Clinical Management Review
Strategies for Successful Management of Severe
Atopic Dermatitis
Kanwaljit K. Brar, MDa, Noreen H. Nicol, PhD, RN, FNPb, and Mark Boguniewicz, MDa Denver, Colo
INFORMATION FOR CATEGORY 1 CME CREDIT
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Date of Original Release: January 1, 2019. Credit may be obtained for
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Copyright Statement: Copyright Ó 2019-2021. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects of
allergic disease to those who research, treat, or manage allergic disease.
Target Audience: Physicians and researchers within the field of
allergic disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is
accredited by the Accreditation Council for Continuing Medical Edu-
cation (ACCME) to provide continuing medical education for physi-
cians. The AAAAI designates this journal-based CME activity for 1.00
Patients with severe atopic dermatitis (AD) are reported to
represent between 10% and 18% of all patients with AD.
However, in this subgroup of patients, quality of life is
significantly affected and patients may have a number of atopic
and nonatopic comorbidities. Treatment of this severe
population has often been reactive with inappropriate use of
systemic corticosteroids and unapproved immunosuppressants.
Recent insights point to the systemic nature of AD, which has
important therapeutic implications. Management of severe AD
requires a comprehensive approach that incorporates proper
a
Division of Allergy-Immunology, Department of Pediatrics, National Jewish
Health, Denver, Colo
b
University of Colorado College of Nursing, Denver, Colo
Conflicts of interest: M. Boguniewicz has served as a consultant for Regeneron and
Sanofi-Genzyme. The rest of the authors declare that they have no relevant con-
flicts of interest.
Received for publication September 11, 2018; revised October 18, 2018; accepted
for publication October 22, 2018.
Corresponding author: Mark Boguniewicz, MD, Division of Allergy-Immunology,
Department of Pediatrics, National Jewish Health and University of Colorado
School of Medicine, 1400 Jackson St, J310, Denver, CO 80206. E-mail:
boguniewiczm@njhealth.org.
2213-2198
Ó 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy,
Asthma & Immunology
https://doi.org/10.1016/j.jaip.2018.10.021
AMA PRA Category 1 CreditÔ. Physicians should claim only the credit
commensurate with the extent of their participation in the activity.
List of Design Committee Members: Kanwaljit K. Brar, MD, Noreen
H. Nicol, PhD, RN, FNP, and Mark Boguniewicz, MD (authors);
Michael Schatz, MD, MS (editor)
Learning objectives:
1. To define criteria for diagnosis of severe atopic dermatitis (AD).
2. To recognize the systemic nature of AD, which has important
therapeutic implications.
3. To identify components of stepwise management of severe AD
following international and national guidelines of care.
4. To discuss systemic treatment including risks versus benefits in se-
vere AD including approved biologic therapy.
Recognition of Commercial Support: This CME has not received
external commercial support.
Disclosure of Relevant Financial Relationships with Commercial
Interests: M. Boguniewicz has served as a consultant for Regeneron and
Sanofi-Genzyme. The rest of the authors declare that they have no relevant
conflicts of interest. M. Schatz declares no relevant conflicts of interest.
diagnosis, assessment of disease severity, and impact on patient’s
and caregiver’s quality of life, along with education regarding the
chronic relapsing nature of the disease as well as treatment
options. Biologics such as dupilumab offer a novel, targeted
therapeutic approach for this systemic disease. Ó 2019
Published by Elsevier Inc. on behalf of the American Academy of
Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract
2019;7:1-16)
Key words: Atopic dermatitis; Eczema; Wet wrap therapy;
Biologics; Dupilumab
INTRODUCTION
Atopic dermatitis (AD) is a common inflammatory skin disease
that is increasingly recognized as a global health problem.1 Data
derived from the Global Burden of Disease Study showed that
dermatitis including AD was the leading skin disease in terms of
global burden of disease measured by disability-adjusted life-
years.2 Epidemiologic studies in the United States have shown a
prevalence of up to 18% in school-aged children3 and 7% in
adults.4,5 However, few studies have stratified AD by severity at the
population level. This review will focus on severe AD. In one study
of children and adults, 18% described their eczema as severe,6
whereas in a study limited to adults, 9.8% rated their AD as
1
2 BRAR ET AL
Abbreviations used
AD- Atopic dermatitis
AZA- Azathioprine
CSA- Cyclosporine A
EASI- Eczema Area and Severity Index
FDA- Food and Drug Administration
HIES- Hyper-IgE syndrome
MTX- Methotrexate
MMF- Mycophenolate mofetil
SCORAD- SCORing Atopic Dermatitis
STAT3- Signal transducer and activator of transcription3
TCI- Topical calcineurin inhibitor
TCS- Topical corticosteroid
TEWL- Transepidermal water loss
WWT- Wet wrap therapy
severe.7 In the recent Atopic Dermatitis in America survey,8 11%
of participants assessed their AD as severe using the Patient-
Oriented Eczema Measure, a validated scoring tool.9
As a chronic, relapsing pruritic disease, AD has a profound
impact on the quality of life of patients and families. In a study of
adults with moderate-to-severe AD, 85% reported problems with
itch frequency, 41.5% reported itching for greater than or equal
to 18 h/d, 55% reported AD-related sleep disturbance on more
than or equal to 5 d/wk, and 21.8% reported clinically relevant
anxiety or depression.10 It is noteworthy that 100% of re-
spondents with severe patient-reported outcome scores were
found to have borderline and/or abnormal Hospital Anxiety and
Depression Scale scores.11 Although atopic comorbidities of AD
including asthma and allergies are well recognized,12 association
of AD with a number of nonatopic comorbidities including
neuropsychiatric and cardiovascular are only beginning to be
reported.13,14 Severe AD in adults was recently shown to be
associated with long-term risk of cardiovascular disease in a
population-based cohort study in the United Kingdom.15
AD is characterized by complex immune dysregulation, as well
as skin barrier abnormalities.16 A number of insights into the
pathophysiology of AD have translational implications with
respect to therapy. These include recognition that nonlesional
skin in patients with AD is characterized by both immune ab-
normalities and broad terminal differentiation defects17 and that
type 2 immune abnormalities present not only in the skin but
also systemically are central to the disease process.18 Among
patients with inflammatory skin diseases, patients with AD are
unique in their colonization or infection by various mi-
crobes.19,20 Altered epidermal lipids in AD skin are associated
with staphylococcal colonization21 and have been shown to be
associated with type 2 cytokine dysregulation.22 Dysbiosis of the
skin microbiome appears to contribute to the disease although
this is a complex and dynamic process that we are just beginning
to understand.23 However, it will likely have important trans-
lational implications for the development of novel therapeutic
targets. In considering severe AD, successful management stra-
tegies will require a comprehensive approach, understanding not
only the complex pathophysiology and systemic nature of the
disease24 but the profound impact it has on the patients’ and
caregivers’ quality of life. In this setting, shared decision making
in choosing appropriate treatment should be an integral part of
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
management.25,26 In addition, using a multidisciplinary team
approach may benefit patients by addressing more than the skin
barrier and immune abnormalities.27 In the recent past, advances
in our understanding of disease mechanisms have serendipitously
coincided with technological advances, ushering in a new era of
targeted therapy for AD.28,29 In this review, we will discuss our
strategies for managing severe AD based on these insights.
DIAGNOSIS OF SEVERE AD
AD should be diagnosed by one of several criteria including
Hanifin and Rajka,30 UK Working Party,31 or AAD Consensus
criteria.32 However, the AAD criteria have not been validated or
compared with other diagnostic criteria. Subsequently, severe AD
should be established by minimum involvement of 10% body
surface area and regardless of body surface area, individual lesions
with severe features, involvement of highly visible areas or those
important for function (eg, neck, face, genitals, palms, and/or soles),
and significantly impaired quality of life (adapted from Boguniewicz
et al25). Note that although global assessment scores including In-
vestigator’s Global Assessment have not been validated in clinical
practice, classifying disease as “clear,” “almost clear,” “mild,”
“moderate,” or “severe” is currently mandated as a primary outcome
measure by the Food and Drug Administration (FDA) in clinical
trials. In contrast, more complex validated scoring systems including
SCORing Atopic Dermatitis (SCORAD) and Eczema Area and
Severity Index (EASI) as well as patient-reported outcome measures
have rarely been incorporated into the clinical setting (Table I). An
additional significant confounding problem for clinicians treating
patients with severe AD is that at present, no biomarker has been
validated to assess disease severity.
DIFFERENTIAL DIAGNOSIS OF SEVERE AD
A number of congenital disorders, inflammatory skin diseases,
infectious diseases and infestations, immunodeficiencies, genetic
disorders, as well as skin malignancies may present with signs and
symptoms that can be misdiagnosed as severe AD. Table II lists
some of the diseases that should be considered in the differential of
AD. These should be considered when a patient first presents with
an eczematous rash, but also when a patient diagnosed with AD
fails to respond to appropriate therapy. Infants presenting with a
generalized scaling erythematous rash along with failure to thrive,
diarrhea, and recurrent cutaneous and/or systemic infections
should be evaluated for severe combined immunodeficiency syn-
drome. Omenn syndrome is an autosomal-recessive severe
combined immunodeficiency that can present with an eryth-
rodermic rash, diarrhea, lymphadenopathy, hepatosplenomegaly,
susceptibility to infections as well as elevated IgE and eosino-
philia.33 Immune dysregulation, Polyendocrinopathy, and
Enteropathy X-linked syndrome can present with eczematous
rash, although patients will usually have recalcitrant enteropathy
and autoimmune features such as type 1 diabetes, thyroiditis,
hemolytic anemia, or thrombocytopenia.34 Wiskott-Aldrich syn-
drome is an X-linked recessive disorder characterized by eczema-
tous rash, thrombocytopenia, severe bacterial infections, and
variable abnormalities in humoral and cellular immunity. Hyper-
IgE syndrome (HIES) due to signal transducer and activator of
transcription3 (STAT3) mutations is an autosomal-dominant
multisystem disorder with eczematous rash, but characterized by
recurrent deep-seated bacterial infections, including cutaneous
cold abscesses and pneumonias often with pneumatocele
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 3
VOLUME 7, NUMBER 1

