptoms [88]. Unlike the solution formulation,
propylene glycol (a common allergen and irritant) is not present in minoxidil foam.
●Platelet-rich plasma – Platelet-rich plasma, which contains growth factors that are important for
cell proliferation and differentiation and has anti-inflammatory properties, may be beneficial in
alopecia areata. In a trial in which 45 patients with chronic, recurring alopecia areata of at least two
years duration were randomly assigned to intralesional injections of autologous platelet-rich plasma,
triamcinolone acetonide, or placebo administered once per month for three months, platelet-rich
plasma injection was most effective for inducing hair regrowth [89]. Platelet-rich plasma therapy
also was associated with reductions in symptoms of burning or itching in affected areas. Additional
studies are necessary to validate the findings of this trial.
●Photochemotherapy – Psoralen plus ultraviolet A (PUVA) photochemotherapy involves topical or

oral administration of a psoralen, a photosensitizing agent, followed by exposure to ultraviolet A
(UVA) light. Several uncontrolled series suggest efficacy rates of 60 to 65 percent, though with a
high relapse rate [90-93]. Other series have found efficacy rates no higher than might be expected
without therapy [94,95]. PUVA photochemotherapy has the potential for long-term adverse effects,
including cutaneous malignancy. PUVA is generally avoided in children for this reason. In our
practices, we avoid PUVA photochemotherapy for both adult and pediatric patients. (See "Psoralen
Topical pimecrolimus [96], topical tacrolimus [97,98], topical cyclosporine [99,100], and
photodynamic therapy [101-103] are not effective for alopecia areata.
Systemic therapies
●Cyclosporine – Cyclosporine may induce hair growth in patients with alopecia areata. However,
cyclosporine therapy is associated with the potential for serious adverse effects that preclude long-
term therapy; therefore, we tend to avoid use of cyclosporine for alopecia areata.
Efficacy data for cyclosporine are limited. A 12-week trial in which 36 adults with moderate to severe
alopecia areata (including 21 adults with alopecia totalis or alopecia universalis) were randomly
assigned to either cyclosporine (4 mg/kg per day) or placebo found a nonstatistically significant
2456
trend favoring benefit of cyclosporine; at week 12, 31 versus 6 percent of patients treated with
cyclosporine or placebo, respectively, achieved at least 50 percent improvement in the Severity of
Alopecia Tool (SALT) score [104]. Additional studies with larger sample sizes or longer treatment
durations may be useful for confirming benefit of cyclosporine.
Data from case series and uncontrolled studies also suggest benefit of cyclosporine given with or
without systemic glucocorticoids [105-108]. Cyclosporine doses higher than 4 mg/kg have also been
utilized [105]. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)
The development of alopecia areata during cyclosporine therapy has also been reported [109-112].
●Ezetimibe-simvastatin –A prospective study of 29 adults with alopecia areata involving 40 to 70

percent of the scalp suggests that ezetimibe-simvastatin (10 mg/40 mg) may be beneficial for
alopecia areata [113]. Of the 19 patients who completed 24 weeks of once-daily therapy (10 patients
were lost to follow-up), 14 had at least 20 percent hair regrowth and 9 had at least 70 percent hair
regrowth. A second phase of the study compared responders who continued treatment for an
additional 24 weeks with responders who stopped therapy. Of the seven patients who continued
treatment, five had continued regrowth or stable disease, one had new hair loss, and one was lost to
follow-up. In contrast, among the seven patients who stopped therapy, one had stable disease, five
relapsed, and one was lost to follow-up. Treatment benefit for alopecia totalis and alopecia
universalis is also documented in case reports [114,115]. A controlled trial is necessary to confirm
efficacy of this therapy.
●Low-dose recombinant interleukin-2 – The finding that impairment of the inhibitory function of
regulatory T cells may play a role in alopecia areata [116] led to a small pilot study that evaluated the
efficacy of interleukin (IL)-2, a cytokine involved in regulatory T cell homeostasis indicated for the
treatment of advanced melanoma and renal cell carcinoma, as a treatment for alopecia areata. In the
study, five women with severe alopecia areata (>50 percent of the scalp surface affected) were given
one course of subcutaneous recombinant IL-2 (1.5 million international units per day) for five days,
followed by three five-day courses of 3 million international units per day at weeks 3, 6, and 9 [117].
Although none of the patients achieved the primary outcome (90 percent improvement in the SALT
score by two or six months after treatment), four of five had a partial response, and continued
improvement was observed between two and six months after the completion of treatment.
Immunohistochemical studies were also performed and revealed an increase in the regulatory T cell
count in scalp biopsy specimens from all patients who exhibited clinical improvement, suggesting
that the promotion of regulatory T cells is a factor in clinical improvement.
Severe toxicity is a limiting factor for the high doses of recombinant IL-2 used for the treatment of
melanoma and renal cell carcinoma. However, adverse effects during low-dose recombinant IL-2
therapy for alopecia areata were mild to moderate and included asthenia, arthralgia, urticaria, and
injection site reactions [117]. Further study is necessary to determine whether low-dose recombinant
IL-2 therapy should have a role in the treatment of alopecia areata.
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Biologic tumor necrosis factor (TNF)-alpha inhibitors are not effective for alopecia areata [118]. In
addition, patients who have been treated with the TNF-alpha inhibitors adalimumab, infliximab, or
etanercept for other autoimmune disorders have developed alopecia areata during the course of
treatment [119-126]. Data on the efficacy of hydroxychloroquine are limited and conflicting [127-
129].


Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given condition. These
●Basics topics (see "Patient education: Hair loss in men and women (The Basics)")
●Beyond the Basics topics (see "Patient education: Alopecia areata (Beyond the Basics)")
SUMMARY AND
RECOMMENDATIONS
●Alopecia areata is a chronic, relapsing disorder that results in nonscarring hair loss. Not all patients
with alopecia areata require treatment; up to 50 percent of patients with limited alopecia areata of
less than one year's duration will experience spontaneous regrowth of hair. (See 'Introduction'
above.)
●The cosmetic effects of alopecia areata can cause severe emotional distress; counseling in such
patients is essential. (See 'Counseling' above.)
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●There is relatively little evidence on treatment from well-designed clinical trials. The response to
treatment is variable, and some patients may elect not to treat this condition. For patients who desire
treatment, we suggest the following:
•We suggest that limited scalp alopecia areata be treated with intralesional injections of
corticosteroids (Grade 2B). (See 'Intralesional corticosteroids' above.)
•In children or adults with limited disease who are unlikely to tolerate intralesional therapy, we
suggest treatment with topical corticosteroids (Grade 2B). (See 'Potent topical corticosteroids'
above.)
•We suggest that patients with extensive alopecia areata, including alopecia totalis, as well as
patients with more limited disease who do not respond to the above therapies be treated with topical
immunotherapy (Grade 2C). Patients should generally be referred to a dermatologist for such
therapy and any additional management. (See 'Topical immunotherapy' above.)
●Patients who do not desire treatment may benefit from cosmetic interventions. Wigs or shaving the
scalp may produce an acceptable cosmetic result. Temporary tattooing can be helpful for loss of
eyebrows. False eyelashes are available for patients with alopecia of the eyelashes. (See 'Cosmetic
options' above.)
●Systemic glucocorticoid therapy may induce hair regrowth, and short courses of treatment are
occasionally utilized to temporarily halt disease progression in patients with rapidly progressing,
widespread, active disease. The potential adverse effects of systemic glucocorticoids make them
unfavorable options for long-term management. (See 'Systemic glucocorticoids' above.)
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Androgenetic alopecia in men: Pathogenesis, clinical features,
and diagnosis
uptodate.com/contents/androgenetic-alopecia-in-men-pathogenesis-clinical-features-and-diagnosis/print
INTRODUCTION Androgenetic alopecia is the most common type of hair

loss in men. The condition is characterized by the progressive loss of terminal hairs on the scalp in a
characteristic distribution. The anterior scalp, mid scalp, temporal scalp, and vertex of the scalp are
typical sites of involvement (picture 1A-D). "Male balding" and "male pattern hair loss" are additional
terms used to refer to this condition.
The pathogenesis, clinical features, and diagnosis of androgenetic alopecia in men will be reviewed
here. The treatment of androgenetic alopecia, androgenetic alopecia in women, and the general
approach to the evaluation and diagnosis of hair loss are discussed separately.
●(See "Treatment of androgenetic alopecia in men".)
and diagnosis".)
●(See "Female pattern hair loss (androgenetic alopecia in women): Treatment and prognosis".)
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EPIDEMIOLOGY Male androgenetic alopecia is a common postpubertal

disorder that occurs worldwide and exhibits increasing prevalence with age. Prevalence estimates
from studies in different countries suggest differences in prevalence based upon race or ethnicity;
however, wide variation in study methods have made comparisons of prevalence estimates difficult
[1-7].
For example, a study in the United States found at least moderate androgenetic alopecia (Hamilton-
Norwood III or above (figure 1)) in 48 percent of 266 healthy men (ages 18 to 49 years), including 16
percent of men between the ages of 18 and 29 years and 53 percent of men between the ages of 40
and 49 years [6]. Prevalences of androgenetic alopecia appeared to be lower in a Korean study that
involved examination of men visiting a hospital for regular health examinations. The Korean study
found androgenetic alopecia (Hamilton-Norwood III or above) in only 14 percent of 5531 men (ages
20 and older), increasing from 2 percent among individuals aged 20 to 29 years to 11 percent among
individuals aged 40 to 49 years [1].
PATHOGENESIS Androgenetic alopecia is considered an androgen-

dependent trait that requires a genetic predisposition. The interaction of these factors and other
mechanisms that remain to be elucidated contributes to follicular miniaturization (the transition of
larger, terminal hair fibers to small vellus hair fibers) in susceptible scalp areas. (See 'Androgens'
below and 'Genetics' below and 'Follicular miniaturization' below and 'Other factors' below.)
Androgens — Consistent with a critical role for androgens, male androgenetic alopecia
typically develops after puberty, a phase associated with a dramatic increase in androgen
production. In addition, men with androgen insensitivity syndrome do not develop the condition [8].
(See "Pathogenesis and clinical features of disorders of androgen action", section on 'Complete
androgen insensitivity (CAIS)'.)
Dihydrotestosterone (DHT) is the key androgen involved in the induction and promotion of male
androgenetic alopecia [9]. DHT is a potent metabolite of testosterone and, compared with
testosterone, has greater affinity for the androgen receptor.
The 5-alpha-reductase enzyme mediates the conversion of testosterone to DHT and exists in two
isoforms in scalp hair follicles: type 1 and type 2. Although both isoforms have a role in
androgenetic alopecia, the role of the type 2 isoform is greater. The type 2 isoform is located in the
outer root sheath of hair follicles as well as the epididymis, vas deferens, seminal vesicles, and
prostate. The type 1 isoform is located in sebaceous glands, epidermal and follicular keratinocytes,
dermal papillae cells, and sweat glands.
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The importance of 5-alpha-reductase is supported by the absence of androgenetic alopecia in men
with mutations in the 5-alpha-reductase type 2 gene [10]. In addition, inhibitors of 5-alpha-reductase
(eg, finasteride, dutasteride) are effective therapies for androgenetic alopecia. (See "Steroid 5-alpha-
reductase 2 deficiency" and "Treatment of androgenetic alopecia in men".)
Intrinsic differences in hormone metabolism and hormone receptors may also contribute to
androgenetic alopecia. Young men with androgenetic alopecia have higher levels of cellular 5-alpha-
reductase and a higher quantity of androgen receptors in the balding scalp than in the nonbalding
scalp [11]. In addition, production rates of DHT are higher in men with androgenetic alopecia than in
men without the condition [12]. Although plasma testosterone concentrations are similar in balding
and nonbalding men [13], elevated levels of unbound testosterone (the active fraction of
testosterone) have been detected in some men with androgenetic alopecia [14,15].
Genetics — Androgenetic alopecia is considered a heritable disorder [16], a concept

supported by the results of familial studies [17-19]. A study of 572 men evaluated in a dermatology
clinic for concerns unrelated to androgenetic alopecia found that young men with a balding father
were more than five times more likely to have androgenetic alopecia than young men with fathers
without the condition (relative risk 5.5, 95% CI 1.26-23.99) [18]. In addition, a study of approximately
500 monozygotic male twins and 400 dizygotic male twins between the ages of 25 and 36 attributed
80 percent of the variance in the extent of hair loss to genetic effects [19].
Multiple genetic susceptibility loci for androgenetic alopecia have been identified [20,21]. Examples
include the androgen receptor (AR)/EDAR2 locus on the X chromosome [22], the PAX1/FOXA2 locus
on chromosome 20p11 [23,24], and HDAC9 gene on chromosome 7p21.1 [16,25]. Chromosome 3q26
may also have a contributory role [26].
Follicular miniaturization — The perception of hair "loss" in

androgenetic alopecia results from shortening of the anagen (growth) phase of hair follicles, rather
than the complete cessation of hair growth in affected areas [27]. The shortened anagen phase
leads to the production of shorter, thinner vellus hair shafts, a process called follicular
miniaturization (picture 2). As additional follicles undergo miniaturization, hair coverage of the scalp
progressively decreases. (See "Evaluation and diagnosis of hair loss", section on 'Hair biology'.)
Follicular miniaturization is caused by a hormonally mediated process at the level of the hair follicle
dermal papilla [28]. At the cellular level, DHT binds to the androgen receptor, and the hormone-
receptor complex then activates the genes responsible for the gradual transformation of large,
terminal follicles to smaller follicles with a shortened anagen phase [29-32]. The precise
mechanisms through which genetic variants contribute to the induction of follicular miniaturization
remain unclear [33]. (See 'Genetics' above.)
The gradual transformation is associated with apoptosis of cells within the dermal papilla and a
reduction in the overall size of the dermal papilla. This may be central to the miniaturization process
given that the size of the dermal papilla correlates well with the caliber of the hair fiber produced.
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Other factors — Although hormone-mediated pathogenic mechanisms have been an
intensive focus of research, a variety of other pathogenic mechanisms may be relevant. These
include Wnt signals, prostaglandin D2 signals, prostaglandin F2-alpha signals, and Janus kinase
(JAK) signals, among others [34,35]. New treatments for androgenetic alopecia based upon
targeting of these mechanisms are under investigation [36,37].
CLINICAL FEATURES Androgenetic alopecia in men is

characterized by varying degrees of hair follicle miniaturization and reduction in terminal hair
density on the scalp in characteristic locations (picture 1A-D). The degree of scalp involvement may
change over time as the condition progresses.
Some men with androgenetic alopecia may occasionally report symptoms such as itching, but it
remains to be fully elucidated as to whether these symptoms are a bona fide feature of androgenetic
alopecia and whether such symptoms correlate with the histologic findings of perifollicular
inflammation that are known to characterize this hair loss condition. (See 'Histopathology' below.)
Many males with androgenetic alopecia who present with concerns about itching have identifiable
reasons separate from the androgenetic alopecia itself, such as seborrheic dermatitis. Whether
androgenetic alopecia itself has a symptomatic phase awaits further study.
Pattern and course — Signs of androgenetic alopecia may first appear during
adolescence. Terminal hair loss typically begins in the temporal scalp, midfrontal scalp, or vertex
area of the scalp (picture 1A-D). The severity of involvement of these areas is highly variable; in
some men, the greatest degree of hair loss occurs at the vertex, and other men exhibit the most
severe hair loss anteriorly. (See "Treatment of androgenetic alopecia in men", section on 'Surgery'.)
Androgenetic alopecia is a continuous process that progresses slowly over the course of many
years. The two most common patterns for progression of hair loss are reviewed in this figure (figure
1). Hair loss occurs in waves of activity, with more rapid intervals of hair loss at certain times
followed by periods of minimal activity.
Classification — The Hamilton-Norwood scale is used to classify androgenetic

alopecia. The scale divides the clinical findings into seven stages and offers a visual depiction of the
sequential stages of balding (figure 1). The scale also describes a less common type A variant of
hair loss in which men demonstrate only the progressive movement of the anterior hairline
posteriorly (figure 1) [38].
Not all men with androgenetic alopecia follow the hair loss patterns outlined by the Hamilton-
Norwood scale. For example, 10 percent of men have a pattern that resembles female androgenetic
alopecia (preservation of the frontal hairline and terminal hair loss in the central scalp) (picture 3)
[39].
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HISTOPATHOLOGY Androgenetic alopecia has distinct
histopathologic findings that can be identified on scalp specimens sectioned horizontally or
vertically:
●Horizontal sections – The histologic features of androgenetic alopecia are more readily seen in
horizontal sections. Depending on the severity of the clinical findings, there is a variable mixture of
terminal, vellus, and vellus-like hair follicles in the dermis. The vellus and vellus-like hairs are less
than 0.03 mm in diameter [40]. Terminal hairs (greater than 0.06 mm) are seen in the reticular
dermis.
The ratios of anagen to telogen (A:T) hair follicles and terminal to vellus (T:V) hair follicles are
altered in androgenetic alopecia and can be readily evaluated with horizontal sections. In the course
of androgenetic alopecia, the A:T ratio is reduced from 12:1 to less than 5:1. The T:V ratio is reduced
from 7:1 to less than 2.5:1 in more advanced cases [41]. These alterations in the T:V ratio can be
extremely helpful in the diagnosis of androgenetic alopecia.
●Vertical sections – Vertical sections show terminal hair follicles rooted in the subcutaneous and
reticular dermis and vellus hair follicles located more superficially in the papillary dermis. Vertical
columns of connective tissue, known as follicular stelae or follicular streamers, can be seen [42,43].
The follicular stelae that originate in the deep dermis and underlie vellus hairs in the more superficial
dermis may represent connective tissue that previously surrounded terminal hair follicles prior to
miniaturization [41].
Inflammation is not uncommon in histologic specimens from androgenetic alopecia despite the fact
that it is classified as a noninflammatory form of hair loss. Mild, perifollicular, lymphohistiocytic
inflammation is present in one-third of biopsies, and moderate inflammation is present in
approximately 40 percent of specimens [42]. This inflammation differs significantly from the intense
peribulbar inflammation that is typically found in alopecia areata. The precise role of the
inflammatory response seems unclear, although its presence early in the course of androgenetic
alopecia and its presence around miniaturized hairs has led some authors to postulate it may
contribute to miniaturization [44].
Mild, perifollicular fibrosis is an additional feature that may be detected [42]. Although perifollicular
fibrosis as well as peri-isthmal/infundibular inflammation can be seen in scarring alopecias, such as
lichen planopilaris, the scarring alopecias also show loss/reduction of sebaceous glands and often
lichenoid-type changes in the outer root sheath that are not present in androgenetic alopecia [45].
The presence of inflammation or fibrosis may have prognostic significance in androgenetic alopecia.
In a study of male patients with androgenetic alopecia treated with topical minoxidil, 55 percent of
22 men with inflammation or fibrosis responded to minoxidil compared with 77 percent of 22 men
without histopathologic evidence for inflammation or fibrosis [42]. Further studies are necessary to
confirm this finding.
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ASSOCIATED DISORDERS Androgenetic alopecia may
have negative psychosocial effects and has been linked to other disorders, such as cardiovascular
disease and prostate cancer.
Psychosocial effects — The psychosocial impact of androgenetic alopecia

on men varies. Overall, the impact tends to be less than for women with female pattern hair loss;
however, men may experience stress related to hair loss, reduced quality of life, and, infrequently,
related body dysmorphic disorder [46]. (See "Female pattern hair loss (androgenetic alopecia in
women): Pathogenesis, clinical features, and diagnosis", section on 'Psychosocial dysfunction' and
"Body dysmorphic disorder: Clinical features".)
Cardiovascular disease — Multiple studies have investigated the