TABLE I. Evaluation of severity of AD

Validated scoring systems for clinician assessment
Scoring system Description Severity rating

SCORAD 3 Components: Mild: <25

A: Extent—Sites affected are shaded on a body drawing and scored by % (head/neck, 9%; Moderate: 25-50
upper and lower limbs, 9% each; anterior trunk, 18%; back, 18%) Maximum Severe: >50
score ¼ 100%
B: Intensity score (0, little or none, to 3, severe) for redness, swelling, crusting/oozing, skin
thickening (lichenification), dryness, scratch marks. Maximum score ¼ 18
C: Subjective score (VAS, 0, none, to 10, worst imaginable) for sleeplessness and itch.
Maximum score ¼ 20
Calculation:
SCORAD (total score) ¼ A/5 þ 7B/2 þ C
Maximum score ¼ 103
EASI 2 Components: Mild: 1.1-7
Area score (% skin affected) recorded for 4 regions (head/neck; trunk/genitals; upper limbs; Moderate: 7.1-21
lower limbs/buttocks): 0 ¼ none; 1 ¼ 1%-9%; 2 ¼ 10%-29%; 3 ¼ 30%-49%; 4 ¼ 50%- Severe: 21.1-50
69%; 5 ¼ 70%-89%; 6 ¼ 90%-100% Very severe: 50.1-72
Severity score for each region calculated on the basis of intensity (0, none, to 3, severe) of
redness, thickness/swelling, scratching, lichenification. Maximum score ¼ 12 for each
region
Calculation:
Total regional scores:
Head and neck: severity score  area score  0.1 (in children 0-7 y,  0.2)
 Trunk: severity score  area score  0.3
 Upper limbs: severity score  area score  0.2
 Lower limbs: severity score  area score  0.4 (in children 0-7 y,  0.3)
EASI (total score): Sum of total regional scores, Maximum score ¼ 72

Validated scoring systems for patient assessment

Scoring system Description Severity rating

Patient-Oriented SCORAD
Adaptation of SCORAD for patients and available as an Mild: <25
APP online (to be shared with the clinician)—similar Moderate: 25-50
scoring as SCORAD: extent of affected areas, severity of Severe: >50
dry skin outside of affected areas, symptom intensity on
affected areas, severity of itching, and sleep disturbance
Shown to be correlated with SCORAD

Patient-Oriented Eczema Measure
Dermatology Life Quality Index
Nonvalidated scoring systems
Scoring system
7 symptoms scored over past week: 0 ¼ no days; 1 ¼ 1-2 d; Clear/almost clear ¼ 0-2
2 ¼ 3-4 d; 3 ¼ 5-6 d; 4 ¼ every day. (Query: Over the last Mild ¼ 3-7
week, on how many days has your skin been . Moderate ¼ 8-16
Severe ¼ 17-24
Very severe ¼ 25-28
itchy, red, bleeding, weeping or oozing clear fluid, cracked,
flaking, felt dry or rough . because of your eczema?).
Maximum score ¼ 28
10-question validated questionnaire providing patient’s Each question is answered according to ratings: “not
perception of the impact of AD on quality of life in the at all” (0), “a little” (1), “a lot” (2), “very much”
previous week. Questions include effect of disease and (3); Maximum score ¼ 30
treatment on physical, psychological, and social well-
being
Description Severity rating

Investigator’s Global Assessment FDA categorization of AD severity based on the investigator’s Scale: 0 ¼ clear to 4 ¼ severe
assessment of a representative lesion based on erythema, induration/
papulation  oozing/crusting

VAS, Visual analogue scale.