relationship between androgenetic alopecia and cardiovascular disease or risk factors for
cardiovascular disease, including studies that have identified elevated rates of cardiovascular
disease in patients with vertex hair loss [47,48], vertex and frontal hair loss [49], early-onset hair loss
[50], and rapidly progressive hair loss [50]. In addition, increased risks for hypertension [51], excess
weight [52], abnormal lipids [53], insulin resistance [54], carotid atheromatosis [55], and death from
diabetes or heart disease [56] have been reported in this population. Studies investigating an
association between androgenetic alopecia and the metabolic syndrome have yielded conflicting
findings [55,57-59].
Distinct guidelines for the detection and prevention of cardiovascular disease in individuals with
androgenetic alopecia have not been established. (See "Metabolic syndrome (insulin resistance
syndrome or syndrome X)".)
Prostate cancer — Studies evaluating the relationship between androgenetic

alopecia in men and prostate cancer have yielded varied results [14,60-66]. A systematic review and
meta-analysis of seven case-control studies (4078 cases and 4916 controls) that used a
standardized tool to classify androgenetic alopecia found an association between vertex pattern hair
loss in androgenetic alopecia and increased risk for prostate cancer (pooled odds ratio [OR] 1.25,
95% CI 1.09-1.44) but did not find an association between any pattern of androgenetic alopecia and
the disease [67]. A subsequent systematic review and meta-analysis that included both case-control
and cohort studies yielded similar findings [68].
An analysis of data from the National Health and Nutrition Examination Survey Epidemiologic
Follow-up Study on 4316 men 25 to 74 years of age followed up from between 1971 and 1974 to
2011 found that androgenetic alopecia was associated with a 56 percent increased risk of death
from prostate cancer (hazard ratio [HR] 1.56, 95% CI 1.02-2.37) [69].
Further confirmation is needed before a recommendation for the use of androgenetic alopecia in
screening decisions for prostate cancer.
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Other — An 18-year prospective study including over 30,000 male participants in the Health
Professionals Follow-up Study found a modest increase in the risk of colon cancer for men with
frontal-only baldness and frontal-plus-mild-vertex baldness compared with men without baldness
(HR 1.29, 95% CI 1.03-1.62; and HR 1.31, 95% CI 1.01-1.70, respectively) [70]. Additional studies are
needed to confirm this association.
DIAGNOSIS The diagnosis of androgenetic alopecia in males is usually

straightforward and can be made through obtaining a history and performing an examination of the
hair and scalp. Slow, progressive, asymptomatic hair loss with evidence of follicular miniaturization
on the temporal, frontal, and/or vertex regions of the scalp supports a diagnosis of androgenetic
alopecia. (See "Evaluation and diagnosis of hair loss", section on 'Hair pull test'.)
History — The patient history should include an assessment of the progression, distribution,
and extent of hair loss, as well as associated symptoms and family history. Men with androgenetic
alopecia typically describe slow, progressive hair loss without associated symptoms. A family
history of similar hair loss is common.
Rapid hair loss or hair loss accompanied by itching, burning, or scalp tenderness suggests an
alternative or coexisting diagnosis. In particular, rapid hair loss related to telogen effluvium may
unmask previously unnoticed androgenetic alopecia. (See "Telogen effluvium".)
The approach to the patient interview for hair loss is reviewed in detail separately. (See "Evaluation
and diagnosis of hair loss", section on 'Patient interview'.)
Physical examination — The physical examination should include careful

examination of the scalp and hair. (See "Evaluation and diagnosis of hair loss", section on 'Physical
examination'.)
Follicular miniaturization in a distribution consistent with androgenetic alopecia essentially confirms

the diagnosis (picture 1A-D). Examination of the caliber of hair fibers against a paper that is a color
that contrasts with the hair facilitates visualization of miniaturized hairs.
Examination with a dermatoscope is also helpful for identification of miniaturized hairs and
diagnosis (picture 2) [71]. Dermoscopic features of androgenetic alopecia include hair diameter
diversity, perifollicular pigmentation/peripilar signs, and yellow dots (table 1) [71,72]. Focal atrichia
(small areas with a complete absence of hair) may also be seen. (See "Overview of dermoscopy of
the hair and scalp".)
Patients with clinical findings of androgenetic alopecia who report rapid hair loss should undergo a
hair pull test to assess for coexisting active telogen effluvium. (See "Evaluation and diagnosis of hair
loss", section on 'Hair pull test' and "Telogen effluvium".)
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Scalp biopsy — Histopathologic examination is not usually necessary for diagnosis.
However, androgenetic alopecia has distinctive histologic features, and biopsies can be used to
confirm the diagnosis in the infrequent cases in which the diagnosis is uncertain [42,73]. (See
'Histopathology' above.)
A 4 mm punch biopsy is the preferred procedure for obtaining a tissue specimen for diagnosis. We
usually obtain two biopsies, one for horizontal (transverse) sectioning and one for vertical
sectioning. Horizontal sectioning of the tissue specimen allows for visualization of more follicles
and tends to yield more useful results than vertical sectioning [42]. (See 'Histopathology' above and
"Skin biopsy techniques", section on 'Biopsy techniques'.)
DIFFERENTIAL DIAGNOSIS Hair loss related to

androgenetic alopecia should be distinguished from other causes of nondiffuse hair loss, such as
hairline maturation, alopecia areata, traction alopecia, cicatricial alopecias, and trichotillomania.
Given its frequent occurrence, androgenetic alopecia may also coexist with these and other hair and
scalp diseases:
●Hairline maturation –Slight recession of the hairline is a normal, hormonally mediated occurrence
that typically begins in early adulthood. In men, this involves up to two centimeters of posterior
recession of the leading edge of the hairline from its childhood position [74]. Minor temporal
recession also occurs, further contributing to a change in the shape of the hairline. The limited
extent of hairline recession contrasts with the more extensive recession and vertex involvement that
occurs in androgenetic alopecia.
●Alopecia areata – Alopecia areata is an immune-mediated form of nonscarring hair loss. Alopecia
areata most often manifests as sudden hair loss in circular, discrete areas but may also present with
larger patches of alopecia or loss of all scalp hair (picture 4). In particular, the rare sisaipho (ophiasis
inversus) pattern, which involves loss of hair on the frontal, temporal, and parietal scalp, may be
mistaken for androgenetic alopecia (picture 5). In contrast to the slow, progressive course of
androgenic alopecia, hair loss in alopecia areata tends to be rapid. A scalp biopsy is useful for
distinguishing challenging cases. (See "Alopecia areata: Clinical manifestations and diagnosis".)
●Traction alopecia – Traction alopecia is a type of hair loss that results from prolonged or repetitive
tension on hair. The location of hair loss correlates with the site of traction. The frontal and temporal
scalp are the most common affected areas (picture 6). A history of a traction-inducing hairstyle and
hair loss in the correlating distribution supports the diagnosis. If the diagnosis remains uncertain, a
biopsy can be helpful. (See "Traction alopecia".)
●Cicatricial (scarring) alopecias – Patches of scarring hair loss or frontal hairline recession from
cicatricial alopecias may be confused with androgenetic alopecia, particularly when clinical signs of
inflammation are minimal or resolved (picture 7A-C). However, unlike androgenetic alopecia, close
examination of the involved scalp will reveal findings consistent with scarring (absence of follicular
ostia and vellus hairs). In addition, a history of inflammatory signs or symptoms (eg, pruritus, pain,
2467
inflamed papules, pustules) in the affected area is often present in cicatricial alopecias. When
necessary, a scalp biopsy can distinguish androgenetic alopecia from cicatricial alopecia. (See
"Evaluation and diagnosis of hair loss", section on 'Cicatricial alopecia'.)
●Trichotillomania – Trichotillomania is a psychiatric disorder characterized by recurrent hair pulling.

Patients often present with bizarrely shaped patches of alopecia and hair shafts of different lengths
due to multiple episodes of hair puling. The diagnosis usually can be made based upon the patient
history. A scalp biopsy can help to confirm the diagnosis in challenging cases. (See "Skin picking
(excoriation) disorder and related disorders", section on 'Trichotillomania'.)

INFORMATION FOR PATIENTS Educational

materials on this topic are available for patients (see "Patient education: Hair loss in men and
women (androgenetic alopecia) (Beyond the Basics)"). We encourage you to print or e-mail this topic
review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this
and other topics.
SUMMARY AND
RECOMMENDATIONS
●Androgenetic alopecia is a common condition in postpubertal males that is characterized by the
loss of terminal hairs in select areas on the scalp. (See 'Epidemiology' above.)
●Hormonal, genetic, and other factors contribute to the development of male androgenetic alopecia.
The effects of dihydrotestosterone on susceptible follicles contributes to follicular miniaturization,
which manifests clinically as the replacement of terminal hairs by short, thin (vellus) hairs. (See
●The appearance of male androgenetic alopecia varies among individuals. The temporal, anterior,
mid scalp, and/or vertex areas of the scalp are typically affected (picture 1A-D). The occipital scalp
is usually spared. The loss of terminal hairs slowly progresses over the course of years. (See
●The diagnosis of androgenetic alopecia is usually made clinically and is based upon the detection
of slow, progressive hair loss and follicular miniaturization in a distribution consistent with
androgenetic alopecia. For the infrequent cases in which the diagnosis is uncertain, a biopsy can be
used to confirm the diagnosis. (See 'Diagnosis' above.)
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●Some men with androgenetic alopecia may experience negative psychosocial effects.
Androgenetic alopecia has also been associated with other disorders, such as cardiovascular
disease and prostate cancer. (See 'Associated disorders' above.)
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Treatment of androgenetic alopecia in men
uptodate.com/contents/treatment-of-androgenetic-alopecia-in-men/print
INTRODUCTION Male androgenetic alopecia (also known as male

pattern hair loss and male balding) is a common, progressive form of hair loss distinguished by the
reduction of terminal hairs on the scalp in a characteristic distribution (picture 1A-D). The anterior
scalp, mid scalp, temporal scalp, and vertex of the scalp are the typical sites of involvement. Hair
loss occurs over the course of years.
Although androgenetic alopecia is a benign and asymptomatic disorder, cosmetic concerns lead
some patients to seek treatment. The primary pharmacologic therapies for men with androgenetic
alopecia are topical minoxidil and oral finasteride. Hair restoration surgery can also result in
cosmetic improvement.
The treatment of androgenetic alopecia in men will be reviewed here. The pathogenesis, clinical
features, and diagnosis of male androgenetic alopecia are reviewed in greater detail separately. (See
"Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis".)
2470
FIRST-LINE THERAPIES Topical minoxidil and oral
finasteride are the therapeutic agents that have been most extensively studied for the treatment of
androgenetic alopecia in men. Both drugs have demonstrated efficacy and high tolerability in
placebo-controlled randomized trials, supporting their status as first-line agents [1]. The response to
treatment with finasteride or minoxidil varies. While some men achieve cosmetically significant
regrowth, others benefit most from the slowing of additional hair loss. Continuation of these drugs is
required to maintain the results of therapy.
Finasteride — Finasteride is an oral inhibitor of dihydrotestosterone (DHT) production

that is efficacious for male androgenetic alopecia.
Mechanism of action — Finasteride competitively inhibits the 5-alpha-reductase

type 2 enzyme, and thereby inhibits conversion of testosterone to DHT [2]. At a dose of 1 mg/day,
finasteride lowers serum and scalp DHT levels by more than 60 percent [3]. The drug has no affinity
for the androgen receptor and does not interfere with testosterone action [2]. (See "Androgenetic
alopecia in men: Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis'.)
Efficacy — A meta-analysis of placebo-controlled randomized trials identified moderate

quality evidence in support of the use of finasteride for treatment of androgenetic alopecia in men
[4]. After 6 or 12 months of treatment, the mean percentage change in hair count was 9 percent
higher among patients treated with finasteride compared with patients who were given placebo (95%
CI 8-11 percent). This difference increased over time. After 48 months of therapy, the mean
percentage change in hair count was 24 percent (95% CI 18-31 percent) higher in patients treated
with finasteride.
The proportion of men who achieve clinically significant responses to finasteride was assessed in
two one-year randomized trials that were included in the meta-analysis [5]. A total of 1553 men aged
18 to 41 years with predominantly vertex hair loss were randomly assigned to oral finasteride (1
mg/day) or placebo for one year, with blinded extension studies for a second year in 1215 of the
men. Finasteride treatment resulted in clinically significant increases in hair count, while treatment
with placebo was associated with progressive hair loss. After two years, scalp coverage as
assessed by the study investigators was improved in approximately two-thirds of men taking
finasteride, versus only 7 percent of men who received placebo. One-third of the men treated with
finasteride had the same amount of hair as they did at the start of the study, and only about 1
percent of patients on finasteride lost hair (versus one-third of patients who received placebo). In
addition, more men in the finasteride group reported increased satisfaction with their hair after
treatment (51 versus 25 percent).
Although most published studies documenting the efficacy of finasteride have focused on the vertex
of the scalp, the efficacy of finasteride is not limited to this area. A randomized trial of 326 men
found that the drug was efficacious for frontal scalp hair thinning [6]. In addition, a subsequent
randomized trial found statistically significant hair growth in the vertex, anterior/mid, frontal, and
2471
temporal scalp, with the best results observed in the vertex and anterior/mid scalp. Age appeared to
be relevant in the response to treatment; treatment was more effective in younger men (ages 18 to
41) than older men (ages 41 to 60).
In addition to improved hair counts, other factors, such as increases in hair thickness, pigmentation,
and length may contribute to the perception of improved scalp coverage during therapy [3]. This
concept is supported by a randomized trial that followed men treated with finasteride for up to 192
weeks and found that net improvements in hair weight were greater than improvements in hair count
[7,8].
Administration — For the treatment of male androgenetic alopecia, the recommended

dose of finasteride is 1 mg per day. The medication may be taken with or without food.
Treatment with finasteride should continue for at least 12 months to assess the drug's full effects,
and the drug must be continued to maintain efficacy. Hair regrowth will be lost over six to nine
months if finasteride is discontinued.
Adverse effects — Occasionally, finasteride has deleterious effects on sexual function.

These include erectile dysfunction, decreased libido, and ejaculatory dysfunction. A systematic
review of nine trials with a total of 3570 patients found an overall absolute increase in sexual
dysfunction of 1.5 percent [4]. The risk for sexual side effects increases with age [9].
Sexual side effects related to finasteride usually resolve after discontinuation of the medication [10].
However, persistent sexual dysfunction after the discontinuation of finasteride was reported in a
survey-based study of 71 men who associated their symptoms of sexual dysfunction with the use of
finasteride for hair loss. The mean age of the study participants was 26 years and the mean duration
of finasteride use was 28 months. Twenty percent of these men reported continued symptoms for
greater than six years after cessation of the medication [11]. Moreover, a follow-up study of 54 of the
interviewed men found that 9 to 16 months after the initial survey, 96 percent continued to report
sexual side effects [12]. Additional studies are needed to validate these findings and evaluate the
frequency with which persistent sexual dysfunction might occur.
Reductions in sperm count also may occur during treatment with finasteride [13,14]. This effect
reverses after drug discontinuation.
Other rare side effects of finasteride include gynecomastia, testicular pain, and depression [15]. Side
effects are more likely to occur with the typical 5 mg dose used to treat benign prostatic
hypertrophy. Although finasteride is teratogenic, the finasteride concentration in semen does not
pose a risk to women trying to conceive.
Precautions — Finasteride may impact measurement of serum prostate specific antigen

(PSA). The PSA can decline significantly in men taking finasteride, resulting in the need to interpret
test results accordingly [16]. (See "Measurement of prostate-specific antigen", section on
'Medications'.)
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Although randomized trials have found that finasteride therapy decreases risk for prostate cancer,
the drug also may increase the risk for high-grade prostate cancer lesions. The relationship between
finasteride treatment and prostate cancer is discussed in detail separately. (See "Chemoprevention
strategies in prostate cancer", section on 'Finasteride: PCPT'.)
Finasteride is metabolized by the liver. Thus, caution is prudent for use in patients with liver
dysfunction. Data are insufficient to conclude whether finasteride influences the risk for male breast
cancer [17]. (See "Breast cancer in men".)
Topical minoxidil — In the United States, topical minoxidil is available without a

prescription as 2% solution, 5% solution, and 5% foam. Due to evidence in support of greater efficacy
of minoxidil 5% solution compared with minoxidil 2% solution in men, use of the 5% concentration is
recommended [18].
The subsequent development of minoxidil 5% foam offered an alternative vehicle for drug delivery
that is preferred by some patients. In addition, unlike minoxidil solution, the foam formulation is free
of propylene glycol, a feature that correlates with a lower risk for skin irritation [19].
Mechanism of action — Minoxidil promotes hair growth by increasing the

duration of anagen, shortening telogen, and enlarging miniaturized follicles [20]. The
pathophysiologic mechanism through which minoxidil influences follicular structure and follicular
cycling is unclear, and the interpretation of the available literature is complicated by studies with
conflicting results [3,20]. Minoxidil is a vasodilator, and the induction of vascular endothelial growth
factor (VEGF) may be a mechanism by which minoxidil helps to maintain the vascularity and size of
dermal papillae (collections of mesenchymal tissue beneath follicles that contribute to follicular
development) [21,22]. Since the volume of a dermal papilla correlates with the size of the emerging
hair follicle, minoxidil-induced support of the dermal papilla may be relevant. In addition, minoxidil is
a regulator of potassium ion channels. This function may also contribute to the drug's beneficial
effects [20,23].
Efficacy — Both 2% and 5% minoxidil solution are more efficacious than placebo in male
androgenetic alopecia [18,19,24]. However, the 5% solution is more effective than the 2% formulation
[18].
In the largest randomized trial that compared the 5% and 2% solutions, 393 men with androgenetic
alopecia were randomly assigned to treatment with 5% or 2% topical minoxidil solution or placebo
[18]. After 48 weeks of therapy, 5% minoxidil was significantly better than the 2% solution or placebo
in terms of change from baseline in nonvellus hair count (increase in count of 18.6, 12.7, and 3.9 per
cm2, respectively), patient ratings of scalp coverage and treatment benefit, and investigator rating of
scalp coverage. Treatment with 5% minoxidil was also associated with an earlier therapeutic
response and an improvement in the patients' psychological perceptions of hair loss. However,
patients treated with 5% compared with 2% minoxidil reported more pruritus and local irritation.
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No randomized trials have directly compared the efficacy of minoxidil 5% foam to minoxidil 5%
solution. The use of the 5% foam is supported by a 16-week placebo-controlled randomized trial of
352 men [19]. Minoxidil 5% foam was associated with significantly greater improvements in target
area terminal hair counts (mean change in terminal hair counts of 20.9 versus 4.7), as well as in
scores from patient self-assessments and an investigator global photographic review.
As with finasteride, the response to treatment with minoxidil is variable. In an early study of 56
patients treated with minoxidil 2% or 3% solution, cosmetically significant improvement occurred in
approximately 30 percent of patients. Patients with shorter durations of baldness, smaller areas of
baldness, and larger numbers of nonvellus miniaturized hairs appeared to respond best to minoxidil
therapy [25].
Administration — Men utilizing minoxidil for androgenetic alopecia should be advised

of the following:
●Minoxidil solution is to be used for an indefinite time. Once stopped, any hair regrowth eventually
will be lost, often over the course of several months.
●Minoxidil is a scalp treatment, not a hair treatment, and must be used exactly as prescribed for
maximum benefit.
●Men should apply 1 mL of minoxidil 5% solution or one half of a capful of the 5% foam twice daily
to involved areas on a dry scalp. The solution can be spread lightly with a finger; massage is not
needed.
●Hair shedding may occur at the initiation of treatment and is thought to occur as a result of the
stimulation of telogen follicles to reenter the anagen phase [26]. The increased hair loss usually
resolves within two months. Patients should be warned of this side effect to prevent the premature
discontinuation of treatment.
●Minoxidil must be used twice a day for at least four months prior to evaluating the initial response
to therapy [27]. Hair shedding may occur at the initiation of treatment and usually decreases within
two months. Hair growth may be seen within four to eight months and stabilizes at 12 to 18 months.
Thus, a full year of treatment is recommended before assessing treatment efficacy.
In the United States, minoxidil usually is not covered by medical insurance.
Adverse effects — Side effects from minoxidil are infrequent. The most common side
effects are contact dermatitis and irritant dermatitis [28]. When given systemically, minoxidil has
antihypertensive properties, but neither 5% nor 2% minoxidil solution alters systolic or diastolic blood
pressure, pulse rate, or body weight when applied topically [29]. Nevertheless, due to the potential for
systemic absorption when the scalp skin barrier is not intact, caution should be used in patients with
cardiovascular disease. Hypertrichosis of the face may occur [30], but generally is not a problem for
men.
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Comparative studies — Few studies have directly compared the efficacy of
topical minoxidil with finasteride [31-33]. Although high quality studies are needed, the available data
from small, incompletely blinded randomized trials suggest that finasteride may be more effective
than minoxidil for the induction of hair growth:
●Only one randomized trial has compared finasteride (1 mg/day) with the 5% concentration of
minoxidil that is recommended for male androgenetic alopecia. In the 12-month open randomized
trial in 65 men with androgenetic alopecia, a higher proportion of patients treated with finasteride
exhibited minimal to dense hair growth than patients treated with minoxidil solution (80 versus 52
percent) [32].
●Data from an evaluator-blinded randomized trial of 99 men with midfrontal and/or vertex
androgenetic alopecia that compared finasteride 1 mg/day with the 2% formulation of minoxidil are
less straightforward. Although patients and evaluating clinicians were more likely to perceive
increased hair growth at three months with minoxidil, at 12 months, finasteride was associated with
significantly greater increases in hair counts, and the differences in patient and evaluator global
assessments of clinical response were not statistically significant (62 versus 56 percent improved
on blinded evaluator assessment) [33].
●A randomized, open trial of 100 men with androgenetic alopecia evaluated the efficacies of
finasteride (1 mg/day) alone, minoxidil 2% solution alone, finasteride and minoxidil in combination,
and finasteride plus ketoconazole 2% shampoo [31]. Increased hair growth was detected in all
groups. Patients who received finasteride alone or in combination with minoxidil or ketoconazole
had significantly greater improvement than patients who received only minoxidil. The best results
were attained by the group treated with both finasteride and minoxidil.
Although the last trial found evidence to suggest that combination therapy with finasteride and
topical minoxidil may be superior to monotherapy with either agent [31], further study is needed to
determine whether combination therapy should be routinely recommended.
SURGERY Permanent improvement in androgenetic alopecia can be attained

through surgical therapy. Hair transplantation using follicular units has become the mainstay of
surgical treatment [34]. More invasive and complex procedures that aim to reorient large areas of
hair-bearing skin, such as scalp reduction and flaps, are now less commonly performed. The ideal
candidates for hair transplantation are patients with stable or medically controlled androgenetic
alopecia who desire permanent improvements in hair loss and have an adequate reservoir of hair for
transplantation.
The basic principle governing hair transplantation is that of "donor dominance." Hair follicles
removed from non-balding occipital scalp and transplanted into areas affected by androgenetic
alopecia will maintain the characteristics of the occipital scalp donor site. Because occipital hair is
relatively resistant to androgenetic alopecia, transplanted hairs will remain large caliber hairs.
2475
Modern hair transplant techniques rely on the use of "follicular units," which are the natural
groupings of one to four hair follicles that occur in the scalp. There are two fundamental ways that a
hair transplant can be performed using follicular units: follicular unit transplantation (FUT) and
follicular unit extraction (FUE).
●Follicular unit transplantation – With FUT, a strip of tissue 8 to 15 mm wide and 20 to 30 cm long is
surgically excised from the occipital scalp under local anesthesia. Follicular units are carefully
dissected from the tissue strip with the aid of microscopes and then transplanted into areas of
androgenetic alopecia. The procedure leaves a thin linear scar in the occipital scalp.
●Follicular unit extraction – FUE involves the removal of individual follicular units, one by one, from
a wide area of the occipital scalp. Although not truly a "scarless" technique, FUE does not leave a
linear scar and has advantages for men who want to wear their hair very short.
It takes five to eight hours to perform a standard hair transplant session, with FUE taking longer to
perform than FUT. A small hair transplant session may involve the transplantation of 800 to 1000
follicular units. A large session (megasession) would involve 3000 to 6000 grafts of follicular units.
Patients can continue to lose nontransplanted hairs within susceptible areas following hair
transplantation, resulting in diminishing satisfaction with the results. The continuation of medical
treatment with minoxidil or finasteride following a hair transplant procedure may help to limit further
loss of preexisting scalp hair. In a randomized trial of 79 men who underwent hair transplantation for
androgenetic alopecia, those treated with finasteride 1 mg for four weeks prior to the transplant and
for 48 weeks after the transplant achieved better results [35].
OTHER THERAPIES Multiple other therapies have been utilized for

androgenetic alopecia. Data on the efficacy of these treatments are more limited than for minoxidil
and finasteride.
Dutasteride — Dutasteride, an inhibitor of both type 1 and type 2 5-alpha-reductase, is

utilized for the treatment of benign prostatic hyperplasia at a dose of 0.5 mg/day (see "Medical
treatment of benign prostatic hyperplasia"). It is prescribed by some clinicians as an off-label
treatment for androgenetic alopecia.
Compared with finasteride, dutasteride is three times more potent of an inhibitor of 5-alpha-
reductase type 2 and 100 times more potent of an inhibitor of 5-alpha-reductase type 1. Serum DHT
concentrations are reduced by 93 to 94 percent with 0.5 mg/day of dutasteride compared with
around 70 percent with 5 mg/day of finasteride [13].
In comparison to finasteride, fewer studies have evaluated the efficacy and safety of dutasteride in
male androgenetic alopecia. Trials in support of the efficacy of dutasteride include:
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●A randomized, placebo-controlled trial in 416 men compared a range of doses of dutasteride with
finasteride 5 mg daily [36]. Hair growth showed a dose-response effect with dutasteride, and after 12
and 24 weeks of therapy, dutasteride 2.5 mg daily was more effective than finasteride. This dose of
dutasteride is much higher than the standard 0.5 mg dose used for benign prostatic hyperplasia. In
this study, 13 percent of men treated with dutasteride 2.5 mg daily reported decreased libido.
●The results of another randomized trial (n = 153) support the efficacy of the lower dose of
dutasteride for males with androgenetic alopecia [37]. The trial found that dutasteride (0.5 mg/day)
was superior to placebo for the treatment of hair loss; the mean increase in hair counts in men
treated with dutasteride was 12.2/cm2, compared with 4.7/cm2 in men treated with placebo. There
was no significant difference in the number of adverse effects reported in both groups. The most
common drug-related adverse effect was sexual dysfunction, which was noted in 4 percent of study
participants in the dutasteride group and 3 percent of those in the control group.
Light therapy — Low level laser light therapy (LLLT) may benefit men with
androgenetic alopecia [38-40]. Randomized trials evaluating the efficacy of LLLT combs for
androgenetic alopecia have found significantly greater increases in terminal hair density in patients
treated with LLLT combs for 26 weeks than in patients given sham treatments [38,39]. Additional
studies are necessary to determine the optimal treatment regimen and the durability of response to
this treatment. LLLT also has been used for the treatment of androgenetic alopecia in females. (See
"Female pattern hair loss (androgenetic alopecia in women): Treatment and prognosis", section on
'Other therapies'.)
The mechanism through which LLLT improves androgenetic alopecia is unclear. Proposed
mechanisms include acceleration of cellular mitosis, stimulation of hair follicle stem cells or
follicular keratinocytes, effects on cell metabolism leading to increased adenosine triphosphate
production and cellular activity, and anti-inflammatory effects [39].
Platelet-rich plasma — There is uncertainty regarding the efficacy of platelet-

rich plasma (PRP) for androgenetic alopecia [41-43]. Various protocols have been used for
treatment. A placebo-controlled randomized half-head trial in 12 men and 13 women with
androgenetic alopecia that evaluated the efficacy of three PRP treatments separated by one month
found a greater increase in hair density in sites treated with PRP (mean increase of 12.8±32.6
hairs/cm2) compared with the change in control areas (mean decrease of 2.1±31.3 hairs/cm2) six
months after the first treatment [42]. However, differences in percentage of anagen hairs, percentage
of telogen hairs, anagen/telogen hair ratio, terminal hair density, and hair count between the treated
and control areas were not statistically significant. A separate single-blind trial in which two scalp
sites in each of the 19 men with androgenetic alopecia were randomly assigned to receive either
PRP injections (two treatments separated by one month) or saline injections as a control did not find
PRP beneficial for improving the number of terminal or vellus hairs six months after the first
treatment [41]. Larger, high-quality trials are necessary to clarify the efficacy of PRP treatment.
2477
Camouflaging agents — A variety of topical camouflaging products can be
used to reduce the appearance of hair loss. These include keratin fibers, which are sprinkled onto
the hair and a variety of scalp colorants (sprays, lotions, powder cakes). By minimizing the contrast
between the color of the scalp and hair, these products reduce the appearance of hair loss. Wigs,
toupees, and hairpieces are also effective camouflaging agents.
Other — Several other treatments for androgenetic alopecia have been studied. A 24-week
placebo-controlled randomized trial with 16 male patients showed improvement in hair density using
the topical prostaglandin analogue latanoprost 0.1% [44]. Topical ketoconazole 2% shampoo may
also have some efficacy in treatment of androgenetic alopecia; a small trial of 39 men with
androgenetic alopecia showed an increase in hair density after six months of treatment [45].
The role of other treatments such as carpronium chloride, t-flavone, adenosine, pentadecane, and
cepharanthine remains to be fully studied. Data are insufficient to recommend the use of topical
finasteride and topical fluridil, both of which are topical antiandrogens [26].
INFORMATION FOR PATIENTS Educational

materials on this topic are available for patients (see "Patient education: Hair loss in men and
women (androgenetic alopecia) (Beyond the Basics)"). We encourage you to print or e-mail this topic
review, or to refer patients to our public website, www.uptodate.com/patients, which includes this
and other topics.
SUMMARY AND
RECOMMENDATIONS
●Male androgenetic alopecia is a common form of hair loss in men that presents with the loss of
terminal hairs in characteristic areas of the scalp (picture 1A-D). Although the condition is benign
and asymptomatic, some men seek treatment due to cosmetic concerns. (See 'Introduction' above.)
●For male patients with androgenetic alopecia who desire treatment, we suggest treatment with oral
finasteride (1 mg/day) over topical minoxidil (Grade 2B). Treatment with minoxidil 5% solution or
foam is an alternative first-line therapy that may be preferred by patients who prefer to avoid
systemic therapy. The response to treatment with both agents is variable. No high quality
randomized trials have directly compared their efficacies. (See 'First-line therapies' above.)
●Men treated with finasteride or minoxidil must continue treatment to maintain efficacy. If treatment
is discontinued, hair loss will occur within several months after the cessation of therapy. (See 'First-
line therapies' above.)
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●Treatment with finasteride and minoxidil is generally well tolerated. Scalp dermatitis is the most
common adverse effect of minoxidil. Occasional patients treated with finasteride experience sexual
side effects. (See 'Adverse effects' above and 'Adverse effects' above.)
●Hair transplantation can result in permanent improvements in hair growth in areas of the scalp
affected by androgenetic alopecia. Continuing treatment with minoxidil or finasteride after hair
transplantation may help to minimize additional loss of preexisting terminal hairs. (See 'Surgery'
above.)
2479
Female pattern hair loss (androgenetic alopecia in women):
Pathogenesis, clinical features, and diagnosis
uptodate.com/contents/female-pattern-hair-loss-androgenetic-alopecia-in-women-pathogenesis-clinical-features-and-
diagnosis/print
Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical features, and
diagnosis
INTRODUCTION Female pattern hair loss (FPHL) is a common form of

nonscarring hair loss that primarily occurs in adult women. The condition is characterized by the
progressive loss of terminal hairs over the frontal and vertex regions of the scalp, resulting in a
visible reduction in hair density (picture 1A-C). Unlike many cases of androgenetic alopecia in men
(male pattern hair loss), the loss of terminal hairs in affected areas is usually incomplete and the
frontal hairline is often spared.
The pathogenesis, clinical manifestations, and diagnosis of FPHL will be reviewed here. Other forms
of nonscarring hair loss and the treatment of FPHL are discussed separately. (See "Evaluation and
diagnosis of hair loss" and "Androgenetic alopecia in men: Pathogenesis, clinical features, and
2480
diagnosis" and "Alopecia areata: Clinical manifestations and diagnosis" and "Alopecia related to
systemic cancer therapy" and "Telogen effluvium" and "Traction alopecia" and "Female pattern hair
loss (androgenetic alopecia in women): Treatment and prognosis".)
TERMINOLOGY In the past, the term "androgenetic alopecia" was the

primary term used to refer to the appearance of the common, progressive loss of terminal hair on the
frontal scalp and/or vertex of the scalp in both men and women. The term "andro" signified a
hormonal etiology and "genetic" signified a contribution of heredity to the clinical phenotype.
Over the years, as more work on hair loss was published, "female pattern hair loss" became the
preferred term for this form of hair loss in women. This newer terminology helps to distinguish the
different clinical features of this process in women versus men and reflects the lack of evidence to
support a hormonal contribution in all cases of the condition.
Further, some authors use the terms "androgen-dependent FPHL" and "androgen-independent FPHL"
to separate women with FPHL due to androgen excess from women with FPHL and normal
androgen levels [1]. The term "female pattern alopecia" has also been used in place of FPHL.
EPIDEMIOLOGY FPHL is a common condition. In a series of

approximately 1000 Caucasian women in the United States, the prevalence of FPHL was 19 percent
[2]. The prevalence of FPHL appears to be lower in the Asian population than among Caucasians [3].
Little is known about the prevalence in women of African descent.
Although FPHL can occur at any time in life beginning in puberty, the condition most commonly
occurs following menopause [4,5]. The age-related rise in FPHL was clearly demonstrated in the
American series mentioned above; FPHL was detected in only 4 of 121 women between the ages of
20 and 29 (3 percent), but in 41 of 140 women between ages 70 and 89 (29 percent) [2]. In a British
study of 377 women who presented to a general dermatology clinic with concerns unrelated to hair
loss, 38 percent of women over the age of 70 years had FPHL [6].
ETIOLOGY AND PATHOGENESIS The visible

thinning of hair over the frontal scalp and vertex of the scalp in FPHL results from a progressive
decrease in the ratio of terminal hairs to shorter, thinner vellus hairs in the affected areas, a process
known as follicular miniaturization [7]. As part of this process, the duration of the anagen (growth)
phase of hair follicles shortens from a normal duration of a few years to only weeks to months [8].
The mechanism through which follicular transformation occurs in FPHL is not completely
understood. Although the crucial roles of androgens and genetic susceptibility in male androgenetic
alopecia are well-accepted, the degree to which these factors contribute to FPHL in most women is
less clear. (See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis",
2481
Androgens — Male androgenetic alopecia occurs as a consequence of the effects of
dihydrotestosterone (a potent metabolite of testosterone) on susceptible hair follicles.
Dihydrotestosterone binds to androgen receptors in hair follicles, resulting in the upregulation of
genes responsible for the gradual transformation of terminal hair follicles to miniaturized hair
follicles. The pattern of the hair loss, which typically spares the occipital scalp, reflects regional
differences in the sensitivity of scalp follicles to androgens (picture 2) [8]. (See "Androgenetic
alopecia in men: Pathogenesis, clinical features, and diagnosis", section on 'Androgens'.)
Some authors have theorized that a similar process contributes to the development of FPHL [9]. This
concept is supported by the observation that women with disorders of hyperandrogenism (eg,
polycystic ovarian syndrome, ovarian hyperthecosis, or adrenal or ovarian androgen-secreting
tumors) may develop early-onset FPHL as a feature of these diseases [10]. However, androgen levels
are normal in most women with FPHL, indicating that our understanding of the pathogenesis of this
disorder remains incomplete [10,11]. In a series of 109 women with moderate to severe FPHL,
laboratory evidence for hyperandrogenism was present in only 39 percent [10].
Proposed theories on the mechanisms through which women with normal androgen levels could
develop FPHL include increased sensitivity of hair follicles to androgens and an influence of
estrogens on the development of this condition [8,12]. The age-related increase in FPHL, with the
highest rates in postmenopausal women, suggests the possibility of a role for estrogen. However,
studies have demonstrated conflicting evidence on whether estrogens stimulate or inhibit hair
growth [8].
Genetics — While it is known that genetic susceptibility influences the development of

male androgenetic alopecia, relatively little is known regarding the genetic basis and inheritance
pattern of female pattern hair loss [8]. An Australian gene-wide association study of Caucasian
women suggested that the aromatase gene (CYP19A1) may contribute to FPHL [13]. However, no
definitive familial inheritance has been identified. Multiple genes may contribute to susceptibility to
FPHL. (See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis", section
on 'Genetics'.)
CLINICAL MANIFESTATIONS FPHL is a