Adapted from Boguniewicz et al.26
4 BRAR ET AL
TABLE II. Differential diagnosis in patients with severe AD
Differential category Diagnostic examples
Congenital disorders Netherton syndrome
Chronic dermatoses Seborrheic dermatitis
Contact dermatitis (allergic or irritant)
Nummular eczema
Psoriasis (erythrodermic and inverse)
Infections and infestations Scabies
HIV-associated dermatitis
Malignancy Cutaneous T-cell lymphoma (mycosis
fungoides/Sézary syndrome)
Immunodeficiencies Wiskott-Aldrich syndrome
Severe combined immunodeficiency
Immune dysregulation, Polyendocrinopathy,
Enteropathy, X-linked syndrome
HIES
Dedicator of cytokinesis 8 mutation-
associated immunodeficiency
Metabolic disorders Zinc deficiency
Proliferative disorders Letterer-Siwe disease
formation.35 Although Staphylococcus aureus is an important
pathogen in this disorder, infection with other microbes, including
invasive fungi such as Aspergillus, may occur.36 In infancy, patients
may present with a papulopustular eruption of the face and scalp.
Other features of HIES include skeletal abnormalities with coarse
facial features and prominent frontal bossing, dental anomalies
with retained primary teeth, bone fractures, and osteoporosis.
Despite elevated serum IgE levels, patients usually are not atopic.
STAT3 is an essential transcription factor for TH17 T-cell devel-
opment and because TH17 T cells play an essential role in pro-
tecting against Candida, patients with mutations in STAT3 are
susceptible to chronic mucocutaneus candidiasis. Patients with
mutations in dedicator of cytokinesis 8, the gene encoding dedicator
of cytokinesis 8 protein, have an immunodeficiency that accounts
for most cases of autosomal-recessive HIES.37,38 These patients
have an eczematous dermatitis with recurrent viral infections,
including recalcitrant warts secondary to human papilloma virus,
disseminated Molluscum, or recurrent herpes simplex infections.
Patients can have central nervous system involvement.39 Of note,
patients with dedicator of cytokinesis 8 immunodeficiency often
have associated food allergies. Malignancies contribute to
morbidity and mortality usually starting in the second decade of
life. One of the current HIES panels (GeneDx) screens for mu-
tations in dedicator of cytokinesis 8, SPINK5, STAT3, and TYK2.
Of note, with next-generation sequencing technologies, new pri-
mary immunodeficiencies with eczematous rashes are being
described, for example, CARD11.40 Contact dermatitis should be
considered in the differential diagnosis of AD, but can also
complicate AD and may present as an exacerbation of underlying
AD. Patients may become sensitized to antibiotics, topical corti-
costeroids (TCSs), and various excipients applied repeatedly to a
damaged skin barrier.41 Patients with facial, hand, or foot
dermatitis, as well as those whose AD appears to worsen with
topicals, should be evaluated by patch testing.42 An important
differential of severe AD, especially in patients presenting with a
diagnosis of adult-onset AD, is cutaneous T-cell lymphoma, and
patients should have appropriate skin biopsies performed.43
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
Patients may have a varied presentation, which may include a
single plaque, hypopigmented macules, often on regions not
exposed to the sun including buttocks, as well as generalized
erythroderma. Infestations with severe pruritus include scabies,
which can have an associated generalized dermatitis. Other diseases
that can be confused with AD include psoriasis, ichthyoses, and
seborrheic dermatitis. Seborrheic dermatitis can overlap with AD
in infants and the adolescent/adult population. Psoriasis can
usually be differentiated from AD on the basis of typical clinical
features, although inverse or flexural psoriasis or erythrodermic
psoriasis may present a diagnostic challenge that can be differen-
tiated on skin biopsy. Zinc deficiency can present with an
eczematous rash with perioral, acral, or perineal distribution as a
result of dietary deficiency, excessive losses with diarrhea, chronic
renal or hepatic disease as well as inadequate absorption associated
with an inherited deficiency of the zinc carrier protein ZIP4.44
MANAGEMENT OF SEVERE AD
Most national and international AD guidelines including the
Joint Taskforce Practice Parameter address AD care in a stepwise
fashion.26,45-51 These guidelines recommend components of
basic daily AD management aimed at preventing dry skin,
treating the eczematous rash, maintaining the skin barrier,
improving the itch, and minimizing exposure to triggers.
Treatment guidelines emphasize the following: (1) Frequent and
liberal use of moisturizers in conjunction with warm baths or
showers to repair the skin barrier. (2) Identification and avoid-
ance of common irritants or infections, temperature extremes,
and proven allergen triggers. (3) Appropriate to the severity of
AD, maintenance with TCSs or other therapeutic agents may be
initiated in a stepwise fashion. (4) During AD flares, TCSs and
topical calcineurin inhibitors (TCIs) are typically prescribed and
wet wrap therapy (WWT) may be used in conjunction with
TCSs (but not with TCIs), oral antibiotics, and other oral
agents.52 (5) Dupilumab is now being added to these guidelines
for moderate-to-severe AD failing the basic therapies.51 In
addition, we advise developing a preventive approach aimed at
minimizing flares, which should be multidisciplinary incorpo-
rating the use of behavioral health strategies when appropriate.27
Figure 1 describes with annotations our diagnostic and treatment
approach to patients with severe AD.
Educational interventions have long been recommended and
used as a critical adjunct at all levels of therapy for patients with
AD to enhance therapy effectiveness. These interventions may be
directed toward patients and caregivers. Education should be
individualized and should include teaching about the chronic or
relapsing nature of AD, exacerbating factors, and therapeutic
options with benefits, risks, and realistic expectations. This
important educational facet of care management is becoming
increasingly difficult to accomplish in routine care visits and
seems to be equally difficult to measure and evaluate.53 Treat-
ment of severe AD needs to incorporate an individualized written
treatment plan based on a shared decision- making process be-
tween patient or caregiver and their clinician. Figure 2 is an
example of an AD Action Plan used at the authors’ institution.25
Nonpharmacologic interventions
Moisturizers. Moisturizers alone will not be effective in the
treatment of severe AD; however, they may reduce the severity of
AD and signs of inflammation, including pruritus, erythema,
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 5
VOLUME 7, NUMBER 1

Patient presents with history of severe pruritic

dermatitis

Evaluation of diseases in differential

Patient meets criteria for diagnosis of AD
diagnosis of AD

No
Yes

Classify severity of AD

Review prior history of AD

Add
A
Address
dd
d d b
basics
i off A
AD
D care:
• Appropriate skin hydration and u s e of moisturizers or skin Not
barrier repair measures improved
• Avoidance of irritants Reassess diagnosis of AD ,
• Identification and avoidance of proven allergens Reassess triggers
• Antiinflammatory therapy with topical steroids or topical Reassess patient/caregiver
calcineurin inhibitor(tacrolimus) understanding of disease and
• Antipruritic
A ti iti interventions
i t ti ( d ti
(sedating tihi t i
antihistamines, shared
h d AD treatment
t t t plan
l as
behavioral modification) well as adherence to plan
• Identification and treatment of complicating bacterial, viral, or
fungal infections (+/- role for 2x/week dilute bleach baths) Not
• Treatment of psychosocial aspe cts of diseas e improved
• Education including developing a shared written AD action plan

Improved Consultation with AD specialist

Consider acute management with WWT
Consider hospitalization
Titration of therapy with consideration of proactive
Consider treatment with dupilumab #
(~2x/week) treatment regimen if able to clear/almost
Consider phototherapy
clear but relapsing course
Consider unapproved systemic immunosuppresive
therapy
Avoid use of systemic steroids