nonscarring form of hair loss that presents as a progressive reduction in the density of terminal
scalp hairs in a characteristic distribution (picture 1A-C). The frontal scalp and vertex of the scalp
are the primary sites of involvement. Although diffuse involvement occasionally occurs, the occipital
scalp is usually relatively spared.
The exact pattern of hair loss varies among women. In some patients, the frontal scalp thinning is
most prominent, resulting in the visualization of a "Christmas-tree" like pattern when the hair is
parted at the midline [14,15], whereas in others, diffuse central thinning is the most pronounced
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feature [16]. The frontal hairline is usually relatively spared, though women frequently exhibit mild
bitemporal thinning [9,17,18]. A combined pattern that resembles male androgenetic alopecia
(frontotemporal recession and vertex loss) is infrequently seen [17].
Scarring, inflammation, and scale are not clinical features of FPHL. If these features are seen in a
patient with hair loss, another scalp disorder may be present in conjunction with FPHL or may be
solely responsible for the clinical findings. (See "Evaluation and diagnosis of hair loss".)
A variety of methods have been used to classify the clinical features of FPHL. The Ludwig scale is
one of the most commonly used grading scales (figure 1) [16]. Other scales that have been used to
describe the severity of FPHL include the Sinclair (picture 3) [7] and Savin [14] scales.
The FPHL Severity Index, a three-component severity scale, has been proposed as a method to
facilitate earlier recognition of FPHL and to assess disease severity over time [19]. The FPHL
Severity Index involves assessment of hair shedding, midline hair density, and trichoscopic findings.
This scale has not been validated.
Psychosocial dysfunction — Many women with FPHL experience
negative psychosocial effects related to the condition [20-22]. As an example, in a questionnaire-
based study that included 96 women with FPHL and 56 female control subjects, 70 percent of the
affected women reported that they were very upset to extremely upset about their hair loss [22].
Women with hair loss experienced more feelings of negative body image, poorer self-esteem, less of
a sense of control over their lives, and had a less satisfying quality of life than the control group. A
separate study in which 58 women were interviewed about the effects of FPHL on their quality of life
also found that hair loss frequently was accompanied by negative psychosocial effects. In this
study, 88 percent of women felt that the hair loss negatively influenced daily life [21].
Adolescent girls with FPHL may also experience psychosocial dysfunction. Girls with FPHL may
suffer from poor self-esteem and impaired functioning at home, school, or work and in interpersonal
relationships [23].
When managing patients with FPHL, clinicians should remain cognizant that the clinical assessment
of the severity of FPHL may not be consistent with the patient’s perception of the severity of hair
loss and the psychosocial impact of the condition. In a questionnaire-based study of 104 women
with FPHL, telogen effluvium, or alopecia areata, the patient perception of the severity of hair loss
tended to be greater than the perception of the examining dermatologist [24]. In addition, the
patients’ severity ratings correlated more closely with the effects of hair loss on patient quality of life
than the severity ratings given by the dermatologist.
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Associated medical conditions — Certain medical disorders
may be associated with FPHL. In addition to causes of hyperandrogenism (eg, ovarian or adrenal
tumors, polycystic ovarian syndrome, adrenal hyperplasia), links between FPHL and insulin
resistance, hypertension, and increased risk for death from diabetes or heart disease have been
reported [25-27]. Further study is necessary to clarify whether the associations between FPHL and
these conditions are valid. Of note, cardiovascular risk factors have been associated with
androgenetic alopecia in men. (See "Androgenetic alopecia in men: Pathogenesis, clinical features,
and diagnosis", section on 'Cardiovascular disease'.)
DIAGNOSIS The diagnosis of female pattern hair loss is usually made clinically.
Scalp biopsies are helpful aids for diagnosis when concomitant disorders of the scalp confound the
clinical findings or the diagnosis is unclear. Laboratory tests to assess for hyperandrogenism are
performed when clinical findings suggestive of hyperandrogenism are present.
Patient history — The patient history can provide clues to support or negate a
diagnosis of FPHL and to identify an underlying hyperandrogenic state. We typically inquire about
the following:
●Age of onset, duration, and rate of progression of hair loss
●Presence of signs of virilization (hirsutism, deepening of voice, clitoral enlargement)
●Gynecologic and obstetrical history (menstrual irregularities, difficulty conceiving)
●Presence of other medical disorders, significant changes in health status, medication list
●Use of hormonal or nutritional supplements that may contain androgens
●Family history of male and female hair loss
A rapid onset of diffuse hair loss may suggest acute telogen effluvium, particularly when the history
suggests a change in health status (eg, serious illness, pregnancy, significant weight loss) or
medication changes within the preceding several months. Of note, telogen effluvium may coexist
with FPHL, and an episode of telogen effluvium may unmask underlying FPHL. The gynecologic
history and assessment for signs of virilization help to identify women for whom an evaluation for
hyperandrogenism is indicated. (See 'Differential diagnosis' below.)
Women with FPHL may first notice their hair loss as the progressive thinning of a ponytail or as
increasing visibility of the scalp through the hair in the frontal and vertex areas of the scalp. These
features are typically noted over the course of months to years. Although the onset and progression
of FPHL is often insidious, occasional patients describe noticing specific episodes of increased hair
loss prior to a noticeable change in terminal hair density. Women may also complain of an increased
propensity for sunburns on the scalp as hair coverage diminishes.
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Physical examination — A full skin examination that includes evaluation of
the scalp, face, body, and nails is advised in patients who present with a new complaint of hair loss.
(See "Evaluation and diagnosis of hair loss", section on 'Physical examination'.)
The examination of the scalp and scalp hair should focus on identifying the distribution of hair loss
and the caliber of hairs within the involved areas. Findings consistent with FPHL include the
detection of terminal hair loss that is primarily localized to the frontal scalp and/or vertex of the
scalp and miniaturized hairs (shorter and thinner hairs or vellus hairs). The use of a sheet of paper
as a contrasting background can facilitate visualization of individual hairs.
Comparing the part width in the frontal or vertex scalp with the occipital scalp, which is usually
relatively spared, provides a visual aid for the assessment of the reduction in hair density. Even in
patients who develop diffuse hair loss from FPHL, hair thinning usually remains most prominent in
the frontal and vertex areas [9,28].
The examination of the scalp should also focus on the detection of clinical features such as
inflammation, scarring, or scale. The presence of these features strongly suggests that the hair loss
is caused by a different disease or that FPHL coexists with another scalp disorder. (See "Evaluation
and diagnosis of hair loss".)
The examination of other body sites may result in the identification of features useful for diagnosis
and patient management. For example, patients with diffuse alopecia areata may have nail
abnormalities and patchy hair loss on other body sites, findings that are not associated with FPHL.
In addition, the presence of hirsutism, acne, and obesity suggest the possibility of a hyperandrogenic
state related to polycystic ovarian syndrome or another hormonal abnormality. (See "Alopecia
areata: Clinical manifestations and diagnosis", section on 'Clinical features' and "Clinical
manifestations of polycystic ovary syndrome in adults".)
Hair pull tests, which can identify increased shedding of telogen hairs, may be positive in early hair
loss on the central scalp, but are typically negative in patients with long-standing FPHL [17]. A
positive hair pull test suggests the possibility of active telogen effluvium or alopecia areata. (See
"Evaluation and diagnosis of hair loss", section on 'Hair pull test'.)
Dermoscopy — Dermoscopy of the scalp (also known as trichoscopy) may be useful for
diagnosis [29,30]. Dermoscopic features of FPHL and male androgenetic alopecia include hair
diameter diversity, perifollicular pigmentation/peripilar signs, and yellow dots [30]. Focal atrichia
may also be present. (See "Overview of dermoscopy".)
Scalp biopsy — Although scalp biopsies usually are not needed to diagnose FPHL,
biopsies can be helpful in cases in which the clinical evaluation does not provide a definitive
diagnosis. Examples of scenarios in which a biopsy may be particularly useful include:
●Distinguishing FPHL from telogen effluvium or diffuse alopecia areata
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●Distinguishing FPHL from scarring alopecia when the clinical differentiation between scarring and
nonscarring alopecia is difficult
●Identifying coexisting scalp disorders
Scalp biopsies should be performed within an affected area and should extend into the
subcutaneous fat. It is best to avoid the bitemporal area, since follicular miniaturization in this area
is common in individuals without hair loss [4].
A 4 mm punch biopsy usually provides sufficient tissue for histologic examination. We typically
perform two 4 mm punch biopsies so that one specimen can be processed with vertical sectioning
and the other with horizontal sectioning [31-33]. Doing so allows the pathologist to examine the hair
follicles in both longitudinal and cross-sections. Many dermatopathologists prefer to receive two
specimens. (See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis",
section on 'Scalp biopsy'.)
The typical histopathologic features of FPHL are identical to those of male androgenetic alopecia.
They include [4,34]:
●Increased number of miniaturized hair follicles and reduced size of sebaceous glands
●Decreased anagen to telogen ratio
●Increased number of follicular stelae
●Perifollicular inflammation around the upper portion of the hair follicle with or without perifollicular
fibrosis
(See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis", section on
'Scalp biopsy'.)
Laboratory tests — Although no serologic tests provide a definitive diagnosis of

FPHL, such tests are helpful for identifying an underlying hyperandrogenic state. Testing for
hyperandrogenism is performed in women with FPHL when the clinical features suggestive of
hyperandrogenism are present (eg, hirsutism, irregular menses, moderate to severe acne, treatment-
refractory adult acne, acanthosis nigricans, or galactorrhea). We typically obtain a free and/or total
testosterone level and dehydroepiandrosterone sulfate (DHEAS) level as initial screening tests [17].
Hormonal contraceptives should be discontinued for at least two months prior to androgen testing
[35]. Additional tests for specific disorders of hyperandrogenism are added as indicated. (See
"Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing'.)
Adjunctive tests — Additional procedures that may be utilized for the evaluation
and follow-up of FPHL include trichograms and phototrichograms. A trichogram is a technique in
which 25 to 50 hairs are grasped with a needle holder and plucked from the scalp followed by an
examination of the proximal ends of the hair to assess for the proportion of hairs in telogen.
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Trichograms are now seldom used in the diagnosis of FPHL. The results of one retrospective study
suggest that dermoscopy (trichoscopy) is more useful for the diagnosis of FPHL than trichograms
[36]. (See 'Dermoscopy' above.)
Phototrichograms are imaging techniques used to closely examine the features of hair loss for
diagnosis and follow-up. A small area of hair is trimmed and followed with imaging for the
proportion of regrowing (anagen) hairs, resting (telogen) hairs, and shed hairs, as well as the rate of
growth, and hair density [37]. Computerized techniques for performing phototrichograms have been
developed (TrichoScan and Folliscope) [38-42]. Phototrichograms are primarily utilized in clinical
studies and specialized hair clinics. (See "Evaluation and diagnosis of hair loss", section on
'Trichograms and phototrichograms'.)
DIFFERENTIAL DIAGNOSIS Multiple hair and scalp

disorders may present with clinical features that resemble FPHL [43]. Careful review of the patient
history, physical examination findings, and biopsy (when necessary) is of value for differentiating
these disorders from FPHL. Of note, since FPHL is a common condition, the coexistence of FPHL
with other disorders must also be considered when patients present with features that are not
entirely consistent with FPHL.
●Telogen effluvium – Telogen effluvium is the disorder that may be most difficult to distinguish
from FPHL. Patients present with acute or chronic noninflammatory, diffuse hair loss [44]. The
clinical history is often of value for identifying this diagnosis. For example, a major illness, severe
psychological trauma, significant weight loss, childbirth, and certain medications may precipitate an
episode of acute telogen effluvium that begins a few months after the insult. In telogen effluvium,
hair loss occurs in all areas of the scalp, although the hair loss may be most evident in the temporal
area (picture 4). A hair pull test often demonstrates increased shedding of telogen hairs in patients
with active telogen effluvium.
●Diffuse alopecia areata –The rare diffuse form of alopecia areata is characterized by diffuse
reduction in hair density (picture 5) [43]. Due to the preferential loss of pigmented hairs, adult
patients may complain of rapid graying of the hair. Though not always present, a personal or family
history of alopecia areata, the detection of circumscribed areas of complete hair loss, and nail
abnormalities offer support to this diagnosis. A biopsy is useful for confirming the diagnosis. (See
"Alopecia areata: Clinical manifestations and diagnosis", section on 'Clinical features'.)
●Central centrifugal cicatricial alopecia –Central centrifugal cicatricial alopecia is a scarring

alopecia that most commonly occurs in women of African descent [45]. The classic location on the
vertex of the scalp contributes to the potential for confusion of this diagnosis with FPHL (picture 6).
The detection of loss of follicular ostia indicates the presence of scarring. Pustules or inflammation
may be detected in early disease. Biopsies are used to confirm the diagnosis. (See "Central
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●Frontal fibrosing alopecia – Frontal fibrosing alopecia is an uncommon scarring alopecia that is
usually characterized by frontotemporal recession, perifollicular erythema and follicular
hyperkeratosis [46]. Eyebrow loss may also occur. The detection of clinical and histologic signs
consistent with a lymphocytic scarring alopecia aid in diagnosis. (See "Lichen planopilaris", section
on 'Frontal fibrosing alopecia'.)
●Traction alopecia –Traction alopecia is a form of hair loss that occurs as a result of chronic
tension on the hair shaft and follicle (picture 7). Tight braiding of the hair is a common cause of this
condition. Hair loss due to traction alopecia is often located at the hairline. Although the hair loss is
reversible initially, hair loss may become permanent if tension on the hair follicles continues. The
patient history is useful for diagnosis.

SUMMARY AND
RECOMMENDATIONS
●Female pattern hair loss (FPHL) is a common, nonscarring form of hair loss that most commonly
occurs in adult women. The highest prevalence of FPHL is found in postmenopausal women. (See
●Although hormonal factors and genetic predisposition are believed to contribute to FPHL, the
mechanism through which these factors lead to FPHL is not entirely clear. The majority of women
with FPHL do not have abnormal levels of serum androgens. (See 'Etiology and pathogenesis'
above.)
●Classically, FPHL presents with a slow, progressive transition of terminal hairs on the frontal scalp
and/or vertex of the scalp to shorter, thinner hairs and vellus hairs. The process results in a visible
reduction in hair coverage on the scalp (picture 1A-C). The occipital scalp and frontal hairline are
often relatively spared. (See 'Clinical manifestations' above.)
●Although FPHL does not cause physical discomfort or physical disability, the hair loss can
contribute to significant psychological distress. (See 'Psychosocial dysfunction' above.)
●The diagnosis of FPHL is usually made clinically, based upon the patient history and physical
examination. The diagnosis is suggested by the detection of a reduction in hair density in the
characteristic distribution and an increased prevalence of miniaturized hairs. Skin biopsies are not
usually performed, but can be helpful when the diagnosis is uncertain or when a concomitant scalp
disorder is suspected. (See 'Diagnosis' above.)
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●The differential diagnosis of FPHL includes several types of nonscarring and scarring hair loss.
Telogen effluvium, central centrifugal cicatricial alopecia, and traction alopecia are examples of
relatively common disorders that share features with FPHL. (See 'Differential diagnosis' above.)
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Female pattern hair loss (androgenetic alopecia in women):
Treatment and prognosis
uptodate.com/contents/female-pattern-hair-loss-androgenetic-alopecia-in-women-treatment-and-prognosis/print
Female pattern hair loss (androgenetic alopecia in women): Treatment and prognosis
INTRODUCTION Female pattern hair loss (FPHL, female pattern alopecia,

androgenetic alopecia in women) is a common form of nonscarring hair loss that most frequently
occurs in adult women and primarily involves the frontal scalp and vertex of the scalp. Untreated,
FPHL results in a slow, progressive decline in the density of scalp hair.
Multiple therapies have been used for the management of FPHL. Topical minoxidil is considered the
first-line treatment. Data are limited on the efficacy of other agents, such as spironolactone,
cyproterone acetate, finasteride, and flutamide. Hair transplantation surgery is an option for women
who have inadequate responses to medical therapy.
The treatment and prognosis of FPHL will be reviewed here. The pathogenesis, clinical
manifestations, and diagnosis of FPHL and the diagnosis and management of androgenetic
alopecia in men (male pattern hair loss) are discussed separately. (See "Female pattern hair loss
(androgenetic alopecia in women): Pathogenesis, clinical features, and diagnosis" and "Androgenetic
alopecia in men: Pathogenesis, clinical features, and diagnosis" and "Treatment of androgenetic
alopecia in men".)
GENERAL CONSIDERATIONS In the absence of

treatment, female pattern hair loss (FPHL) leads to progressive hair loss in affected areas, though
not to complete baldness. Women may find the loss of hair distressing, and many women who
present for the evaluation of FPHL desire treatment. (See "Female pattern hair loss (androgenetic
alopecia in women): Pathogenesis, clinical features, and diagnosis", section on 'Psychosocial
dysfunction'.)
As in the treatment of many other forms of hair loss, it is essential to thoroughly inform the patient
of the following:
●The therapeutic options (including the side effects of treatments)
●The importance of long-term, consistent adherence to treatment
●The prolonged time usually required to achieve a clinically evident response (often several months)
2490
●Realistic expectations for the results of treatment
The primary therapeutic goals in women with FPHL are to minimize further hair loss and to induce
regrowth of terminal hairs. Photographs are valuable aids for following the response to treatment.
The response to treatment varies widely. In our experience, not all women who respond to treatment
achieve cosmetically significant hair regrowth. In some women, a positive response to treatment
manifests only as a reduction in the progression of hair loss.
FIRST-LINE THERAPY Of the interventions utilized for female

pattern hair loss (FPHL), topical minoxidil has the strongest evidence in support of its efficacy [1,2].
Topical minoxidil is also a relatively safe treatment. (See 'Side effects' below.)
Topical minoxidil — Topical minoxidil is available in a variety of formulations. In

the United States, minoxidil may be obtained as a 2% solution, 5% solution, or 5% foam.
Efficacy — The exact mechanism through which minoxidil improves FPHL is not completely
understood. It is theorized that the drug may prolong the anagen (growth) phase of hair follicles,
shorten the telogen (resting) phase, and induce enlargement of miniaturized follicles, thereby
contributing to the conversion of miniaturized hairs to terminal hairs [3]. (See "Treatment of
androgenetic alopecia in men", section on 'Mechanism of action'.)
The efficacy of topical minoxidil for FPHL is supported by a systematic review and meta-analysis of
randomized trials that found that women treated with topical minoxidil (1, 2, or 5% formulations)
were significantly more likely to report clinically significant hair regrowth than women in the placebo
groups (risk ratio 1.93, 95% CI 1.51-2.47) [2]. In addition, the mean increase in hair counts within
treated areas was higher in women treated with minoxidil than in women in the placebo groups. A
subsequent randomized trial that compared minoxidil 5% foam with placebo also supports the
efficacy of minoxidil [4].
Product selection — All three formulations of minoxidil (2% solution, 5% solution, and
5% foam) are effective for FPHL. Historically, many clinicians recommended use of minoxidil 5%
solution or foam based upon a perception of greater efficacy than minoxidil 2% solution; however,
data to support this assertion are lacking. In a systematic review of randomized trials evaluating
interventions for FPHL, none of the four trials that compared minoxidil 2% with minoxidil 5% found a
significant difference in efficacy between the two concentrations [2].
Minoxidil 5% foam offers drug delivery in a vehicle that may be preferred by some women and is
associated with a reduced risk for side effects (eg, scalp pruritus, dandruff, sideburn hypertrichosis)
compared with twice daily application of the 2% solution [5]. In a vehicle-controlled randomized trial
(n = 404), the incidences of scalp irritation and hypertrichosis with once daily use of minoxidil 5%
foam were comparable with vehicle [4].
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Administration — Minoxidil 2% solution (1 mL) is usually applied twice daily. Minoxidil
5% solution (1 mL) or foam (one-half capful) is usually applied once daily. Patients should be
instructed to apply minoxidil to the scalp, not the hair. The patient should massage minoxidil onto
the scalp with fingers, and hands should be washed after application. Women should apply the
product at least two hours before bed to allow adequate time for drying. This may help to avoid the
inadvertent spread of the solution to other body sites during sleeping.
Treatment with minoxidil takes at least four months to exhibit a visible effect. Use of the product for
at least 12 months prior to concluding inefficacy is recommended [6].
Side effects — Shedding of hair commonly occurs during the first two to eight weeks of
minoxidil treatment [5,6], an event likely due to the release of telogen hairs as follicles are stimulated
to transition from telogen to the anagen phase [7]. Patients should be warned about this side effect
to avoid the premature cessation of treatment.
Potential local adverse effects of minoxidil include scalp pruritus, flaking, and facial hypertrichosis.
The low risk for scalp irritation with use of the 5% foam formulation may be related to the absence of
propylene glycol, a common contact allergen, in this formulation. Hypertrichosis usually resolves
within four months if treatment is discontinued [6]. (See "Treatment of androgenetic alopecia in
men", section on 'Adverse effects'.)
SECOND-LINE THERAPY Systemic agents that inhibit

androgen production or action, such as spironolactone, finasteride, cyproterone acetate, and
flutamide, are primarily used for the management of female pattern hair loss (FPHL) in the following
situations:
●Women with FPHL related to hyperandrogenism
●Women who respond poorly to monotherapy with minoxidil
Although some studies and case reports suggest that spironolactone, finasteride, cyproterone
acetate, and flutamide can improve FPHL, data on the efficacy of these therapies in FPHL are
limited. A systematic review found insufficient evidence to confirm the efficacy of these
interventions [2].
Due to the absence of sufficient evidence to confirm the efficacy of these agents, some authors have
suggested limiting their use to women with hyperandrogenism [6]. However, there is some evidence
that suggests that both women with hyperandrogenism and without hyperandrogenism may
respond to antiandrogen therapy [8-11]. We have seen favorable responses in both populations.
In general, our first choice for systemic treatment is spironolactone due to the extensive history of
use of this drug in women for other indications (eg, hirsutism, acne, polycystic ovarian syndrome).
Cyproterone acetate is used for FPHL in many countries, but is not available in the United States
2492
[12]. Flutamide is used infrequently for FPHL due to concerns regarding drug-induced hepatotoxicity.
We typically instruct patients to continue topical minoxidil during systemic therapy.
Spironolactone — Spironolactone is an aldosterone antagonist that competitively

blocks androgen receptors and weakly inhibits androgen synthesis [13,14]. Data in support of the
use of spironolactone for FPHL include open-label and retrospective studies, case reports, and case
series [8,15-19]. In the open-label study, 80 women (ages 12 to 79, most with normal androgen
levels) were treated with spironolactone (200 mg per day) or cyproterone acetate (50 mg per day for
postmenopausal women and 100 mg per day for 10 days per month in conjunction with an oral
contraceptive pill for premenopausal women) [8]. All women were treated for at least 12 months, and
the average duration of treatment was 16 months. No significant difference in efficacy was detected
between the two treatments. Overall, 44 percent of patients had regrowth, 44 percent had no change
in hair density, and 12 percent had continued hair loss.
Although formal studies of the efficacy of combination therapy have not been performed, we usually
continue treatment with topical minoxidil in patients who receive spironolactone therapy. In a case
report, the addition of minoxidil 5% solution (applied twice daily) appeared to augment clinical
improvement in FPHL in a woman who was taking spironolactone (200 mg per day) [17].
The typical dose of spironolactone utilized for adult women with FPHL is 200 mg per day. Treatment
is usually begun at a lower dose (eg, 50 mg per day). The daily dose may be increased by 50 mg
monthly as tolerated [20]. Spironolactone should be continued for at least six months prior to
assessing its efficacy [20].
Potential side effects of spironolactone include headache, decreased libido, menstrual irregularities,
orthostatic hypotension, fatigue, and hyperkalemia. Spironolactone may cause feminization of a
male fetus, and should not be administered during pregnancy. The drug is often given in conjunction
with oral contraceptives in premenopausal women to prevent pregnancy, as well as to reduce
menstrual irregularity. Serum potassium levels and blood pressure should be followed periodically
[13].
Cyproterone acetate — Cyproterone acetate is an antiandrogen that may be

effective for FPHL. Cyproterone acetate is not available in the United States.
The efficacy of cyproterone acetate in FPHL is difficult to assess since studies evaluating the
efficacy of the drug have used variable treatment regimens and have yielded mixed results [8,21-24].
As mentioned above, an open-label study of 80 premenopausal and postmenopausal women (most
with normal androgen levels) that compared treatment with cyproterone acetate and spironolactone
found that both treatments appeared to be effective, and did not find a significant difference in
efficacy between the two groups [8]. (See 'Spironolactone' above.)
In contrast, a randomized trial raised questions about the efficacy of cyproterone acetate for FPHL.
In the one-year trial, 66 premenopausal women (many with acne, hirsutism, or menstrual cycle
irregularities) were randomized to receive either topical minoxidil 2% solution plus an oral
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contraceptive containing ethinyl estradiol and gestodene or cyproterone acetate (50 mg per day for
20 days per menstrual cycle) plus an oral contraceptive containing ethinyl estradiol and 2 mg of
cyproterone acetate [22]. While minoxidil appeared to be effective for inducing hair regrowth (change
in hair count between first and last measurement = 7.7±9.3 per 0.36 cm2), statistically significant
hair regrowth did not occur in the cyproterone acetate group (change in hair count between first and
last measurement = -0.2±6.7 per 0.36 cm2). Among patients treated with cyproterone acetate,
women with irregular menstrual cycles seemed to respond better than women without irregular
menstrual cycles; however, this difference was not statistically significant.
The dosing regimen for cyproterone acetate for FPHL is not standardized. When used in the
treatment of FPHL, some authors have suggested the following regimens for premenopausal women
[25]:
●100 mg per day on days 5 to 15 of the menstrual cycle and 50 mcg of ethinyl estradiol on days 5 to
25
OR
●50 mg of cyproterone acetate on days 1 to 10 and 35 mcg on ethinyl estradiol on days 1 to 21
Postmenopausal women may be treated with 50 mg daily [8].
Potential side effects of cyproterone acetate include menstrual cycle irregularity, weight gain, breast
tenderness, reduced libido, depression, and nausea [25].
5-alpha reductase inhibitors — Finasteride is a type 2 5-alpha-

reductase inhibitor that is frequently used in the treatment of male androgenetic alopecia.
Finasteride inhibits the conversion of testosterone to dihydrotestosterone, thereby reducing the
effects of dihydrotestosterone on hair follicles [26]. (See "Treatment of androgenetic alopecia in
men", section on 'Finasteride'.)
Few studies have evaluated the efficacy and safety of finasteride in women with FPHL, and the
available studies have utilized varied treatment regimens and have found different results. Although
a 12-month placebo-controlled randomized trial of 137 postmenopausal women with FPHL and
normal serum androgen levels found that treatment with finasteride 1 mg per day did not seem to be
of benefit [27], uncontrolled studies utilizing higher doses of finasteride (2.5 or 5 mg per day) have
suggested that finasteride may be of benefit in some women without hyperandrogenism [9-11].
Conflicting data also exist regarding the value of finasteride in hyperandrogenemic women with
FPHL. A one-year open-label trial in which 36 premenopausal women with FPHL and
hyperandrogenism were randomized to receive finasteride (5 mg per day), flutamide (250 mg per
day), or cyproterone acetate (50 mg per day for 10 days per month) plus ethinyl estradiol (25 mcg for
20 days per month) found that the results achieved with finasteride were similar to those seen in 12
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women who were recruited to the study but refused therapy [21]. In contrast, a case series of four
women with hyperandrogenism and hair loss (two premenopausal and two postmenopausal) found
that the condition stabilized or improved during finasteride therapy [28].
Prior to a recommendation for the routine use of finasteride for FPHL, additional studies are
necessary to clarify the population of women with FPHL who may benefit from treatment and to
identify the most appropriate treatment regimen.
Finasteride is usually well-tolerated by women [27]. Studies in men have included reports of reduced
libido and breast swelling or tenderness [26]. Finasteride is also teratogenic; the drug may induce
feminization of a male fetus. Thus, treatment with finasteride should be avoided in women who are
pregnant or considering becoming pregnant. When the drug is given to premenopausal women who
may become pregnant, the use of reliable contraception is indicated.
Dutasteride, a type 1 and type 2 5-alpha-reductase inhibitor, was reported as effective in a 46-year-
old woman who had attained only minimal improvement in FPHL with finasteride. [29]. Further study
is necessary to determine the efficacy and safety of dutasteride in the treatment of FPHL [30].
Flutamide — Flutamide is an antiandrogenic agent infrequently utilized for the treatment

of FPHL. A few studies have found evidence in support of its efficacy [21,31,32]. In a prospective
cohort study of 101 premenopausal women with FPHL (including 12 with elevated testosterone
levels at baseline) who were treated with flutamide (250 mg for one year, 125 mg for one year, then
62.5 mg per day for two years), statistically significant improvement in hair loss severity scores were
detected within six months, and continued improvement was noted up to two years [32]. The mean
percentage improvement was 15 percent at six months and 28 percent at two years. Flutamide was
also reported to be effective in a premenopausal woman with normal androgen levels who failed to
improve with spironolactone and minoxidil [33]. The woman had hair regrowth when flutamide was
added to topical minoxidil 5% applied daily.
Potential side effects of flutamide include reduced libido, gastrointestinal distress, and liver function
test abnormalities [32]. Hepatic failure is a rare side effect and concern regarding this possibility has
limited the use of flutamide therapy. However, significant elevations in transaminases were seen in
only 4 percent of patients in the prospective cohort study, and the transaminase abnormalities
resolved rapidly after treatment cessation [32].
SURGERY Surgical interventions similar to those performed for male androgenetic

alopecia are an option for women with female pattern hair loss (FPHL) who do not achieve a
satisfactory response with pharmacologic therapy [34-37]. Through the transplantation of terminal
hairs from unaffected areas of the scalp to affected sites, patients can achieve cosmetically
favorable improvements.
2495
Disadvantages of hair transplantation include high cost; significant time investment for patients;
side effects such as early temporary hair loss, pain, and infection; and the potential for transplant
failure. Some patients with FPHL are poor candidates for hair transplantation, including patients with
diffuse hair loss or in whom hair density in the donor area (typically the posterior scalp) is
insufficient [35]. (See "Treatment of androgenetic alopecia in men", section on 'Surgery'.)
OTHER THERAPIES Women with FPHL may benefit from low-level

laser light therapy (LLLT), also referred to as "photobiomodulation therapy." Randomized trials
comparing 26 weeks of treatment of FPHL with an LLLT comb device three times per week to
treatment with a sham device have found greater improvements in terminal hair density among
patients treated with LLLT combs than among patients given sham treatment [38]. Further study is
necessary to determine the best regimen for LLLT and to clarify the duration of effect. Low-level
laser therapy has also been used for male androgenetic alopecia [39]. (See "Treatment of
androgenetic alopecia in men", section on 'Light therapy'.)
Latanoprost 0.1%, a topical prostaglandin analog, was reported to increase hair density in a small
randomized trial of men with androgenetic alopecia [40]. However, injections of bimatoprost, another
prostaglandin analog, were not effective in a woman with FPHL [41]. Additional study is necessary to
determine whether prostaglandin analogues are of value in FPHL.
Platelet rich plasma (PRP) has been utilized for the treatment of androgenetic alopecia in men and
women. Although there are data that suggest benefit, studies evaluating this approach for FPHL are
limited, and uncertainty remains regarding the role of this treatment [42-45]. A placebo-controlled,
randomized, half-head trial that included 12 men and 13 women with androgenetic alopecia found a
greater increase in hair density in sites treated with PRP compared with control sites six months
after the first of three monthly PRP treatments, suggesting benefit of PRP [46]. Additional study is
necessary to confirm the effects of PRP and determine optimal regimen for this treatment. (See
"Treatment of androgenetic alopecia in men", section on 'Platelet-rich plasma'.)
Limited data suggest oral minoxidil may be an alternative treatment for FPHL [47-49]. A 24-week,
open-label trial that randomly assigned 52 women with FPHL to either minoxidil (1 mg per day) or
once-daily application of minoxidil 5% solution did not find a statistically significant difference in
effect on total hair density (12 versus 7 percent increase, respectively) [47]. However, the adverse
event of mild hypertrichosis occurred more frequently in the oral minoxidil group than in the topical
minoxidil group (27 versus 4 percent). Other adverse events in the oral minoxidil group included a
slight increase in mean heart rate at rest and one occurrence of pretibial edema.
The efficacy of mesotherapy, microneedling, topical estrogens, topical progesterone, and

supplements (such as iron, biotin, ginseng, saw palmetto, green tea, and caffeine) on FPHL are
unclear [7,50].
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PROGNOSIS Once female pattern hair loss (FPHL) develops, the condition
typically progresses over time, resulting in diminishing coverage of affected areas of the scalp by
hair. Unlike male androgenetic alopecia, progression to complete baldness usually does not occur.
Although topical minoxidil and other pharmacologic therapies are effective in some women with
FPHL, the response to treatment is variable. Treatment may result in no effect, the inhibition of
further hair loss, or a variable degree of regrowth of hair. Since the response to treatment may be
incomplete, initiating treatment at an early stage, prior to the development of extensive hair loss, is
preferred. Pharmacologic therapy must be continued indefinitely to maintain the response.

SUMMARY AND
RECOMMENDATIONS
●Female pattern hair loss (FPHL) is a common form of nonscarring hair loss that typically occurs in
adult women. A variety of topical and systemic therapies have been used for the management of
this condition. The response to treatment varies. (See 'Introduction' above and 'Prognosis' above.)
●For women with FPHL who desire treatment, we suggest topical minoxidil as first-line therapy
(Grade 2A). At least one year of treatment with minoxidil is required prior to drawing conclusions
regarding treatment efficacy. (See 'Topical minoxidil' above.)
●Data are limited on treatments other than minoxidil for FPHL. Systemic agents that inhibit
androgen action or production, such as spironolactone, cyproterone acetate, finasteride, and
flutamide, may be useful in some patients. Further studies are necessary to define which women
benefit from these therapies. (See 'Second-line therapy' above.)
●Hair transplantation surgery can provide cosmetically favorable results in women with FPHL.
Surgical intervention is an option for women who fail to achieve satisfactory improvement with
medical therapy. (See 'Surgery' above.)
●Without treatment, the FPHL typically progresses slowly, though areas of complete baldness
similar to those seen in male androgenetic alopecia usually do not occur. Because the response to
treatment may be incomplete, initiating treatment early in the course of FPHL is preferred. (See
'Prognosis' above.)
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Telogen effluvium - UpToDate
uptodate.com/contents/telogen-effluvium/print
INTRODUCTION Telogen effluvium is a form of diffuse, nonscarring hair

loss that presents as a transient or chronic loss of hair. Hair loss in telogen effluvium occurs as a
result of an abnormal shift in follicular cycling that leads to the premature shedding of hair.
A wide variety of endogenous and exogenous factors have been linked to the induction of telogen
effluvium. Examples include major surgery, serious illness, childbirth, protein or caloric malnutrition,
drugs, and severe emotional distress. In some cases, the inciting cause is unclear or multiple
inciting triggers are identified.
The clinical features, diagnosis, and management of telogen effluvium will be reviewed here. An
overview of the evaluation of patients with scalp hair loss is provided separately. (See "Evaluation
and diagnosis of hair loss".)
EPIDEMIOLOGY Data on the epidemiology of telogen effluvium are

limited. The disorder is one of the most common forms of nonscarring hair loss for which patients
present for clinical evaluation [1]. Telogen effluvium does not appear to have a predilection for
particular racial or ethnic groups.
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Most experts divide telogen effluvium into acute and chronic variants. Acute telogen effluvium may
occur at any age, including infants and children [2-4]. For unclear reasons, women are more likely to
present for evaluation of acute telogen effluvium than men [5]. Chronic telogen effluvium is much
less common than the acute variant, and is most frequently diagnosed in women between the ages
of 30 and 60 years [6,7]. Chronic telogen effluvium can further be subdivided into chronic and
chronic-repetitive clinical presentations. (See 'Clinical features' below.)
PATHOGENESIS The excessive hair shedding that characterizes telogen

effluvium occurs as a result of altered regulation of the hair follicle growth cycle. Normally, each
follicle on the human scalp cycles independently through three major phases: anagen (growth),
catagen (transformation), and telogen (rest). The end of the four to six week telogen phase is
marked by the shedding of hair from the follicle [8]. (See "Evaluation and diagnosis of hair loss",
section on 'Hair cycle'.)
The asynchronous cycling of scalp hair follicles in humans prevents periodic episodes of mass
shedding of hair. Rather, shedding of hair occurs on a continuous basis. In the absence of scalp or
hair disorders, 50 to 150 hairs typically are shed each day [9].
Telogen effluvium occurs when the proportion of hair follicles in the telogen phase increases
significantly, resulting in subsequent prominent shedding of hair. On the normal human scalp, only
about 10 percent of follicles are in the telogen phase at any given time, while anagen and catagen
follicles account for approximately 90 and <1 percent of follicles, respectively [10]. In telogen
effluvium, it is estimated that 7 to 35 percent of the follicles that normally would have remained in
the anagen phase shift into the telogen phase [11].
Mechanism — The mechanism of hair loss in telogen effluvium is not completely

understood. It is generally accepted that an identifiable or occult, physiologic event stimulates a
change in follicular cycling due to an insult to the anagen bulb (one of the two hair growth centers).
Several theories of the mechanism of hair loss have been proposed, some of which have been
associated with specific stimuli for telogen effluvium [8]. Immediate anagen release and delayed
anagen release are the most commonly cited theories:
●Immediate anagen release – Immediate anagen release may be a common mechanism for telogen
effluvium. According to this theory, a significant proportion of anagen follicles are stimulated to
enter telogen prematurely. Immediate anagen release may be the primary mechanism for telogen
effluvium related to physiologic stress (eg, high fever) or drugs [8].
●Delayed anagen release – The theory of delayed anagen release describes prolongation of the
duration of anagen, thereby delaying the onset of telogen. Hair loss is noted once the stimulus for
sustaining anagen ends and the affected follicles enter telogen and subsequently shed. Delayed
anagen release may be the primary mechanism for postpartum telogen effluvium [8,12].
2499
Additional theories for the mechanism of telogen effluvium have been proposed [8,13]. Abnormal
shortening of the anagen phase could contribute to an increase in hair shedding by augmenting the
proportion of follicles in the telogen phase. In addition, shortening of the telogen phase could lead to
the simultaneous release of hair from a large proportion of telogen follicles (immediate telogen
release). Reduced variance in the duration of anagen has been proposed as a mechanism of chronic
telogen effluvium [13]. Last, a delay in telogen release could lead to an increase in hair shedding due
to the sudden release of hairs from follicles that were stimulated to remain in the telogen phase for
an extended period. Delayed telogen release may account for seasonal fur shedding in mammals.
Inciting factors — A wide variety of factors have been associated with the
induction of telogen effluvium based upon clinical observations. However, data to confirm and define
the level of risk for telogen effluvium related to these factors are lacking. It is estimated that in
approximately one-third of patients with acute telogen effluvium, an inciting factor cannot be
identified [5]. The cause of chronic telogen effluvium usually is more difficult to identify, but careful
history taking can be helpful. (See 'Diagnosis' below.)
Potential inciting factors for telogen effluvium include:
●Acute or chronic major illness
●Collagen vascular disease [14]
●Febrile illness
●Major surgery
●Childbirth (telogen gravidarum)
●Rapid weight loss
●Protein or caloric dietary restriction
●Nutritional deficiencies [15]
●Iron deficiency anemia
●Congenital or acquired zinc deficiency (see "Overview of dietary trace elements", section on
'Deficiency')
●Endocrine disorders (eg, hypothyroidism or hyperthyroidism)
●Drugs, supplements, or toxins (table 1)
●Significant emotional stress
●Inflammatory conditions of the scalp (eg, seborrheic dermatitis)
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●Infectious conditions that affect the scalp (eg, fungal, bacterial, viral, or spirochetal)
The relationship between serum levels of ferritin or vitamin D and telogen effluvium is controversial.
Studies evaluating the relationship between serum ferritin levels and telogen effluvium have yielded
conflicting results [16-24], contributing to continued uncertainty about a relationship between these
conditions as well as the value of iron supplementation in non-anemic patients (see 'Supplements'
below). Although a link between vitamin D status and hair loss has been proposed [16,17], additional
studies are necessary to determine whether vitamin D status plays a role in telogen effluvium.
CLINICAL FEATURES The major clinical finding in telogen

effluvium is an acute or chronic reduction in scalp hair density. Less than 50 percent of scalp hair is
typically lost. Therefore, progression to complete balding does not occur [6].
Because only a portion of the hair is lost, the severity of hair loss may not be readily apparent in
patients with a history of voluminous hair prior to the onset of telogen effluvium. In such cases, the
patient history and viewing of prior photographs may provide the clinician with a clearer idea of the
change in hair density.
The progression of telogen effluvium typically follows one of two courses (figure 1):
●Acute telogen effluvium – Telogen hair loss develops within two to three months after the inciting
factor, and reverses once the inciting factor is eliminated. The time for clinically relevant hair
regrowth is between 6 to 12 months, since length of hair is important for the perception of regrowth.
●Chronic telogen effluvium – Idiopathic condition in which telogen hair loss persists for more than
four to six months; some patients develop a chronic-repetitive pattern of telogen effluvium in which
chronic telogen effluvium is punctuated by additional episodes of acute hair loss as a result of
multiple intermittent triggers.
The distribution of scalp hair loss in telogen effluvium typically is diffuse; however, hair loss may be
most noticeable in the bitemporal (picture 1), frontal, and vertex areas [6]. A patchy, or "moth-eaten"
pattern of hair loss is often evident in syphilis-related telogen effluvium (picture 2).
In the absence of a concomitant hair or scalp disorder, the scalp and hair shafts appear normal, with
normal variation in hair shaft diameters, and symptoms are absent. In addition to the scalp, telogen
effluvium may affect other hair-bearing areas [11,25].
Hair loss due to telogen effluvium may lead to the recognition of a preexisting hair loss disorder that
was not as obvious previously. For example, this may occur in patients with early stage male or
female androgenetic alopecia or central centrifugal cicatricial alopecia. (See "Androgenetic alopecia
in men: Pathogenesis, clinical features, and diagnosis" and "Female pattern hair loss (androgenetic
alopecia in women): Pathogenesis, clinical features, and diagnosis" and "Central centrifugal
cicatricial alopecia".)
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HISTOPATHOLOGY With the exception of telogen effluvium induced
by inflammatory disorders that affect the scalp, such as seborrheic dermatitis, scalp biopsies from
patients with telogen effluvium do not demonstrate inflammation. An increased proportion of
telogen follicles is the key histopathologic finding [26]. Unlike androgenetic alopecia, the proportion
of vellus hair follicles is not increased [7]. Because of the absence of increased vellus hair follicles,
variation in hair shaft diameters is much less than that observed in androgenetic alopecia.
Patients with telogen effluvium induced by inflammation in the scalp, such as may occur in
seborrheic dermatitis or syphilis, will demonstrate an increased proportion of telogen follicles as
well as histopathologic findings consistent with the inciting disorder. As an example, biopsies of
syphilitic alopecia usually demonstrate lymphoplasmacytic, perivascular, and perifollicular infiltrates
[27]. (See "Seborrheic dermatitis in adolescents and adults", section on 'Histopathology'.)
DIAGNOSIS The diagnosis of telogen effluvium can usually be made based upon
the patient history, physical examination, and a hair pull test. The recognition of diffuse,
noninflammatory, nonscarring hair loss should raise clinical suspicion for telogen effluvium,
particularly when it occurs acutely and is preceded by a physiologic or psychologic stressor. A scalp
biopsy is not necessary in most cases. (See 'Clinical features' above.)
Patient history — The patient history is of great value in the evaluation of the
patient with suspected telogen effluvium. A thorough patient history confirms a course of hair loss
consistent with telogen effluvium, may reveal the underlying cause(s) of telogen effluvium, and is
useful for ruling out other causes of hair loss. In older adult patients or other patients with multiple
medical disorders, the cause of telogen effluvium may be multifactorial. (See 'Inciting factors' above
and "Evaluation and diagnosis of hair loss".)
Key inquiries include:
●Course of hair loss (date of onset, duration, apparent triggers)
●Characteristics of hair loss (estimated amount of hair lost daily, appearance of lost hair shafts
[intact versus broken hairs])
●Medical history (see 'Inciting factors' above)
•Recent or chronic medical illness
•Major surgeries
•Rapid weight loss
•Restricted diets
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•Recent childbirth, miscarriage, or abortion
•Iron deficiency anemia
•Nutritional deficiency (ie, zinc, protein)
•Thyroid disorder
•Review of systems to identify unknown underlying disorders
●Psychologic stressors
●Drug and nutritional supplement history
●History of toxic exposure
●Family history of hair disease(s)
In addition, the patient history may provide clues that a different (or concomitant) hair loss disorder
is present. Inquiring about the menstrual and reproductive history of women may lead to
consideration of the possibility of androgenetic alopecia due to androgen excess. Similarly, a careful
family history may elucidate information that raises suspicion for a heritable hair loss disorder. (See
"Evaluation and diagnosis of hair loss", section on 'Inherited and acquired structural hair disorders'.)
Physical examination — Patients should receive a careful examination of