Improved

FIGURE 1. Annotated approach to the patient with severe AD. *For example, Hanifin and Rajka, UK Working Party, American Academy of
Dermatology Consensus. †See Table II. zFor example, clinician evaluation (Investigator’s Global Assessment, SCORAD, EASI) and/or
patient-reported (AD global assessment, Patient-Oriented SCORAD) (see Table I). xOnset, course, area involved, suspected triggers,
complications (eg, infections), hospitalizations, associated atopic and nonatopic comorbidities, previous treatment including What? How
much? and Where? jjSee Fig. 2. (National Jewish Health Atopic Dermatitis Action Plan). {Consider biopsy, patch testing, genetic testing.
#FDA approved for patients 18 years or older with moderate-to-severe AD not adequately controlled with topical steroid or when topical
steroid not indicated. Document severe AD, body surface area greater than 10%, previous therapies. **CSA, MTX, MMF, AZA. ††While
FDA approved, systemic corticosteroids should be avoided or used for shortest course possible, usually while transitioning to a systemic
therapy with slower onset of action.

fissuring, and lichenification.54 In a Cochrane Database Review
of 77 studies of emollient and moisturizer use in eczema,
moisturizer use resulted in lower SCORAD, fewer flares with
prolonged time to flare, and less TCS use. There was a lower
investigator-assessed disease severity with moisturizer use, which
was further improved when combined with active topical treat-
ment.55 The components of topical moisturizers treat underlying
xerosis and inflammation by maintaining skin hydration while
reducing transepidermal water loss (TEWL). Emollients, such as
glycol, glyceryl stearate, and soy sterols, lubricate and soften the
skin, whereas occlusive agents, such as petrolatum, dimethicone,
and mineral oil, help the skin to retain moisture by reducing
TEWL due to evaporation. Humectants, such as glycerol,
glycerin, urea, and propylene glycol, help to attract and retain
water in the skin.46 There is no convincing evidence of efficacy of
one type of moisturizer over another, including prescription
emollient devices, and no studies define an optimal amount or
frequency of moisturizer application.46,54 Of note, application of
petrolatum has been shown to upregulate antimicrobial peptides
and innate immune genes, as well as key epidermal barrier dif-
ferentiation markers.56 We recommend liberal use of moistur-
izers, which is most effective when combined with bathing.
Selection of moisturizer should be individualized on the basis of
patient preference and providers’ discretion. In general, use of
bland moisturizers with few irritants and sensitizers is
recommended.41
6 BRAR ET AL
FIGURE 2. Atopic Dermatitis Action Plan.
Bathing practices. Regular (daily) bathing with warm water
is beneficial in moderate-to-severe AD therapy by hydrating the
skin and removing potential skin-exacerbating agents including
serous crusts, allergens, and irritants.46,51 The act of bathing can
have added benefit of relaxation. At the authors’ center, “soak
and seal” was developed over 3 decades ago as a fundamental
concept to teach proper daily skin care emphasizing use of hy-
dration, moisturizers, cleansers, and topical medications to help
maintain an intact skin barrier.57,58 The “soak and seal” or “soak
and smear” technique can be beneficial in severely inflamed
lesions and involves bathing in plain warm (not hot, but also not
lukewarm) water for 10 to 15 minutes, followed by quick pat
drying and immediate application (within 2-3 minutes) of topical
medications and moisturizers as appropriate.59,60 This helps to
reduce evaporative losses and drying effect. There is no current
evidenced-based standard for the frequency or duration of
bathing.61 Limited data exist on the benefit of additives to the
bath, and therefore, additives are not recommended. Cleansers
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JANUARY 2019
used should be hypoallergenic, fragrance-free, and neutral to low
pH. Bathing plays an adjunctive role in the management of
severe AD when combined with the use of moisturizers and
pharmacologic treatment.
Bleach baths. Bleach (sodium hypochlorite) baths are an
inexpensive and widely available nonpharmaologic intervention,
which has likely contributed to bleach baths being frequently
recommended as a low-cost adjuvant therapy in patients with
AD. Current guidelines include bleach baths in their recom-
mendations although their efficacy in treating AD has recently
been questioned. The addition of dilute sodium hypochlorite in
bath water, or bleach baths, has demonstrated efficacy in clini-
cally improving moderate-to-severe AD in children.62,63 Bleach
baths are thought to reduce skin inflammation and thereby
decrease colonization of S aureus bacteria on the skin. This can
be beneficial, because staphylococcal exotoxins are known to
exacerbate AD and severity of AD correlates with S aureus
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FIGURE 3. WWT. A, Bathing of child with AD and head involvement. Have the patient take a warm soaking bath for 10 to 15 minutes
before this procedure or soak the area to receive wraps. B, Pat away excess water. Immediately apply the prescribed undiluted topical
corticosteroid to affected areas and fragrance-free moisturizing cream or ointment to nonlesional skin. Use clean plastic spoons, tongue
depressor, or creams with pump dispenser to access products to avoid contamination. If wraps are to be applied to a large portion of the
body or used on small children, work with 2 people if possible. It is necessary to work rapidly to prevent chilling. C, WWTwith application
of first wet layer. Have the dressings soaking in very warm water. Squeeze out excess water. Dressing should be warm and wet, but not
dripping. In infants and small children, place wet tube socks first over the hands. Then, start at the feet and move upward. Cover the feet
with wet tube socks as well and then place first wet layer of thinner cotton or cotton-blend pajamas on next. D, WWTwith application of
second dry layer. Place second layer of dry tube socks over the wet layer on hands, then place the heavier dry pajamas over the entire
body (footed pajamas in children are preferred or sweat suits for older individuals). E, Wrap head only when affected to a degree war-
ranting the wrap. In small children, this is much easier to accomplish with 2 individuals. First apply warm, wet gauze usually wrapping 2
or 3 times to cover adequately. F, Wrap the same area with dry gauze in approximately an equal amount. Twist the dry gauze over the
bridge of the nose. G, Place an expandable surgical netting or very flexible bandage over the wet gauze to hold in place. H, Full-body WWT
of child with severe generalized AD. Ensure that the patient is able to move and see properly. WWT is not only accepted but can be
enjoyed with proper education and age-appropriate explanation. Take steps to avoid chilling. Comforting a small child with a warm blanket
just removed from the dryer and cuddling helps pass the time. Wraps are generally removed after 1 to 3 hours or can be re-wet. These
figures and procedure information are reprinted with permission from Nicol and Boguniewicz.58 Please refer to the original article for
comprehensive WWT procedure and practical information.
8 BRAR ET AL
density on the skin.64 However, a recent study noted that bleach
baths did not reduce S aureus colonization/infection or improve
AD.65 The benefit of bleach baths may also be due to im-
provements in skin barrier function, with patients with AD
reporting reduction in itch scores, as well as improved TEWL
and stratum corneum cohesion after 12 weeks of twice-weekly
baths.66 Although a recent systematic review found that addi-
tion of bleach as a disinfectant did not provide further clinical
benefit,67 patients with AD whose course is complicated by
recurrent skin infections can be tried on once- or twice-weekly
dilute bleach baths. Common side effects of bleach baths
include increased xerosis and irritation of skin and nasal passages.
Wet wrap therapy. WWT in AD treatment is generally
defined as a treatment modality using layers of bandages, cotton
clothing, or gauze over or together with topical medication,
usually TCSs. At the authors’ center, Nicol57 published one of
the first detailed descriptions of WWT in AD in 1987. This
article described the technique using illustrative photos and
demonstrated how WWT could be simplified by using wet
clothing in place of bandages to make this treatment less time
intensive and less expensive. Specialized nursing care and edu-
cation are important to ensure proper use of WWT. Mecha-
nistically, WWT increases contact time with topical therapies,
allowing for better absorption, decreases pruritus as a result of the
cooling effects of the wet layer, and provides a physical barrier
protecting the skin from damage associated with scratching.
Improvement in TEWL can be demonstrated 1 week after
discontinuation.68
In an observational cohort study of 72 children with
moderate-to-severe AD referred to the Day Program at National
Jewish Health, Nicol et al52 showed a significant decrease in AD
severity as measured by SCORAD following WWT therapy used
on average for 7 days. Clinical benefits could still be observed 1
month later, assessed by parental Atopic Dermatitis Quickscore,
despite WWT being discontinued before discharge. WWT has
continued to be used to reduce disease severity in children with
moderate-to-severe AD flares and/or severe refractory disease and
is used with undiluted TCSs of appropriate potency. After a
soaking bath, a wetted layer of bandages, gauze, or a cotton suit is
applied over a layer of topical corticosteroid or emollient, fol-
lowed by a dry outer layer.69 A cotton suit, which covers hands
and feet, works best as an outer layer, because this serves as a
barrier, which physically prevents scratching (see Figure 3, A-H,
with annotations).58
A recent systematic review revealed low evidence that WWT is
more effective than conventional treatment with TCSs in AD.70
However, the review included all ages and severities of AD
(including mild) and included only 6 true randomized controlled
trials while acknowledging that results were reported incompletely
in some trials as well as use of WWT with diluted or low-potency
corticosteroids. Future studies must carefully describe all proced-
ure components with validated tools and outcomes to aid inter-
pretation. WWT should be considered as a potential treatment
option ahead of systemic immunosuppressive therapies for pa-
tients with moderate-to-severe AD failing conventional therapy.52
Selected wet wraps to restricted areas of the skin can be considered
for “more stubborn plaques” of AD. WWT should be used
cautiously, and only in moderate to severe AD, because overuse of
wraps can lead to skin occlusion with resultant associated rashes,
such as folliculitis and miliaria.
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
Pharmacological interventions for severe AD
Topical corticosteroids. TCSs are considered to be the
mainstay of AD therapy and have been used for decades with
more than 110 randomized clinical trials supporting their
use.45,46 They reduce the production of proinflammatory cyto-
kines, interfere with antigen processing, and reduce the activity
of immune effector cells, with resultant reduced skin inflam-
mation, and reduced S aureus bacterial load.46,71 TCSs are
typically administered to treat active eczematous lesions evi-
denced by erythema, oozing, crusting, and/or chronic cutaneous
manifestations of AD including lichenification. TCSs can also be
used as maintenance or prophylactic therapy for prevention of
relapses.45,46
TCS therapy including the strength and frequency of use is
very provider-specific. Selection of steroid should be guided by
location and extent of lesional skin, patient preference, and
severity of disease. Additional consideration should be given to
the vehicle and excipient, particularly in severe AD, where allergy
to corticosteroid or vehicle may be contributing to severity.41
Although TCSs have been studied in adult patients, and less so
in pediatric patients, there is a paucity of long-term data. Fluti-
casone propionate 0.05% cream, desonide 0.05% gel and foam,
and hydrocortisone butyrate 0.1% lotion are currently the only
TCSs that are FDA approved for use in infants as young as 3
months, but of note for up to 3 or 4 weeks.71 Many of the TCSs
commonly used in children were developed long before pediatric
trials were required.
TCSs range in potencies and are grouped accordingly into 7
classes, from very low/lowest potency (VII) to very high potency
(super potent) (I).54 TCSs can be absorbed through the skin and
though complications are rare, they can occur at any age. In
general, the lowest effective potency to achieve disease control
should be used. Low-potency (class VI-VII) TCSs are generally
applied to sensitive and thin areas, such as the face, skin folds,
and genitalia. High-potency (class I-II) TCSs should not be
applied to the face and other sensitive areas such as the axillae or
groin. Higher potency TCSs can be used in short-term courses to
rapidly control significant flares, but should be followed by a
stepwise decrease in potency and then tapered to the lowest
effective potency for long-term management. This minimizes the
adverse effects of skin atrophy, telangiectasia, acne, hypo-
pigmentation, and striae, which are the more common side
effects of TCSs. Patients should be monitored for local and
systemic adverse events as described in the guidelines, in
particular children, because they have a proportionately greater
body surface area to weight ratio, resulting in a higher degree of
absorption of topical agents. Currently, there are no guidelines
on optimal dosing and quantity of TCS application and multiple
dosing recommendations are available.46 A commonly recom-
mended schedule for active inflammation is twice-daily applica-
tion of TCSs for up to 4 weeks, but once daily may be equally
sufficient.26
Complications and side effects of TCSs may occur with
inappropriate class of steroid, duration of therapy, site of
application, and overuse of occlusive techniques. Long-term
treatment with a potent TCS can result in development of
TCS withdrawal or “steroid addiction” as it is often referred to
by the lay community.72 TCS withdrawal appears to occur
more often in women and is reported primarily on the face and
genital areas. Symptoms of TCS withdrawal include erythema,
 VOLUME 7, NUMBER 1
J ALLERGY CLIN IMMUNOL PRACT
TABLE III. Dosing and monitoring of systemic immunosuppresants used in severe AD (adapted from Sidbury et al48)
Dosing Cyclosporine MTX AZA MMF

Adult dosing 150-300 mg/d 7.5-25 mg/wk 1-3 m/kg/d 1-1.5 g PO BID
Pediatric dosing 3-6 mg/kg/d 0.2-0.7 mg/kg/wk 1-4 mg/kg/d 30-50 mg/kg/d
Time to response (wk) 2 8-12 8-12 8-12
Baseline monitoring BP  2 measurements CBC w/diff/plt TPMT CBC w/diff/plt
CMP w/Mgþ, Kþ CMP CBC w/diff/plt CMP
Uric acid Hep B/C CMP TB
U/A with micro TB Hep B/C HIV if indicated
Fasting lipids HIV if indicated TB HCG if indicated
TB HCG if indicated HIV if indicated
HIV if indicated PFTs if indicated HCG if indicated
HCG if indicated
Follow-up monitoring BP every visit CBC w/diff/plt CBC w/diff/plt, CMP Q2 wk  2 mo, CBC w/diff/plt Q2 wk  1 mo; then
then Q1 mo  4 mo; then every other Q1 mo  3 mo; then Q 2-3 mo
month and with dose increases
CBC w/diff/plt LFTs Q 1 wk  2-4 wk and 1 wk after each
major dose increase, then Q 2 wk  1 mo,
then Q 2-3 mo on stable doses
CMP w/Mgþ, Kþ Renal function Q 6-12 mo
Uric acid Annual TB Annual TB Annual TB
U/A with micro HCG as indicated HCG as indicated HCG as indicated
Fasting lipids
Q 2 wk  2-3 mo and 2-4
wk after dose increases
Annual TB
HCG as indicated
Maximum length of treatment 6 mo to 1 y May be safe up to 5 y May be safe up to 5 y Up to 24 mo in children
(limited data) (limited data) Up to 36 mo in adults
(limited data)

BID, Twice a day; BP, blood pressure; CBC, complete blood cell count; CMP, comprehensive metabolic panel; diff, differential; HCG, human chorionic gonadotropin; Hep, hepatitis; LFT, liver function test; PFT, pulmonary function test;
plt, platelet; PO, per os (by mouth); Q, every; TB, tuberculosis; TPMT, thiopurine methyltransferase; U/A, urinalysis; w/, with.