the scalp hair and scalp skin. Scale, inflammation, pustules, and scarring are not features of isolated
telogen effluvium. The detection of such findings suggests the presence of a different (or
concomitant) scalp disorder. Abnormalities of the hair shaft also are not features of telogen
effluvium. If many broken hairs are visualized in a patient with a complaint of hair loss, the clinician
should consider the possibility of heat or chemical-related damage to the hair shaft, trichotillomania,
or a structural hair disorder. (See "Evaluation and diagnosis of hair loss", section on 'Scalp and hair
examination'.)
In addition, the entire skin surface should be examined to identify the extent of hair loss and to
detect features of other hair or scalp disorders. Examination of the nails should be performed and
may offer clues to the cause of telogen effluvium. As examples, Beau lines in the nails suggest the
recent occurrence of a significant medical illness (picture 3A-B), and patients with iron deficiency
anemia may demonstrate koilonychia (nail "spooning") (picture 4). (See "Overview of nail disorders",
section on 'Nail signs of systemic diseases'.)
Hair pull test — A hair pull test should be performed as part of the physical examination
in patients who present with clinical findings suggestive of telogen effluvium. The test aids in the
recognition of active hair shedding. We grasp 50 to 60 hair fibers close to the skin surface and tug
the hairs from the proximal to distal ends. The extraction of more than six to ten hair fibers is
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abnormal [28]. We repeat the pull test in several areas of the scalp. Examination of the hair shafts
with a light microscope is then used to confirm that the loose hairs are telogen hairs (figure 2). (See
"Evaluation and diagnosis of hair loss", section on 'Hair pull test'.)
Of note, a false-negative hair pull test can occur if the patient has shampooed or vigorously groomed
the hair on the day of examination. Conversely, a false-positive hair pull test may be noted if the
patient has not shampooed or combed the hair for several days.
Dermoscopy — Data on dermoscopic findings in telogen effluvium are limited. Acute

telogen effluvium may demonstrate empty follicles and many regrowing hairs of normal thickness
(>0.03 mm). Dermoscopic findings may help to distinguish chronic telogen effluvium from female
pattern hair loss (female androgenetic alopecia); the latter exhibits greater hair diameter variability
[29].
Wood's light examination — Seborrheic dermatitis of the scalp can lead to

telogen effluvium. Although a physical examination demonstrating greasy scale and erythema on
the scalp and a characteristic distribution usually is sufficient for diagnosis, examination with a
Wood's lamp (a source of ultraviolet A light) can aid in the diagnosis of seborrheic dermatitis by
highlighting the presence of scale. In addition, Malassezia yeasts, which are thought to play a role in
seborrheic dermatitis, can fluoresce upon exposure to ultraviolet light [30]. In the author's personal
experience, illumination of areas of seborrheic dermatitis with a Wood's lamp yields orange
fluorescence and can also reveal white or yellow scaling on the scalp not noted with visible light.
Procedures — Investigation beyond the clinical history and physical examination is not
necessary for the diagnosis of most patients with telogen effluvium. However, additional diagnostic
procedures can be helpful for evaluating patients in whom the diagnosis is unclear.
Scalp biopsy — Scalp biopsies are not necessary to diagnose most cases of telogen
effluvium, and are reserved for occasional patients in whom the diagnosis is uncertain. In contrast,
we usually perform scalp biopsies in patients who present with features suggestive of chronic
telogen effluvium because it can be difficult to clinically distinguish chronic telogen effluvium from
diffuse presentations of alopecia areata and female pattern hair loss. (See 'Differential diagnosis'
below and "Alopecia areata: Clinical manifestations and diagnosis" and "Female pattern hair loss
(androgenetic alopecia in women): Pathogenesis, clinical features, and diagnosis", section on 'Scalp
biopsy'.)
We typically take two 4 mm punch biopsies to allow for one specimen that is sectioned horizontally
and a second specimen that is sectioned vertically. Our preferred site for biopsy is an area outside
sites of predilection for androgenetic alopecia to reduce the possibility of diagnostic confusion; thus,
when feasible, we avoid the bitemporal, frontal, and vertex areas of the scalp. Preferred is the leading
edge of the alopecic area. Examination of the biopsy specimens by a dermatopathologist
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experienced in the evaluation of hair and scalp disorders is ideal. (See 'Histopathology' above and
"Evaluation and diagnosis of hair loss", section on 'Scalp biopsies' and "Skin biopsy techniques",
section on 'Punch biopsy'.)
Trichograms and phototrichograms — Less commonly performed

techniques that can help to confirm a diagnosis of telogen effluvium include trichograms and
phototrichograms. These techniques provide an assessment of the proportion of telogen and
anagen hair follicles on the scalp. Trichograms and phototrichograms are primarily used in
specialized clinical hair centers and research studies. These procedures are described in greater
detail separately. (See "Evaluation and diagnosis of hair loss", section on 'Trichograms and
phototrichograms'.)
Hair collection — A hair collection can be useful for quantifying the amount of hair that
is being lost as well as following the course of telogen effluvium. To perform a hair collection, we
instruct patients to collect hair that sheds during morning hair grooming each day for two weeks.
Hair loss of greater than 100 to 150 hairs per day is consistent with an effluvium. The collected hairs
can be examined under a microscope to confirm that they are telogen hairs.
Laboratory tests — The purpose of laboratory work-up of patients with telogen

effluvium is to identify an underlying cause. There are no serologic studies that definitively diagnose
telogen effluvium.
The author typically obtains the following tests:
●Complete blood count with red blood cell indices (to assess for anemia, particularly helpful on the
first evaluation)
●Complete metabolic panel (to assess for signs of underlying disease)
●Thyroid stimulating hormone (to assess for a thyroid disorder) (see "Laboratory assessment of
thyroid function", section on 'Evaluating for thyroid dysfunction')
●Ferritin (see "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section
on 'Diagnostic evaluation')
We routinely obtain a ferritin level because we often provide iron supplementation in patients with
telogen effluvium and ferritin levels below a certain threshold regardless of the presence of anemia.
However, no high quality studies have evaluated the use of iron supplementation in non-anemic
patients with telogen effluvium, and the value of iron supplementation in this population is uncertain.
(See 'Supplements' below.)
The selection of additional laboratory studies is guided by the need to rule out disorders in the
differential diagnosis or to further investigate patients with signs or symptoms suggestive of a
particular underlying disease. As examples, a hormonal work-up to rule out hair loss related to
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hyperandrogenemia would be appropriate in women with signs of virilization, acne, and obesity, and
further evaluation with an ANA or other studies would be appropriate for a patient with signs or
symptoms of an underlying autoimmune disease. In addition, dietary history may reveal nutritional
deficiencies that should be evaluated, such as protein ingestion of less than 40 g per day and low
zinc levels.
DIFFERENTIAL DIAGNOSIS A variety of nonscarring

hair and scalp disorders share clinical features with telogen effluvium.
●Anagen effluvium – Anagen effluvium is an acute loss of anagen hair fibers secondary to
chemotherapy or toxin exposure and represents acute loss of greater than 80 percent of the scalp
hair. Exclamation point hairs (short, 1 to 3 mm hairs with a tapered base) that result from dystrophic
hair growth are a common finding. Microscopic evaluation of the proximal ends of hairs dislodged
during a hair pull test demonstrates normal or dystrophic anagen hairs rather than telogen hairs.
(See "Alopecia related to systemic cancer therapy".)
●Androgenetic alopecia (male or female pattern hair loss) – Features of androgenetic alopecia that
are useful for distinguishing this condition from telogen effluvium include a clinical examination that
demonstrates a characteristic pattern of hair loss and miniaturized hairs (picture 5A-C). A biopsy
can be useful for differentiating between these diagnoses in difficult cases. Of note, the two
conditions may coexist, and telogen hair shedding can occur early in the course of androgenetic
alopecia. (See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis" and
diagnosis".)
●Diffuse alopecia areata – Diffuse alopecia areata is an uncommon form of alopecia areata that is
characterized by the diffuse loss of scalp hair, resulting in the appearance of generalized hair
thinning (picture 6). Similar to anagen effluvium, exclamation point hairs may be present and
performance of the hair pull test may reveal dystrophic anagen hairs. A biopsy revealing an
inflammatory infiltrate consistent with alopecia areata differentiates this condition from telogen
effluvium. (See "Alopecia areata: Clinical manifestations and diagnosis".)
●Loose anagen syndrome – Loose anagen syndrome is a rare nonscarring hair loss disorder that
manifests with easily extracted anagen hairs from the scalp (picture 7). Young children are typically
affected, particularly females with blond hair. Characteristically, examination of shed hairs reveals
anagen hairs with ruffled cuticles (picture 8).
●Structural hair disorders – A variety of structural hair disorders cause weakening of the hair shaft
that results in easily fractured hair. Unlike telogen effluvium in which hair is shed from the follicle,
these conditions result in increased breakage of hair. Close examination and 2x magnification of the
loose hair will reveal broken hairs and may also reveal characteristic findings of a particular
structural hair disorder. (See "Evaluation and diagnosis of hair loss", section on 'Inherited and
acquired structural hair disorders'.)
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MANAGEMENT
First-line interventions — Telogen effluvium is usually a reactive and
reversible disorder. Therefore, identifying and correcting the underlying cause is the most important
component of patient management. Techniques for camouflaging hair loss and psychologic support
are useful adjuncts for managing the psychosocial effects of hair loss.
Removal or treatment of underlying cause — Although

spontaneous improvement is expected for patients with telogen effluvium related to an isolated
event (eg, childbirth), patients with telogen effluvium related to a persisting insult should have the
cause eliminated or treated when feasible. For example, treatment for an associated illness or
dietary deficiency can be implemented. If drug-induced telogen effluvium is suspected, the suspect
drug must be discontinued for at least three months to determine whether hair loss will improve off
therapy [5]. In addition, concomitant hair or scalp disorders (eg, seborrheic dermatitis) should be
treated.
Cosmetic measures — Consultation with a cosmetologist can help patients

identify measures that minimize the cosmetic effects of hair loss. Hair styling techniques, hair
coloring, scalp coloring, and hair prostheses can be useful for camouflaging hair loss. Hair
transplantation is not indicated for patients with telogen effluvium.
Psychologic support — Hair loss can have a profound psychosocial impact, which
may seem out of proportion to the degree of hair loss [31,32]. Thus, consideration of the patient's
emotional well-being is an important component of patient management. The patient's concerns
should be addressed by the clinician in a sensitive manner. In addition, education about the hair
growth cycle and the expected course of telogen effluvium (including an explanation that complete
hair loss is not expected to occur), may help to reassure patients. Follow-up evaluations can be
helpful for reassuring the patient as well as for identifying patients who require further evaluation
because of persistent telogen effluvium.
Other interventions — The efficacy of topical minoxidil and a variety of

nutritional supplements in telogen effluvium is unclear.
Topical minoxidil — Topical minoxidil is primarily used for the treatment of male and
female androgenetic alopecia. The drug promotes hair growth by prolonging anagen, shortening
telogen, and enlarging miniaturized hair follicles. (See "Treatment of androgenetic alopecia in men",
section on 'Mechanism of action'.)
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Although its efficacy in telogen effluvium has not been evaluated, we prescribe topical 2% or 5%
minoxidil for patients with chronic telogen effluvium in an attempt to maintain hair density and
stimulate regrowth of hair. Minoxidil 2% is applied twice daily to the entire scalp while 5% is usually
used once per day. The effects of minoxidil on hair growth are not evident immediately; we suggest a
full year of use prior to concluding that minoxidil is ineffective. Treatment must be continued
indefinitely to maintain benefit. In our opinion, minoxidil is not helpful for telogen effluvium that is
expected to resolve spontaneously or that has an inciting cause that can be eliminated.
Of note, occasionally increased hair shedding has been observed within the first two to eight weeks
of treatment with minoxidil in patients treated for androgenetic alopecia. This is thought to result
from the release of hairs from telogen follicles as they are stimulated by minoxidil to transition from
telogen to anagen [1,33]. A telogen effluvium frequently follows the cessation of topical minoxidil in
patients with androgenetic alopecia [34].
Supplements — Although it is well accepted that patients in whom iron deficiency

anemia is detected should receive iron supplementation, the use of iron supplementation for the
treatment of telogen effluvium in the absence of iron deficiency or iron storage anemia is
controversial. Supplementing iron intake to reach ferritin levels greater than 30, 40, or 70 mcg/L in
patients with hair loss has been recommended by some experts based upon a belief that treatment
for hair loss is optimized at greater serum ferritin levels [1,18,22,35]. In one small placebo-controlled
randomized trial of 12 women with chronic telogen effluvium who were treated with iron and lysine
supplements (n = 5) or placebo (n = 7) for six months, a 31 percent reduction in the proportion of
hairs in the telogen phase was detected in the treatment group, compared with a 9 percent increase
in the proportion of telogen hairs in the placebo group [22]. (See "Treatment of iron deficiency
anemia in adults".)
The uncertainty regarding the impact of iron supplementation on telogen effluvium has contributed
to disagreement among experts about the need for iron supplementation and the target for the
ferritin level when iron therapy is given. Based upon personal clinical experience that suggests
benefit, the author routinely prescribes dietary modification or oral iron supplementation for patients
with telogen effluvium to obtain and maintain serum levels of ferritin well within the reference range
of the assay used at her institution (at least 70 mcg/L). Of note, ferritin reference ranges are assay-
specific. Additional studies are necessary to clarify whether iron supplementation is beneficial for
non-anemic patients with telogen effluvium. The impact of other supplements such as zinc (in the
absence of symptomatic zinc deficiency), biotin, and vitamin D on telogen effluvium also is unclear.
Photography — Photographs are less helpful in telogen effluvium than in

androgenetic hair loss, alopecia areata, or primary scarring alopecia. However, standardized
photographs of midline part, central, and occipital scalp at the time of diagnosis provide a baseline
assessment and a frame of reference for future visits. Since hair grows 0.5 to 1 cm a month,
photographic follow-up will also allow for assessment of regrowth [36].
2508
PROGNOSIS The prognosis of telogen effluvium is dependent on the ability to
remove or treat the inciting factor. If the underlying cause spontaneously resolves or can be
eliminated, the course of telogen effluvium is self-limited. Patients typically exhibit active shedding
that persists for two to three months followed by stabilization and regrowth of hair. Cosmetically
significant improvement is usually noted within 6 to 12 months. Telogen effluvium in which the
underlying cause cannot be identified or removed may persist for years [37]. Complete baldness
does not occur in acute or chronic telogen effluvium [7].
SUMMARY AND
RECOMMENDATIONS
●Telogen effluvium is one of the most common forms of nonscarring hair loss for which patients
present for clinical evaluation. Both children and adults may develop telogen effluvium. (See
●Telogen effluvium results from an alteration in follicular cycling that leads to the excessive
shedding of telogen hairs. A wide variety of endogenous and exogenous factors have been linked to
induction of telogen effluvium. Examples include serious illness, major surgery, childbirth, rapid
weight loss, nutritional deficiency, profound emotional stress, and drug exposure. The cause of
telogen effluvium may be multifactorial in patients who have multiple medical problems or who are
taking multiple drugs. In some cases, an inciting factor cannot be identified. (See 'Pathogenesis'
above.)
●Hair loss in telogen effluvium manifests as a diffuse reduction in hair density. In most cases, the
course is self-limited, with hair loss beginning two to three months after the inciting factor and
reversing once the inciting factor resolves or is eliminated. (See 'Clinical features' above.)
●Chronic telogen effluvium is a less common, idiopathic presentation of telogen effluvium that most
commonly occurs in women between the ages of 30 and 60 years. Chronic telogen effluvium may
persist for years. (See 'Clinical features' above.)
●Less than 50 percent of the normal hair density usually is lost in telogen effluvium. Progression to
complete balding does not occur. (See 'Clinical features' above and 'Prognosis' above.)
●The diagnosis of telogen effluvium can usually be made based upon the patient history and
physical examination. Laboratory screening tests can be helpful in identifying an etiology. Scalp
biopsies are typically reserved for patients in whom the diagnosis is uncertain. (See 'Diagnosis'
above.)
●The most important component of the management of patients with telogen effluvium is the
identification and removal of the underlying cause. Data are insufficient to determine whether iron
supplementation is beneficial in the absence of iron deficiency or iron storage anemia. (See
2509
2510
Traction alopecia - UpToDate
uptodate.com/contents/traction-alopecia/print
INTRODUCTION Traction alopecia is a form of hair loss that results from

prolonged or repetitive tension on hair. Traction alopecia most commonly occurs along the frontal or
temporal scalp, but can also occur in other sites of the scalp and in other hair-bearing areas (picture
2511
1A-C).
Having a high clinical suspicion for traction alopecia in at-risk populations and obtaining a detailed
history of current and past hair care practices is essential for making the diagnosis. Early
recognition and cessation of the offending hair care practice is critical because sustained traction
can lead to permanent hair loss.
The clinical features, diagnosis, and management of traction alopecia will be reviewed here. An
overview of the evaluation of patients with hair loss is provided separately. (See "Evaluation and
diagnosis of hair loss".)

FACTORS Traction alopecia can occur when hair follicles are subjected to prolonged
or repetitive tension. Although epidemiologic data on traction alopecia are limited [1-4], it appears
that traction alopecia is most frequently diagnosed in females of African descent with Afro-textured
hair. The relatively high prevalence in this population is most likely related to the frequent use of
traction hairstyles (eg, braids or hair weaves). In support of this theory, traction alopecia occurs in
other populations in association with the use of traction hairstyles, such as tight ponytails [5-7],
chignon or bun hairstyles (as often worn by ballerinas) [8,9], hair extensions [10], hair pins (as for
securing nursing caps) [11], and the Sikh practices of tightly twisting long hair on the scalp and
knotting the beard hair [12,13].
Differences in exposure to traction hairstyles likely contributes to the higher prevalence of traction
alopecia in females compared with males and adults compared with children in populations of
African descent. In a study of 874 adults in South Africa, traction alopecia was detected in 32
percent of women compared with only 2 percent of men [1]. Increasing prevalence with age was
demonstrated in a study of 1042 schoolchildren (ages 6 to 21 years) in South Africa; traction
alopecia was present in 9 percent in girls in their first year of school (age 6 to 7 years) compared
with 22 percent in girls in their last year of high school (age 17 to 21 years) [2]. No male
schoolchildren had traction alopecia. Traction alopecia can also occur in infants. A case report
documents traction folliculitis (an early presentation of traction alopecia) in an eight-month-old child
[14].
Limited data suggest that use of chemical relaxers may increase risk for traction alopecia. In a study
of 574 South African schoolgirls and 604 South African adult women, girls or women with a history
of traction applied to chemically relaxed hair had the highest likelihood for traction alopecia (odds
ratio 3.47, CI 1.94-6.20) [15]. A history of certain hair dressing-associated symptoms (pain, pimples,
crusts) may also be associated with increased risk for traction alopecia. The same study found that
the majority of patients (81 percent) with traction alopecia admitted to a history of tight painful
braids, painful pimples, and stinging sensations during chemical relaxers with or without formation
of crusts [15].
2512
PATHOGENESIS The exact pathogenesis of traction alopecia is yet to be
elucidated. Traction on hair may induce a perifollicular inflammatory process that is asymptomatic
or associated with clinical signs of folliculitis. As a result of this inflammation, follicles may become
miniaturized or dormant, resulting in finer hairs, vellus-like hairs, and reduced hair density [6,16,17].
Initially, hair loss secondary to traction alopecia is nonscarring and reversible if the cause of traction
and the inflammatory reaction is discontinued. With persistent traction, irreversible damage to the
hair follicles leads to permanent (scarring) alopecia.
Further study is necessary to clarify whether the high levels of interleukin (IL) 1-alpha (a
proinflammatory cytokine) in scalp sebum relative to levels of IL-1 receptor antagonist (a
competitive inhibitor of IL-1-alpha) in scalp sebum detected in a study of 36 asymptomatic black
South African women indicates a proinflammatory state that may predispose women with Afro-
textured hair to scalp inflammation and alopecia [18]. Pending further data, exposure to traction
hairstyles is considered the primary factor contributing to the development of traction alopecia.
CLINICAL FEATURES The clinical findings of traction alopecia

can include inflammatory papules, pustules, reduced hair density, reduced hair length and caliber,
and alopecic patches (table 1). The manifestations depend on the stage and severity of disease. The
scalp is the most common site of traction alopecia, with the frontal hairline and the temporal scalp
above the ears most frequently affected. However, traction alopecia may appear in other sites on the
scalp or in other body areas in which hair follicles are subjected to traction.
In the earliest stages of traction alopecia, hair loss may be absent or limited to a subtle decrease in
hair density. At this stage, patients may have only traction folliculitis, manifesting as perifollicular
erythema, perifollicular inflamed papules, or perifollicular sterile pustules in sites of traction (picture
2) [14]. Patients may describe this presentation as "pimples on the scalp." Scalp scaling and pruritus
may accompany traction folliculitis.
Traction folliculitis can be transient, resolving as tension on the hair follicles decreases due to the
removal of traction or hair growth. Therefore, direct questioning may be necessary to determine
whether a patient has experienced traction folliculitis.
With persistent traction, noticeable hair loss occurs, which may progress from decreased hair
density to patches of complete alopecia. Marginal traction alopecia, the most common presentation,
affects the frontal and temporal scalp above the ears (picture 1A). However, hair loss in the back of
the scalp or occiput can also be seen. The "fringe sign," which is defined as fine or miniaturized
residual hairs retained at the margin of the anterior hairline with hair loss posterior to the fringe,
typically is present (picture 1B) [6]. Marginal alopecia often occurs in association with hairstyles
incorporating tight ponytails, buns, or braids [5,6].
2513
Nonmarginal alopecia occurs in areas other than the frontal or temporal scalp. For example, women
who frequently wear their hair in a tight chignon or bun can develop patchy hair loss of the occipital
scalp. Nonmarginal traction alopecia can also occur as a result of hair extensions [10], pins used to
secure hats [11], or other regular use of hair accessories (picture 3) [10]. Linear, curved, or horseshoe
patterns of hair loss can occur when hair is tightly braided on the scalp in preparation for the
attachment of sewn-in or glued-in curtain-like hair extensions (hair wefts), as is often done for hair
weaves (picture 1C) [14,19,20].
The presence of hair casts can be a sign of ongoing traction alopecia [21-24]. Hair casts are
moveable collections of white scale that encircle the hair (picture 4). Hair casts are composed of
keratin derived from root sheath cells and occur in association with a variety of scalp disorders [23].
HISTOPATHOLOGY The histopathologic findings in traction

alopecia may differ based upon the stage of disease:
●Early traction alopecia –Biopsies of traction alopecia less than one year in duration may
demonstrate trichomalacia (twisted or deformed anagen bulbs), increased numbers of telogen and
catagen hairs, a normal number of terminal follicles, and preserved sebaceous glands [6]. The
dermis may exhibit mild perifollicular chronic inflammation.
●Late-stage traction alopecia – Long-standing traction alopecia characteristically demonstrates

follicular miniaturization, follicular "drop-out" (loss of terminal hair follicles), and retained sebaceous
glands (picture 5) [6,16,17,25]. Lost terminal follicles are replaced with fibrous tracts. Dermal
inflammation is minimal or absent.
Although fibrosis is considered a histopathologic feature of late-stage traction alopecia,

histopathologic assessment for fibrosis may not be a reliable indicator of the stage of traction
alopecia (early versus late-stage) and, additionally, may not correlate with the overall severity of hair
loss. A study of specimens from 45 patients with traction alopecia found poor agreement among
three dermatopathologists in the assessment for perifollicular and interfollicular fibrosis and did not
find a correlation between fibrosis and the clinical severity score [26].
DIAGNOSIS The diagnosis of traction alopecia usually can be made based upon
the clinical evaluation. A history of traction hairstyles with hair loss in a concordant distribution is
essential for diagnosis. A history of signs of traction folliculitis (perifollicular erythema, inflamed
papules, or pustules at sites of traction) prior to significant hair loss offers additional support for the
diagnosis. (See 'Clinical features' above.)
A variety of other scalp and hair disorders can result in patterned hair loss that may be mistaken for
traction alopecia. When the diagnosis is uncertain, a skin biopsy can be performed to aid in ruling
out other disorders as the cause of hair loss and confirming the diagnosis. The histopathologic
findings of traction alopecia are not pathognomonic; therefore, the biopsy must be interpreted in the
context of the clinical findings. (See 'Histopathology' above.)
2514
History — A high index of suspicion is often necessary to diagnose traction alopecia,
particularly since patients may not associate hair loss with their hairstyling practices. Questions that
can be helpful in the evaluation include:
●"When did the hair loss start?" and "Was the hair loss sudden in onset or gradual?" – Hair loss in
traction alopecia typically is gradual. Occasionally, hair loss is perceived as acute if associated with
another cause of hair shedding (eg, telogen effluvium) or is noted upon removal of braids or weaves
[19].
●"Where have you noticed the most hair loss?" – Localized or patchy hair loss is characteristic of
traction alopecia. Diffuse hair loss or a complaint of hair loss "all over" is not typical of traction
alopecia.
●"Have you had symptoms in the area of hair loss?" – If asked specifically, many patients with
traction alopecia will admit to symptoms including tenderness, pimples, stinging, or crusting at
some point prior to hair loss [1,2].
●"What is your normal hair care routine?" – A history of current or previous traction hairstyles is
necessary for a diagnosis of traction alopecia. Knowledge of other hair care practices, such as
frequent use of direct heat (eg, flat irons or curling irons) on the hair shaft [27] and chemical relaxers,
is useful because such measures increase hair fragility and may contribute to additional hair loss
[28,29].
Physical examination — The physical examination of a patient with

suspected traction alopecia on the scalp should include assessment of both the scalp and hair.
The examination should begin with a global assessment of the general appearance of the hair. The
texture, color, and length of the hair as well as the current hairstyle should be noted, as variations of
these features can mask or augment the appearance of hair loss. If there is recognizable hair loss,
the pattern and severity of hair loss should be assessed. In traction alopecia, the distribution of hair
loss should correlate with the areas subjected to traction.
Examination of the scalp can be performed by examining the skin along the hairline, then parting the
hair in a systematic manner that allows for a thorough assessment of the scalp skin. Particular
attention should be paid to signs of inflammation (eg, erythema, inflamed papules, pustules, or
scale) as these may indicate traction folliculitis, as well as to the presence or absence of follicular
ostia in the involved areas. In traction alopecia, follicular ostia are usually retained, with the
exception of late-stage disease, which may have diminished follicular ostia.
Closer examination should include visual assessment of hair fibers in the involved areas. In traction
alopecia, hair fibers often become finer as a result of follicular damage or follicular miniaturization.
The clinician should also examine the patient for the presence of hair casts. Hair casts frequently
2515
occur in traction alopecia and are an indicator of persistent traction [21-24]. Hair pull tests, which are
used to assess for hair cycle disturbances resulting in hair loss, are typically negative in traction
alopecia. (See "Evaluation and diagnosis of hair loss", section on 'Hair pull test'.)
In clinical studies, the severity of marginal traction alopecia has been assessed using the Marginal
Traction Alopecia Severity (M-TAS) score [15].
Dermoscopic examination is a useful adjunctive tool in the diagnosis of traction alopecia.

Dermoscopy may detect hair casts that are less easily seen with the naked eye [21]. In addition,
dermoscopy may be helpful in visualizing the follicular ostia (pinpoint white dots), which can be
diminished in persistent traction alopecia. The presence of empty follicles, vellus hairs, broken hairs,
black dots, and circular hairs may also help support the diagnosis of traction alopecia, though these
changes may vary depending on whether the traction is early or late stage [30,31]. (See "Overview of
dermoscopy".)
Biopsy — A biopsy is not necessary for diagnosis of traction alopecia in the majority of
cases, but should be done when there is doubt regarding the diagnosis. In contrast to many other
hair loss disorders, the biopsy should be from the center as opposed to the periphery of an alopecic
area. (See "Skin biopsy techniques".)
One 4 mm punch biopsy sectioned horizontally may allow for the detection of histologic findings
consistent with traction alopecia. However, many dermatopathologists prefer two biopsies to allow
for examination of both horizontal and vertical sections. (See 'Histopathology' above.)

of traction alopecia differs based upon whether the patient presents with traction folliculitis,
marginal tractional alopecia, or nonmarginal alopecia (table 1).
Traction folliculitis — Pustular eruptions secondary to bacterial folliculitis or

tinea capitis are in the differential diagnosis of early traction folliculitis. Bacterial or fungal cultures
can differentiate these conditions from the sterile pustules of traction folliculitis. Of note, the
lymphadenopathy often present in tinea capitis is absent in traction alopecia. (See "Infectious
folliculitis" and "Tinea capitis".)
Marginal traction alopecia — Marginal traction alopecia may

resemble the ophiasis pattern of alopecia areata and frontal fibrosing alopecia:
●Alopecia areata – Alopecia areata is an autoimmune condition that usually presents with sudden-
onset patchy hair loss. Occasionally, hair loss occurs in a band-like distribution along the hairline,
known as the ophiasis pattern (picture 6). This presentation can be difficult to distinguish clinically
from traction alopecia. Both disorders usually exhibit retained follicular ostia. The presence of
exclamation point hairs (short hairs less than a few millimeters in length with tapered bases) within
2516
the involved area suggests alopecia areata (picture 7). When necessary, a biopsy can aid in
distinguishing these disorders. Histopathologic examination of alopecia areata reveals peribulbar
lymphocytic inflammation and an absence of fibrotic fibrous tracts. (See "Alopecia areata: Clinical
manifestations and diagnosis".)
●Frontal fibrosing alopecia – Traction alopecia involving the frontal and temporal hairline can be
difficult to distinguish from frontal fibrosing alopecia (FFA), an uncommon form of cicatricial
(scarring) alopecia (picture 8A-B). Both conditions present with hair loss in a band-like pattern along
the frontal hairline. In FFA, there is loss of the follicular ostia and the involved scalp appears pale
and sclerotic. Isolated terminal hairs may remain in areas of involvement (the "lonely hair sign") and
there is an absence of vellus hairs [32]. The "fringe sign" of traction alopecia is absent. Eyebrow loss
is a common associated feature of FFA. Hyperpigmentation of the face and neck consistent with
lichen planus pigmentosus may be another frequent associated finding in patients with highly
pigmented skin [33]. Histopathologic examination of FFA shows a loss of sebaceous glands and an
inflammatory infiltrate and interface dermatitis around hair follicles. (See "Lichen planopilaris",
section on 'Frontal fibrosing alopecia'.)
Nonmarginal traction alopecia — Nonmarginal traction alopecia

should be distinguished from hair loss secondary to trichotillomania, syphilis, alopecia areata, or
tinea capitis:
●Trichotillomania – Trichotillomania is a condition in which a person pulls, twists, plucks, or

otherwise manipulates the hair in an obsessive or repetitive manner to the point where there is
visible hair loss (picture 9). Unlike many cases of traction alopecia, the hair loss in trichotillomania
usually spares the marginal hairline because manipulation of hair in these areas may be more
painful. In the areas of hair loss, the hair shafts are broken, with blunt ends, and there may be signs
of irritation or trauma of the scalp. Often, trichotillomania is associated with other behavioral or
psychiatric disorders including anxiety, depression, obsessive-compulsive disorders, or others. On
histologic examination, pigment casts, trichomalacia (twisted or deformed hairs), and a catagen
shift may be present. (See "Skin picking (excoriation) disorder and related disorders", section on
'Trichotillomania'.)
●Syphilis – Patchy hair loss often described as a "moth-eaten" pattern can occur in secondary
syphilis (picture 10). This pattern of hair loss may be similar to the patchy traction alopecia that can
occur as a result of hair extensions. A high level of suspicion is always warranted, and appropriate
serology should be ordered if syphilis is suspected. (See "Syphilis: Screening and diagnostic testing"
and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected
patients", section on 'Clinical manifestations'.)
●Alopecia areata – Patchy alopecia areata can resemble nonmarginal traction alopecia. The onset
of alopecia areata tends to be sudden, unlike the typical gradual onset of traction alopecia. Alopecia
areata is also in the differential diagnosis of marginal traction alopecia. (See 'Marginal traction
alopecia' above and "Alopecia areata: Clinical manifestations and diagnosis".)
2517
●Tinea capitis – Tinea capitis is a common disorder in children that may present with patchy hair
loss. Scale is usually present and is typically more prominent than the mild scale that may
accompany traction alopecia (picture 11). A potassium hydroxide (KOH) preparation of involved
hairs or fungal culture confirms a diagnosis of tinea capitis. (See "Tinea capitis".)
MANAGEMENT Data on the treatment of traction alopecia are limited. No

controlled trials have been performed, and recommendations in the literature are primarily based on
case reports and expert opinion.
The therapeutic options for traction alopecia include behavioral changes and medications aimed at
halting progression of the disorder and promoting regrowth of hair. When treatment is unable to
induce adequate hair regrowth, as is often the case for late-stage disease, hair transplantation or
cosmetic techniques to camouflage hair loss can be beneficial. (See 'Early-stage traction alopecia'
below and 'Late-stage traction alopecia' below and 'Cosmetic camouflage' below.)
Early-stage traction alopecia — The detection of traction alopecia

at an early stage (within one year of onset) is desirable because the potential for hair regrowth
diminishes with increasing duration of traction and increasing severity of alopecia. The most
important intervention for early-stage traction alopecia is discontinuation of the traction hairstyle.
Adjunctive interventions, such as topical or intralesional corticosteroids, oral antibiotics, and topical
minoxidil are often used to in an attempt to minimize additional hair loss and augment regrowth of
hair. (See 'Cessation of traction hairstyles' below and 'Adjunctive interventions' below.)
Cessation of traction hairstyles — Discontinuation of traction hairstyles

is recommended for all patients with traction alopecia. In general, this would include avoidance of
particular styles of braids, weaves, twists, dreadlocks, ponytails, hair buns, hair extensions, or other
styling techniques that exert tension on the hair. Loose, low-hanging ponytails or buns are preferred
methods for tying hair because of a lower risk of TA, especially in natural hair [15,34].
However, changing hairstyling techniques can be difficult for patients because of strong personal
preference or cultural, religious, or professional requirements. Patients who are unable to completely
discontinue a traction hairstyle should be encouraged to alter the hairstyle in a manner that
minimizes tension on the hair. In addition, patients should be educated that the development of pain,
tenderness, or pimples from a hairstyle should not be tolerated. If such symptoms occur, the
hairstyle should be removed or adjusted immediately. Taking down the traction hairstyle when at
home may be an additional helpful measure for patients who are required to wear a traction hairstyle
in professional or social settings.
In addition, we typically encourage patients to avoid insults to the hair that may cause hair breakage,
augmenting the extent of hair loss. Avoidance of chemical relaxers and appliances that directly
apply heat to the hair shaft (eg, curling irons or flatirons) is preferred, though not always feasible for
2518
patients. In particular, because limited data suggest that wearing traction-inducing hairstyles on
chemically relaxed hair may increase risk for traction alopecia [15], we encourage patients who are
unable to stop traction hairstyles to discontinue use of chemical relaxers.
Adjunctive interventions — Topical minoxidil is often applied in an attempt to

augment the growth of hairs in affected areas. In addition, interventions to reduce active
inflammation, such as topical or intralesional corticosteroid therapy and oral antibiotics with
antiinflammatory properties are often prescribed in an attempt to reduce the inflammatory response
that may contribute to hair loss in traction alopecia. Although these treatments are commonly used
[35], they have not been evaluated in clinical trials.
Our typical approach to adjunctive therapy consists of treatment with topical minoxidil for patients
with early-stage traction alopecia who present without clinical signs of active inflammation (eg,
erythema, inflamed papules, pustules, or scale). When patients present with clinical signs of
inflammation, we usually begin with either local administration of a corticosteroid or administration
of an oral tetracycline antibiotic. The latter is preferred when pustules are present [35]. Patients are
transitioned to topical minoxidil therapy once signs of inflammation subside.
Topical minoxidil — Topical minoxidil, a drug frequently used for androgenetic alopecia, is
also used in an attempt to improve hair growth in traction alopecia. It is theorized that minoxidil may
prolong the anagen (growth) phase of hair follicles, shorten the telogen (resting) phase, and induce
enlargement of miniaturized follicles, thereby contributing to the conversion of miniaturized hairs to
terminal hairs [36]. Data on efficacy for traction alopecia are limited to case reports documenting
improvement after treatment with minoxidil 2% solution [37]. (See "Treatment of androgenetic
alopecia in men", section on 'Mechanism of action'.)
Minoxidil is commercially available in a 5% solution or foam and a 2% solution. We typically instruct

patients to apply minoxidil 5% solution or foam once daily to the scalp. Twice-daily application of
minoxidil 2% solution is an alternative.
Treatment should be continued for at least four months prior to assessing for initial signs of a
response. A full year of treatment may be necessary to judge efficacy. If hair growth improves,
treatment should be continued until regrowth is stable for at least three to four months.
Skin irritation and facial hair growth are potential side effects of topical minoxidil. The 5% foam
formulations may be less likely to cause skin irritation than 2% solutions. However, in women, the
risk for facial hypertrichosis may be greater with the 5% formulation than with the 2% formulation
[38]. Facial hypertrichosis typically resolves within a few months after cessation of minoxidil [38].
Initial shedding of hair during the first several weeks of treatment may also be seen [39].
Local corticosteroids — Patients with clinical signs of inflammation may benefit from
local corticosteroid therapy. Local corticosteroids can be administered through application of
medium- to high-potency topical corticosteroids (group 2 to 4 (table 2)) or through intralesional
injection [6,35,40].
2519
Topical corticosteroid therapy is usually applied twice daily to the entire affected area. Intralesional
corticosteroid therapy is often administered as a 10 mg/mL concentration of triamcinolone
acetonide. Both the center and periphery of the area of hair loss should be injected. Individual
injections are typically spaced approximately 1 cm apart with approximately 0.1 mL injected per site.
Injection sessions are typically performed at an interval of four to six weeks. We typically do not
administer more than 20 mg of triamcinolone acetonide per treatment session. (See "Intralesional
corticosteroid injection".)
Treatment with these agents is discontinued once clinical signs of inflammation resolve. A typical
course of treatment is one to two months for topical corticosteroids and two injection sessions for
intralesional corticosteroids.
Skin atrophy is a potential adverse effect of local corticosteroid therapy. The side effects of topical
and intralesional corticosteroid therapy are reviewed in detail separately. (See "Topical
corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Intralesional
corticosteroid injection", section on 'Side effects, complications, and pitfalls'.)
Oral antibiotics — Oral tetracycline antibiotics (eg, tetracycline, doxycycline, minocycline)