BRAR ET AL
9
10 BRAR ET AL
burning/stinging, exacerbation with heat or sun, pruritus, pain,
and facial hot flashes. Two subtypes have been identified
including a papulopustular variant and an eryth-
ematoedematous variant. A culture of steroid phobia has
contributed to underuse and poor patient adherence. Patient
and caregiver education should address this topic, because ste-
roid phobia could be a factor when adherence is not optimal,
and if not resolved by information and counseling, then other
treatment options should be discussed.26,53
Topical calcineurin inhibitors. TCIs are a class of nonste-
roid anti-inflammatory agents currently approved by the FDA as
second-line agents in the management of AD. Tacrolimus oint-
ment is indicated for moderate-to-severe AD, with tacrolimus
0.03% approved for children aged 2 years and older and 0.1%
ointment approved for patients older than 15 years. Although the
FDA issued a boxed warning for topical calcineurin inhibitors, this
was due primarily to a theoretical risk of malignancy based on
cancers seen only with oral tacrolimus use in solid organ transplant
patients.73 In addition, since this warning, a number of studies
have failed to demonstrate this causation, and incidence of ma-
lignancy in the treated population is similar to that in the general
population.74 However, because of this warning, significant
additional time is often required of prescribing providers to educate
patients and caregivers to encourage optimal use and adherence
and discuss safety. Of note, in their systematic review of TCSs and
TCIs, Siegfried et al75 found that data supporting long-term use of
TCIs are robust, documenting safety and efficacy, whereas data
supporting long-term TCS use are limited to low- to mid-potency
products. In addition, in an evaluation of a large cohort of 293,253
patients with AD, Arellano et al76 did not find any increased risk of
lymphoma in patients treated with TCIs, but reported that severity
of AD was the main factor associated with increased risk of lym-
phoma. Of note, a recent European longitudinal study did show
that TCI use was associated with an increased risk of lymphoma.77
However, the authors stated that the low incidence rates imply that
even if the increased risk is causal, it represents a small excess risk for
individual patients. In addition, they pointed out that residual
confounding by severity of AD, increased monitoring of severe
patients, and reverse causation could have affected the results.
TCIs do not cause the telangiectasia, skin atophy, or striae,
which have all been associated with inappropriate and long-term
use of more potent TCSs. Because of the lack of these specific
side effects, TCIs have been especially useful for AD involving
the face, including periocular and perioral areas, as well as axillae
and groin regions. The most common side effects are burning
and stinging, which tend to be transient for most patients,
although have been reported to be more persistent in a subset of
patients due to neuropeptide release and can be aggravated by
sweating or alcohol intake.78 Although approved for twice-daily
noncontinuous use, guidelines support 2 to 3 times weekly
proactive therapy in patients who are able to achieve clear/almost
clear skin, but have a relapsing course.45,46 Another approach is
to use rotational therapy, where TCI use is alternated with TCS
use. This may work best in patients in whom steroid resistance is
suspected.79,80
SYSTEMIC THERAPY FOR SEVERE AD
In the authors’ AD Program, the decision to initiate systemic
therapy for patients with severe AD involves a careful reevaluation
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
of the patient’s diagnosis, understanding of their disease including
psychosocial aspects, previous treatment, adherence issues, as well
as systemic treatment options with risks versus benefits
(Figure 1).27 A similar approach has recently been described by the
International Eczema Council.81 Current preferred therapeutic
options have been proposed in recent publications.25,26
Dupilumab
Dupilumab is a fully human mAb developed with Veloc-
Immune technology approved by the FDA for use in adults with
moderate-to-severe AD in March 2017. By blocking IL-4 re-
ceptor alpha, it interferes with signaling by both IL-4 and IL-13,
2 key type 2 cytokines.29 In 2 phase 3 trials, 36% to 38% of
adult patients with moderate-to-severe AD inadequately
controlled on topical treatment treated with dupilumab mono-
therapy 300 mg every other week after an initial 600 mg loading
dose achieved a primary outcome of an Investigator’s Global
Assessment of 0 or 1 (clear or almost clear) and a reduction of 2
points or more in that score from baseline at week 16.82 In
addition, improvement of at least 75% in EASI from baseline to
week 16 was reported in approximately 50% of patients on
dupilumab. It is important to recognize that median disease
duration in patients enrolled in the phase 3 trials was approxi-
mately 26 years, median affected body surface area was more
than 50%, and median EASI was approximately 30 (21.1 ¼
severe AD). In addition, approximately 33% of patients had
received systemic corticosteroids and 26% to 31% had been
treated with systemic immunosuppressants in the 2 trials.
Importantly, patients who did not achieve “clear” or “almost
clear” still had significant improvement as assessed by EASI and
in peak pruritus Numerical Rating Scale score.83 Injection-site
reactions and conjunctivitis were more frequent in the
dupilumab-treated patients than in the placebo groups. Although
the conjunctivitis has not been fully explained, it was for the
most part self-limited, and only 1 patient in the phase 3 mon-
otherapy trials discontinued study treatment.82 Nevertheless, this
adverse event requires further elucidation. It is worth noting that
this adverse event was not reported in the dupilumab trials in
asthma or chronic sinusitis with nasal polyposis.84,85 Although
Wollenberg et al86 have published their experience with
dupilumab-treated patients with AD developing conjunctivitis,
given the need for better understanding of this complication, the
authors of this review prefer to send any patient not responding
to lubricating ophthalmic drops to an ophthalmologist.
A long-term study (LIBERTY AD CHRONOS) reproduced
both the efficacy and safety of the monotherapy trials.87 In this
52-week study, patients could use concomitant TCS or TCI if
TCS was not advisable as needed on the basis of disease activity.
An additional trial in adults with AD with inadequate response to
or intolerance of cyclosporine A (CSA), or for whom CSA
treatment was medically inadvisable (LIBERY AD CAFÉ), also
provided similar efficacy and safety data.88 In a recent random-
ized, double-blinded, placebo-controlled study, dupilumab was
shown not to affect antibody responses to vaccines in adults with
AD.89 Adults with moderate-to-severe AD on dupilumab 300
mg or placebo weekly were immunized with Tdap and quadri-
valent meningococcal polysaccharide vaccine at week 12. Similar
positive IgG responses to tetanus and meningococcal poly-
saccharide were observed with dupilumab/placebo at week 16.
Importantly, in a recent multicenter randomized study, biopsies
from dupilumab-treated patients (though note, not with the
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 11
VOLUME 7, NUMBER 1

TABLE IV. Practical pearls for managing severe AD

Participate in shared decision making with the patient and/or caregiver
 Spend time listening to the patient and/or caregiver
 Understand the patient’s goals and expectations (less itching, clearer skin, better sleep, other quality-of-life issues)
 Clarify current medications and which ones are succeeding or failing
 Give treatment options explaining the risks and benefits of these treatments
 Consider all of the patient’s socioeconomic factors and ability to adhere with treatment recommendations (insurance, affordability,
reimbursement, patient’s daily schedule, and work/school/family obligations)
Explain the nature of the disease
 Realize that deterioration in previously stable AD may result from secondary bacterial or viral infection, development of contact allergy, poor
understanding or adherence to recommended treatment
Clarify the severity of the patient’s AD
 Explain how much body surface area is involved—more than 10% of the body is considered moderate-to-severe AD
 Understand the extent or significant impact on quality of life (social, emotional, school, or professional functioning)
Work to find the right treatment plan and individualize for the patient to promote adherence to agreed plan
 Explain the role of proper skin hydration and moisturizers as daily care regardless of other treatments
 Prescribe, as appropriate, TCSs and TCIs after taking into account patient’s age, site to be treated, extent/severity of disease, being sure to
prescribe adequate amounts
 Clarify patient’s vehicle preference for moisturizers and topicals
 Demonstrate how to apply topical agents
 Address steroid phobia or underuse if appropriate
 Provide written recommendations regarding skin care including bathing and medicines including prescription and over-the-counter products
including WWT
 Consider use of biologics or phototherapy if failing conventional topical treatments, as appropriate
 Consider use of other systemic therapies if failing other treatments
 Prescribe, as appropriate, oral sedating antihistamines, topical and/or oral antimicrobials
Provide patient education materials and additional support measures
 Give patient education materials that support the specific messages and recommendations you are providing—not all do!
 Consider structured educational interventions (eczema school, online programs, or patient support and advocacy groups)
 Recommend environmental measures to avoid skin irritants and proven allergens or triggers
 Recommend psychosocial support
 Review skin care and reinforce key messages at follow-up visits