are commonly used for traction alopecia in patients with clinical signs of inflammation based upon
the antiinflammatory effects of these drugs. Use of these agents is preferred over local
corticosteroids when pustules are present [35].
Typical adult doses are similar to those used for acne and include tetracycline (500 mg twice daily),
doxycycline (50 to 100 mg twice daily), or minocycline (50 to 100 mg twice daily). Treatment is
continued until clinical signs of inflammation resolve. A typical treatment course is one month or
until resolution of the folliculitis.
Tetracyclines should not be administered to children under the age of nine years or pregnant women
because of risk for discoloration of developing permanent teeth. Common side effects of
tetracycline and doxycycline include gastrointestinal distress and photosensitivity. Minocycline use
may be associated with gastrointestinal distress, dizziness, skin discoloration, serum sickness, or a
lupus-like syndrome.
Late-stage traction alopecia — Patients presenting with traction

alopecia that has persisted for years are unlikely to experience significant hair regrowth with
treatment. Still, attempts to maximize any potential for regrowth through removal of the traction-
inducing hairstyle (if still in use) and a trial of topical minoxidil is reasonable [37]. (See 'Cessation of
traction hairstyles' above and 'Topical minoxidil' above.)
Patients with permanent hair loss may achieve cosmetic benefits from hair transplantation.
Cosmetic camouflage techniques are an alternative to hair transplantation. (See 'Hair
transplantation' below and 'Cosmetic camouflage' below.)
2520
Hair transplantation — Hair transplantation can restore hair growth in areas of
traction alopecia. Hair transplants performed with micro-grafting, mini-grafting, and follicular unit
transplantation have been reported as effective in individual patients [35,41,42]. Of note, special
consideration should be given to hair shape and styling methods to achieve the best results from
hair transplantation in patients with curly, Afro-textured hair [43]. For example, care must be taken to
avoid transection of curved hair follicles when separating grafts [43].
Cosmetic camouflage — A variety of interventions can effectively conceal areas

of hair loss [44]. Cosmetics that decrease the color contrast between the scalp and hair can reduce
the visibility of hair loss and are available in a variety of application methods (eg, topical hair fibers,
powders, camouflaging lotions or sprays, and scalp tattoos) [44]. Use of a hair piece or wig is also
helpful for camouflaging hair loss from traction alopecia, provided tight clips, glues, or tape are not
used.
PROGNOSIS The prognosis for traction alopecia is excellent if traction is

stopped early in the course of the disorder. However, chronic traction alopecia eventually becomes
permanent and unresponsive to cessation of traction and pharmacologic interventions. (See
PREVENTION Traction alopecia is preventable. Programs to educate adults

and parents or guardians of children and adolescents about the risk factors for traction alopecia and
early signs of traction alopecia may aid in reducing incidence [34,45]. Educating hairdressers may
also be of benefit for the prevention and early detection of traction alopecia.
Key messages to communicate to the public include:
●Hairstyles should be painless; a painful hairstyle should be removed immediately.
●Hairstyles causing skin redness, pimples, or hair loss should be removed immediately.
●Traction hairstyles (eg, braids or weaves) should be worn infrequently and for short periods.
●It is preferable to avoid traction hairstyles on chemically relaxed hair.
●Massaging or vigorously brushing the affected scalp does not stimulate hair regrowth and is not
recommended for traction alopecia.
Clinicians may also help to reduce the burden of traction alopecia by recognizing signs of traction
alopecia in children or adults who present for the evaluation of other medical conditions. A
discussion about methods to avoid additional hair loss may stimulate behavioral changes and
benefit patients with traction alopecia.
2521
SUMMARY AND
RECOMMENDATIONS
●Traction alopecia is a type of hair loss that occurs as a result of prolonged or repetitive tension on
hair and hair follicles. Traction hairstyles, such as braids, hair weaves, tight ponytails, or tight hair
buns can lead to the development of traction alopecia. (See 'Epidemiology and risk factors' above.)
●Traction alopecia is most frequently diagnosed in females of African descent with Afro-textured
hair because of the common use of traction hairstyles in this population. However, traction alopecia
can occur in children or adults with any type of hair. (See 'Epidemiology and risk factors' above.)
●The earliest clinical sign of traction alopecia may be the development of traction folliculitis.
Traction folliculitis is characterized by the development of perifollicular erythema, inflamed papules,
or pustules in sites of traction on hair (picture 2). (See 'Clinical features' above.)
●The location of hair loss in traction alopecia correlates with the site(s) of traction. Hair loss most
frequently occurs on the frontal or temporal scalp (picture 1A). The "fringe sign," persistence of fine
or miniaturized hairs in the anterior hairline with greater hair loss posterior to this fringe, is a
common finding (picture 1B). (See 'Clinical features' above.)
●The diagnosis of traction alopecia usually can be made based upon the clinical evaluation. A
history of a traction hairstyle and hair loss in a correlating distribution is essential for diagnosis. A
biopsy can be helpful if the diagnosis is uncertain. (See 'Diagnosis' above.)
●Early recognition of traction alopecia is critical. Patients with early traction alopecia may
experience significant hair regrowth with treatment. Hair regrowth is less likely to occur in
longstanding traction alopecia. (See 'Prognosis' above.)
●Discontinuation of traction hairstyles is the primary treatment for traction alopecia. Modifications
of hairstyling routines may be necessary for patients who cannot completely discontinue traction
hairstyles for professional, cultural, religious, or other reasons. (See 'Management' above.)
●Adjunctive therapies are often prescribed in an attempt to minimize additional hair loss and
augment hair regrowth. We suggest a trial of topical minoxidil for patients who desire treatment
(Grade 2C). If signs of inflammation are present, treatment with local corticosteroids or oral
antiinflammatory antibiotics is typically given prior to minoxidil treatment. (See 'Adjunctive
interventions' above.)
●Traction alopecia is preventable. Education of the public may help to reduce the incidence of
traction alopecia. (See 'Prevention' above.)
2522
Lichen planopilaris - UpToDate
uptodate.com/contents/lichen-planopilaris/print
INTRODUCTION Lichen planopilaris (LPP) is an uncommon inflammatory

scalp disorder that is clinically characterized by perifollicular erythema, follicular hyperkeratosis, and
permanent hair loss. LPP is considered a follicular form of lichen planus based upon shared
pathologic features and the frequent coexistence of clinical findings of these disorders. (See "Lichen
planus".)
LPP is divided into three clinical variants:
2523
●Classic LPP
●Frontal fibrosing alopecia (FFA)
●Graham-Little-Piccardi-Lasseur syndrome (Graham-Little syndrome, GLPLS)
The three variants of LPP are distinguished primarily by the clinical pattern of involvement. Whereas
patchy scalp involvement is a common presentation of classic LPP (picture 1), band-like alopecia
involving the frontal scalp is typical of FFA (picture 2). GLPLS is defined by a triad of features:
cicatricial alopecia on the scalp, noncicatricial alopecia in the axillae and groin, and widespread
lichenoid follicular papules.
The treatment of LPP is challenging due to a paucity of data on the efficacy of therapies and an
inconsistent response to treatment. However, because uncontrolled LPP results in irreversible hair
loss, rapid diagnosis and the prompt institution of treatment are important for the management of
patients with LPP.
The diagnosis and management of LPP will be reviewed here. Lichen planus is discussed separately.
(See "Lichen planus".)
CLASSIFICATION The participants of a 2001 workshop on cicatricial

alopecia sponsored by the North American Hair Research Society proposed a classification scheme
for cicatricial alopecias that is primarily based upon the pathologic features of each disorder [1].
Lichen planopilaris (LPP) was classified as a primary lymphocytic cicatricial alopecia, a member of a
group of inflammatory scalp disorders that demonstrate a lymphocyte-predominant inflammatory
infiltrate, follicular destruction, and permanent hair loss. The classification of the cicatricial
alopecias is reviewed separately. (See "Evaluation and diagnosis of hair loss", section on 'Cicatricial
alopecia'.)
EPIDEMIOLOGY Epidemiologic data on lichen planopilaris (LPP) are

limited. Although it is accepted that LPP is uncommon, the incidence and prevalence of LPP are
unknown. Data from select North American tertiary hair research centers suggest that patients with
LPP account for less than 1 percent to 8 percent of new patients who present to such centers for
evaluation [2,3].
Adults between the ages of 25 and 70 years are the primary population affected by LPP; however,
LPP also is occasionally observed in children [2,4-6]. A retrospective study of 45 patients with
classic LPP found a mean age of onset of 52 years [7].
All three variants of LPP appear to be more common in females than in males [2,4,7,8]. In the
retrospective study of 45 patients with classic LPP mentioned above, the female to male ratio was
4:1 [7]. Other studies have found less dramatic sex differences; in a retrospective study of 25
patients with LPP, the female to male ratio was 1.8:1 [2]. Postmenopausal women are the primary
2524
population affected by the frontal fibrosing alopecia (FFA) variant of LPP [8-11]. In a retrospective
study of 355 patients with FFA (343 women and 12 men), the mean age was 56 years (range 21 to 81
years) [8]. Although Graham-Little-Piccardi-Lasseur syndrome (GLPLS) can occur in males, most of
the reported cases have occurred in Caucasian women between the ages of 30 and 60 years [12].
Data are insufficient for definitive conclusions about racial or ethnic predilections for LPP. The
possibility of a reduced risk in individuals of Asian origin was suggested by data from a tertiary hair
center in Canada [2]. Although Asians (not including East Indians) accounted for 25 percent of the
3500 patients evaluated at the center over five years, only one of the 25 patients with LPP was Asian.
Additional studies are necessary to confirm whether there are racial or ethnic differences in the
prevalence of LPP.
Patients with LPP may have an increased risk for thyroid disease. In a case-control study of 166
patients with LPP and 81 control patients evaluated in a dermatology clinic, thyroid disease was
significantly more frequent among patients with LPP (34 versus 11 percent of patients) [13].
Hypothyroidism was the most common thyroid abnormality in both groups. Further study will be
useful for confirming a relationship between LPP and thyroid disease.
PATHOGENESIS The pathogenesis of lichen planopilaris (LPP) is poorly

understood. Similar to cutaneous lichen planus, LPP is postulated to be an immune-mediated
disorder characterized by an autoreactive, lymphocytic inflammatory process against an unknown
self-antigen. In LPP, follicular antigens may be the target of a cell-mediated cytotoxic immune
reaction.
The permanent loss of hair that characterizes LPP is postulated to emanate from the site in which
inflammation occurs. Unlike alopecia areata, a nonscarring form of hair loss in which inflammation
is most concentrated around the follicular bulb, LPP demonstrates an inflammatory infiltrate
concentrated around the follicular infundibulum and isthmus (figure 1 and picture 3). The follicular
"bulge," a site of pluripotent stem cells involved in regeneration of the lower portion of the hair follicle
during follicular cycling is located within this same region. Damage to the bulge region may account
for the development of permanent alopecia [14].
Endogenous or exogenous agents, such as drugs, viruses, or contact sensitizers have been
proposed as potential triggers for the autoimmune response observed in LPP [4,15,16]. Binding of
components of these agents to keratinocytes could represent an initial trigger for an inflammatory
process. However, a role for specific endogenous or exogenous factors remains unclear.
Other observations that may offer insight into the pathogenesis of LPP include the detection of
reduced expression of peroxisome proliferator-activated receptor (PPAR)-gamma in specimens of
LPP, and the detection of antibodies against the INCENP protein in a patient with Graham-Little-
Piccardi-Lasseur syndrome (GLPLS) [17,18]. PPAR-gamma is a transcription factor that may be
critical for the maintenance of normal pilosebaceous units and INCENP is a component of the
centromere involved in cell mitosis. In addition, the predilection of frontal fibrosing alopecia (FFA) for
postmenopausal women and the apparent response of some cases to antiandrogenic treatment has
2525
raised questions about whether androgens are involved in the pathogenesis of FFA [9,19]. Further
study is necessary to determine the relevance of a retrospective study that found a higher rate of
early menopause among women with FFA than in the general population [8].
A genome-wide association study in two European cohorts of females with FFA and female controls
identified susceptibility loci for FFA, supporting a genetic predisposition to the development of this
condition [20]. The strongest effect on FFA susceptibility was found at 6p21.1 within the major
histocompatibility complex (MHC) region, which upon further analysis was attributed to HLA-
B*07:02 allele. HLA-B*07:02 is postulated to facilitate hair follicle autoantigen presentation, an event
that may contribute to lymphocytic destruction of the follicular bulge. Other susceptibility loci
identified in the study include 2p22.2, 8q24.22, and 15q2.1. The findings suggest a pathogenic role
for risk alleles in MHC class I molecule-mediated antigen processing and T cell homeostasis and
function.
CLINICAL PRESENTATION Classic lichen planopilaris

(LPP), frontal fibrosing alopecia (FFA), and Graham-Little-Piccardi-Lasseur syndrome (GLPLS) have
both overlapping and distinct clinical features. Perifollicular inflammation, follicular hyperkeratosis,
and cicatricial alopecia occur in all three variants. The distribution of involvement is the most
prominent distinguishing clinical feature.
Classic lichen planopilaris — The most common sites for initial

involvement in classic lichen planopilaris (LPP) are the vertex and parietal areas of the scalp. The
earliest clinical signs are perifollicular erythema and follicular hyperkeratosis manifesting as
perifollicular keratotic spines or follicular keratotic plugs. Eventually, patients develop skin-colored or
erythematous patches of alopecia that are a few millimeters to a few centimeters in breadth (picture
4) [21]. Close examination will reveal markedly reduced or absent follicular ostia. Occasionally,
residual islands of normal or inflamed hair-bearing follicles remain within the patches of alopecia.
Perifollicular erythema and follicular hyperkeratosis often remain evident at the periphery of areas of
alopecia in patients with active disease [7]. Tufted hairs similar to those seen in folliculitis decalvans
also may be seen [2].
The extent of scalp involvement varies; patients may present with single or multiple scalp lesions
and involvement may be focal or extensive (picture 5) [2,22]. Small patches of alopecia can slowly
progress and become interconnected, leading to a reticulated pattern of alopecia (picture 1) [23,24].
Associated itching, burning, or scalp tenderness is common. Rarely, linear presentations of LPP on
the face or trunk occur [25,26].
Concomitant features of cutaneous, nail, or mucosal lichen planus are not uncommon in patients
with LPP. It is estimated at the time of presentation, 17 to 28 percent of patients with LPP have
evidence of lichen planus in other body sites [21]. Involvement of other sites may precede or follow
the development of LPP [7].
2526
Frontal fibrosing alopecia — FFA is characterized by the development
of frontotemporal loss of both terminal and vellus hairs. Hair loss occurs in a band-like distribution
that is usually 1 to 8 cm in diameter (picture 2) [21,27]. Often, a small number of isolated hairs are
spared within the band of alopecia, a finding that has been referred to as the "lonely hair sign" [8,28].
Similar to classic LPP, erythematous and hyperkeratotic follicles are often found at the periphery of
areas of alopecia. Hypopigmentation may also be evident in the affected area [29]. Pruritus or
trichodynia may be present [8].
Involvement of other scalp sites, such as the periauricular, parietal, or occipital areas, may
accompany the classic distribution of FFA (picture 6) [8,9]. In addition, in a retrospective study of 60
women with FFA, diffuse features of LPP on the scalp were found in 8 percent of patients [9]. Men
may have involvement of the sideburns and facial hair [30].
Eyebrow involvement is common in FFA, occurring in 50 to 83 percent of patients [8,9]. Eyebrow

involvement may precede or follow scalp disease. Eyelash involvement also may occur, though it is
less common. In a retrospective study of 355 patients with FFA in Spain, 14 percent had eyelash
involvement [8]. Men with FFA may experience beard involvement [8].
Patients with FFA also may develop hair loss in areas other than the scalp and face. Body, axillary, or
pubic hair loss was documented in 24, 21, and 18 percent of patients in the Spanish retrospective
study, respectively [8].
In addition, involvement of vellus hair follicles on the face ma

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Contents

INTRODUCTION Dermoscopy is a noninvasive, in vivo technique

●(See "Dermoscopic evaluation of skin lesions".)

●(See "Dermoscopy of pigmented lesions of the palms and soles".)

●(See "Dermoscopy of facial lesions".)

●(See "Dermoscopy of mucosal lesions".)

●(See "Dermoscopy of nail pigmentations".)

●(See "Overview of dermoscopy of the hair and scalp".)

●(See "Dermoscopic algorithms for skin cancer triage".)

TYPES OF DERMATOSCOPES Dermatoscopes

Three types of dermatoscopes are available:

●Nonpolarized light, contact

●Polarized light, contact

●Polarized light, noncontact

Nonpolarized and polarized light dermoscopy provide complementary information (table 1)

COLORS AND STRUCTURES The visualization of

Vascular structures — In amelanotic and hypomelanotic lesions, the vascular

The dermoscopic evaluation of vascular structures includes morphology (dotted, serpentine,

CLINICAL ROLE OF DERMOSCOPY The

Diagnostic accuracy for melanoma — Three meta-analyses

Several factors may affect the diagnostic performance of dermoscopy:

●Experience of the examiner

●Diagnostic algorithm and threshold for a positive test

●Prevalence of melanoma in the patient population examined

●Clinical context and patient-related factors [45,46]

Indications — Dermoscopy aids in the evaluation of pigmented and nonpigmented skin

●Any new or changing lesion

●Lesions that appear clinically suspicious for skin cancer

SOCIETY GUIDELINE LINKS Links to society and

INTRODUCTION Dermoscopy is a noninvasive, in vivo technique

●(See "Overview of dermoscopy".)

●(See "Dermoscopy of facial lesions".)

●(See "Dermoscopy of pigmented lesions of the palms and soles".)

●(See "Dermoscopy of nail pigmentations".)

●(See "Dermoscopic algorithms for skin cancer triage".)

THE TWO-STEP ALGORITHM FOR

FIRST STEP: MELANOCYTIC

Criteria for melanocytic lesions — The structures that

●Aggregated (three or more) or peripheral rim of globules

●Streaks (pseudopods and radial streaming)

●Homogeneous blue pigmentation

●Parallel pattern (for lesions on palm and soles)

●Pseudonetwork (facial skin)

Dermatoﬁbroma — While the presence of a network is indicative of a melanocytic

Criteria for basal cell carcinoma — The diagnostic criteria for

●Large blue-gray ovoid nests

●Multiple blue-gray, nonaggregated globules

●Spoke-wheel structures, including concentric globules

●Ulceration and small erosions

Criteria for squamous cell carcinoma — The diagnostic

●Glomerular vessels, usually focally distributed

●White circles or keratin pearls

Criteria for seborrheic keratoses — Most of the dermoscopic

●Multiple milia-like cysts (three or more).

Criteria for hemangioma/angioma and

Vascular structures in skin lesions — Both melanocytic and

Featureless lesions (feature poor, nonspeciﬁc,

●ABCD rule of dermoscopy (table 3)

●Menzies method (table 4)

●The seven-point checklist (table 5)

●Color, architectural disorder, symmetry, homogeneity/heterogeneity of dermoscopic structures

●Pattern analysis (table 7)

Online tutorials on dermoscopy can be found at www.dermoscopedia.org,

ABCD rule of dermoscopy — The ABCD rule of dermoscopy is a semi-