FDA-approved dosing regimen) improved not only markers of
cutaneous and systemic type 2 inflammation but also reversed
epidermal barrier abnormalities.90
Currently, dupilumab is the only drug approved for systemic
treatment of AD in adults in the United States other than sys-
temic steroids. As discussed below, systemic steroids are not
recommended for this chronic disease. Recognition of AD as a
systemic disease provides a strong rationale for the treatment of
appropriate patients with this biologic. The approved dosing
regimen is a 600 mg loading dose subcutaneously followed by
300 mg subcutaneously every 2 weeks. Injections can be self-
administered at home, and patients do not require any labora-
tory monitoring or need to have autoinjectable epinephrine. In
the United States, trials with dupilumab in adolescents with
moderate-to-severe AD (NCT03054428) have been completed
and studies in children aged 6 to 11 years with severe AD
(NCT03345914) are currently ongoing. In addition, pediatric
and adolescent patients with severe AD have been effectively
treated with dupilumab prescribed off-label.91
Phototherapy
Phototherapy can be considered in older children and adults
who have failed treatment with topical medications or systemic
immunosuppressants. Phototherapy can be used simultaneously
with topical treatment with TCSs. Caution should be exercised if
a patient is using TCIs because prescribing information for these
medications recommend to limit exposure to natural and artifi-
cial light.48 Phototherapy is not approved in children younger
than 12 years though there have been a few pediatric clinical
trials that demonstrate improvement in pruritus and moderate
improvement in the extent of AD.26,92-94 Side effects include
erythema, burning, stinging, and possible reactivation of herpes
infection; efficacy of long-term use is not known.48,95 There are
various forms of phototherapy available, including natural sun-
light, narrow-band ultraviolet light B, broad-band ultraviolet
light B, ultraviolet light A, ultraviolet light A and B, and topical
and systemic psoralen plus ultraviolet light A.48 Narrow-band
ultraviolet light B is the most preferred form of phototherapy
due to accessibility, provider familiarity, and efficacy with min-
imal side-effect profile.95 Psoralen plus ultraviolet light A is not
commonly recommended because of adverse effects compared
with the other forms of phototherapy, which include headaches,
nausea, and vomiting, hepatotoxicity, and increased photosen-
sitivity with oral psoralen.48
Treatment should be individualized on the basis of minimal
erythema dose, and patient’s underlying Fitzpatrick skin type.26
Use of phototherapy can be restricted because of time commit-
ment and unavailability of specialty equipment, and may be
difficult to implement in younger children.26,94 Home photo-
therapy units may offer an alternative solution in these cases, but
there are no studies of efficacy or safety of home phototherapy in
AD. Of note, in a subset of patients with severe AD, sunlight
12 BRAR ET AL
exposure can exacerbate symptoms, so routine use of sunscreen is
recommended for all patients with AD.96,97
Systemic immunosuppressants
Systemic immunosuppressants such as cyclosporine, azathio-
prine (AZA), mycophenolate, and methotrexate (MTX) have
been used in the management of chronic severe AD when pa-
tients have failed conventional topical treatments of AD.26,98
Before approval of dupilumab, they had been considered a
next-step option after failure of high-potency topical medica-
tions, along with phototherapy.25,26 Of note, all the immuno-
suppressants are used off-label for treatment of pediatric and
adult patients with AD in the United States. They are typically
reserved for short-term use (under 1 year) because of associated
toxicities, though a recent study suggests that MTX and AZA
may be safe for long-term (up to 5 years) use.99 They should be
prescribed by an experienced specialist because there is an
increased risk of infections, and need for frequent laboratory
monitoring (Table III). They may be effective in children and
adults with severe AD, in conjunction with continued use of
topical treatment.26,98
Cyclosporine
CSA is a calcineurin inhibitor that inhibits T-cell activation
and subsequent IL-2 production. CSA is the first-line immu-
nosuppressant that is effacacious as a short-term therapy in severe
AD; duration of therapy is usually restricted to 6 months to 1
year because of associated toxicities.48,100 Dosing guidelines for
CSA provide a range recommendation of 3 to 6 mg/kg/d in
children and 150 to 300 mg/d in adults, typically dosed at
5 mg/kg/d in the pediatric population.48 A retrospective trial of
15 children treated with CSA found that those children treated
for a longer duration (17.7  10.7 months) were less likely to
relapse than those treated for a shorter duration (10.2  2.7
months). Relapse was noted at follow-up of 22.7  15.0
months.101 However, longer duration of treatment is limited by
the side effects of CSA, which include infection, nephrotoxicity,
hypertension, tremor, hypertrichosis, headache, gingival hyper-
plasia, and increased risk of skin cancer and lymphoma.48 Pa-
tients must have careful and frequent blood pressure and
laboratory monitoring while on treatment.48 One alternative to
an abrupt discontinuation of therapy, which may result in
relapse, is continuation of intermittent maintenance therapy.102
This resulted in maintenance of response in a small group of
patients with severe AD who had been treated for a year with
CSA, which was then tapered to weekend CSA administered at 5
mg/kg/d. Notably, blood pressure and creatinine levels remained
stable before and during the 2-day weekend therapy. Further
randomized controlled studies are needed to determine whether
this intermittent scheduling alternative is a safer long-term
option with continued efficacy in those with severe AD.
Methotrexate
MTX is a folic acid antagonist that affects T-cell activities and
is used routinely in the management of psoriasis in adults and
children. In AD, time to maximum effect averages 10 weeks,
with minimal to no further efficacy after 12 to 16 weeks with
further dose escalation.48 There are a few head-to-head trials
comparing MTX to other systemic immunosuppressants.103 In a
study of children with severe AD, MTX and CSA had similar
efficacy over 12 weeks of treatment.104 There was no statistically
significant difference in SCORAD reduction, and mean absolute
J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
reduction was approximately 25 to 26 in both groups. In a trial
of 42 adults, MTX was compared with AZA over 12 weeks, and
had similar efficacy with a 42% versus 39% improvement in
mean SCORAD.103 Efficacy was also seen in secondary param-
eters, though more myelosuppresion was observed in the AZA
group. Adverse events included liver enzyme elevation and skin
infections in the MTX group. Results were comparable between
the 2 agents regardless of filaggrin mutation status.
Dosing of MTX in AD is derived from the dosing used in
psoriasis. The medication is generally given once weekly and can
be titrated upward until effect is reached. In adults, dosing ranges
from 7.5 to 25 mg/wk, and in children it is weight based at 0.2
to 0.7 mg/kg/wk.48 Folic acid supplementation is recommended
and may be protective against hematologic and gastrointestinal
toxicity. Common side effects include nausea, vomiting, and
stomatitis, which can be minimized by administering medication
in 3 divided doses given 12 hours apart.105 Patients should be
monitored for rare, but severe and potentially irreversible side
effects, such as bone marrow suppression and pulmonary
fibrosis.48,54
Azathioprine
AZA is another systemic agent that has shown modest efficacy
in both pediatric and adult AD. Its use is also limited by adverse
effects.98,106 It works as a purine analog that inhibits the cell
cycle of lymphocytes, resulting in immunosuppression. AZA is
metabolized by thiopurine methyltransferase enzyme, and thio-
purine methyltransferase activity levels should be measured at
baseline to determine appropriate dosing of the drug. It may take
4 weeks before response to treatment is seen.107 Adverse effects
of the drug include nausea, vomiting, and gastrointestinal
symptoms, and more severely myelosuppression, neutropenia,
lymphopenia, and hepatotoxicity. In addition, AZA has received
a boxed warning regarding a rare, but potentially lethal hep-
atosplenic T-cell lymphoma. Pediatric dosing varies, but most
studies recommend 2.5 mg/kg/d, with a maximum of 4 mg/kg/
d.48 Dosing can be initiated at 2 mg/kg/d, and then gradually
titrated up to minimize nausea and vomiting, while carefully
monitoring for myelosuppresion. There is only 1 long-term
study of long-term AZA use in AD, which followed 43 adults
in the Netherlands treated with AZA and MTX for 5 years.99
This study suggests that with dose modifications, AZA may be
safely used in the long-term management of AD with reduction
in severity of AD.
Mycophenolate mofetil
Mycophenolate mofetil (MMF) is an immunosuppressant
drug that inhibits both T- and B-lymphocyte proliferation via
inhibition of inosine monophosphate dehydrogenase.48 MMF
has been used as monotherapy in children aged 2 years and older
with severe refractory AD.108 Initial response to treatment may
take up to 8 weeks, and full efficacy may not be seen until 12
weeks. It may be considered as a successive treatment to be used
in the long-term after CSA. Common side effects include nausea,
vomiting, abdominal pain, headaches, and fatigue, which may be
transient, and avoided with slow upward titration of enteric-
coated medication.48 More serious, but rare, adverse effects
include hematologic abnormalities and genitourinary symptoms,
such as urgency, frequency, and dysuria. In a trial of 14 children
treated with MMF, few adverse effects were seen at dosing of 40
to 50 mg/kg/d in young children and 30 to 40 mg/kg/d in
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 7, NUMBER 1
adolescents.108 Guidelines suggest dosing ranges in adults of 0.5
to 3 g/d, which is typically divided into 2 doses, and in children
dosing is based on body surface area of 600 to 1200 mg/m2,
which can be adjusted for increased hepatic metabolism in
children.48,54 Long-term safety and efficacy are not known.
MMF was used for up to 24 consecutive months in 1 study of
children, and for up to 36 months in adults without significant
adverse effects.48,109
Systemic corticosteroids
Systemic corticosteroids such as prednisone, prednisolone, and
methylprednisolone are the only FDA-approved treatment for
inflammatory skin disease, including AD.54 However, their
routine use in moderate-to-severe AD is not recommended,
because risks of treatment far outweigh the temporary benefit of
use.45,48,110 In one study comparing systemic corticosteroids
with MTX for the treatment of AD in adults, only 1 out of 21
patients achieved remission in their AD, resulting in study
termination due to the severe exacerbations of the other pa-
tients.111 Once systemic corticosteroids are initiated, subsequent
discontinuation is often associated with rebound flaring of dis-
ease.26,48 Additional adverse effects include hypertension, glucose
intolerance, weight gain, adrenal suppression, increased in-
fections, decreased bone density, and decreased linear growth in
children.48,112 Corticosteroids can be used concurrently with
another therapy for a short time period as a bridge therapy,
because other therapeutics, such as phototherapy or MTX, may
take up to several weeks before efficacy is seen.26 Dosing is
typically 0.5 to 1.0 mg/kg, and it is recommended to restrict
courses to 2 to 3 weeks.48 Pediatric patients on systemic corti-
costeroids should be monitored for blood pressure and growth
percentiles, and receive ophthalmologic and hypothalamic-
pituitary-adrenal axis suppression testing.48,54
Other systemic off-label treatment
Omalizumab. Omalizumab, a recombinant humanized mAb
that inhibits binding of IgE to the high-affinity IgE receptor
(FcεRI) on the surface of mast cells and basophils, has been used
in AD with variable results. A case series of 7 patients aged 6 to
19 years with severe AD demonstrated clinical improvement after
3 to 6 months of treatment.113 However, a systematic review and
meta-analysis of omalizumab in AD found that fewer than 50%
of the patients treated with this biologic achieved a significant
clinical improvement.114 In addition, in the 2 randomized
controlled trials in that review, patients failed to show any sig-
nificant clinical improvement with omalizumab or their clinical
resoponse was comparable to that of the control group. However,
the authors did note that 43% of patients treated with omali-
zumab had a good response, suggesting that a subset of patients
with AD, possibly those with an urticarial component to their
disease, might still benefit from this therapy.
Recombinant IFN-g. Recombinant human IFN-g is a bio-
logic response modifier that has been used in the treatment of
moderate-to-severe AD with variable results.115 Side effects
included flu-like symptoms, transient transaminase elevation,
and granulocyte suppression. Although defects in IFN-g have
been identified in individuals with AD complicated by dissemi-
nated herpes simplex viral infection, the authors of a small review
of pediatric patients with confirmed eczema herpeticum and
BRAR ET AL 13
severe AD treated with subcutaneous IFN-g did not observe any
significant improvement in either subset.116
CONCLUSIONS
Severe AD may present a diagnostic as well as therapeutic
challenge. Patients with this degree of disease severity suffer
disproportionately as reflected by patient-reported outcome
scores. Thus, clinicians need to approach the management of
severe disease in a comprehensive manner. A number of practical
pearls may be helpful to incorporate into a successful treatment
strategy (Table IV). In the past year, approval of dupilumab, a
biologic targeting key cytokine abnormalities in AD, has trans-
formed the therapeutic landscape, including in adults with severe
AD. Given the rich pipeline of biologics, small molecules, and
other drugs that are being actively evaluated in AD,117 man-
agement of AD will need to be appropriately modified as results
from clinical trials are translated into clinical practice.
Acknowledgments
We acknowledge all the members of our multidisciplinary
Atopic Dermatitis Day Program team and thank Dusty Christian
for help with our manuscript.
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