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4 5766962260329104939 PDF
Severe Psoriasis
JASHIN J. WU, MD
Los Angeles, CA, USA
MARK G. LEBWOHL, MD
Department of Dermatology
Icahn School of Medicine at Mount Sinai
New York, NY, USA
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
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A catalog record for this book is available from the Library of Congress
DANE HILL, MD
Center for Dermatology Research SANDRA PENA, BS
Department of Dermatology Center for Dermatology Research
Wake Forest School of Medicine Department of Dermatology
Winston-Salem, NC, USA Wake Forest School of Medicine
Winston-Salem, NC, USA
MICHAEL KELLY-SELL, MD
Department of Dermatology SHIVANI P. REDDY, BS
University of Michigan University of Illinois College of Medicine
Ann Arbor, MI, USA Chicago, IL, USA
vii
VIDHI V. SHAH, BA ANJALI S. VEKARIA, MD
University of Missouri–Kansas City School of Resident
Medicine Department of Dermatology
Kansas City, MO, USA Icahn School of Medicine at Mount Sinai
New York, NY, USA
viii
Foreword
Alan Menter, MD
Chair, Department of Dermatology
Clinical Professor of Dermatology
University of Texas Southwestern Medical School
Dallas, TX, USA
Preface
Jashin J. Wu, MD, Editor Steven R. Feldman, MD, PhD, Editor Mark G. Lebwohl, MD, Editor
The first edition of Therapy for Severe Psoriasis fills an insight into therapies in the pipeline that may
the need for an up-to-date resource for the rapidly be approved in the near future.
changing treatment arena for severe psoriasis. High- We hope that this textbook serves as both a
lights of this book are chapters devoted to newly reference book and a practical guide in treating
approved therapies such as apremilast, secukinu- patients with severe psoriasis. We look forward
mab, ixekizumab, and biosimilars. This is the golden to further advances in therapy for severe psoriasis
era for treating patients with severe psoriasis. As in the coming years, and we plan to update this
more and more medications are approved, each textbook with a second edition in a few years’ time.
wave seems to demonstrate higher efficacy with
minimal adverse events. It is hoped that this text-
book summarizes and guides the dermatologist in ACKNOWLEDGMENTS
learning and choosing among the myriad of options. The editors thank Russell Gabbedy, Colleen Viola, Louise
The lead authors of each chapter are world Cook, and others at Elsevier for their steady support over
leaders in their fields regarding their topics, and the 6-month period of writing, revising, and editing this
we thank them and their coauthors in textbook. The editors acknowledge the patients who
developing comprehensive but readable chap- allowed their photos to be used for educational pur-
ters. The opening chapter gives an updated poses like this and also for giving the authors inspiration
overview of psoriasis, including epidemiology, in developing strategies to treat their severe psoriasis.
pathogenesis, and clinical findings in each of the
subtypes of psoriasis. Each chapter devoted to Jashin J. Wu, MD
therapy has a concluding paragraph that frames
Steven R. Feldman, MD, PhD
the therapy in their own “expert” algorithm of
when to use the treatment. The final chapter gives Mark G. Lebwohl, MD
xi
CHAPTER 1
Overview of Psoriasis
Michael Kelly-Sell, MD, Johann E. Gudjonsson, MD, PhD
KEYWORDS
Psoriasis Plaque psoriasis Clinical subtypes Pustular psoriasis Nail psoriasis
Comorbidities
KEY POINTS
Today, psoriasis is a global disease causing significant impairment in quality of life, disfiguring
morbidity, and increased mortality.
Psoriasis affects men and women equally. Two-thirds of patients are thought to have mild disease,
and one-third of patients are thought to have more severe involvement.
Psoriasis is found in practically all racial groups and is thought to affect approximately 2% of the
world’s population.
Psoriasis may appear at any age, but it most commonly presents between the ages of 15 and 30.
Over the last 20 years, many of the immunologic drivers of psoriasis have been uncovered, and this
research has been translated to the clinic with the development of increasingly powerful but
selective biologic drugs targeting these immune pathways.
1
2 Therapy for Severe Psoriasis
that 2 different forms of psoriasis exist: type I pso- center with increasing parakeratosis, capillary
riasis, with onset before the age of 40; and type II elongation, and perivascular infiltration of various
psoriasis, with age of onset after the age of 40. types of immune cells. Mature psoriatic lesions
Both types of psoriasis respond similarly to contain elongated and uniform rete ridges with
treatment. thinning of the epidermis overlying the dermal
papillae. The tips of the rete ridges may become
Cause and Pathogenesis clubbed with dilated, tortuous capillaries in the
The root cause of psoriasis remains unknown. How- dermal papillae. There is typically confluent para-
ever, research is beginning to link the complex ge- keratosis and hyperkeratosis.5 More inflammatory
netic, biochemical, and immunologic abnormalities cells are present with CD41 T cells and dendritic
that underlie the disease. These changes can be cells in the upper dermis and CD81 T cells in the
seen in both psoriatic lesions and normal- epidermis. Neutrophils are commonly seen in pso-
appearing skin of psoriatic patients. riatic lesions and form characteristic collections in
There is strong evidence suggesting at least a the spinous layer (spongiform pustules of Kogoj)
partial genetic basis in psoriasis. Genome linkage and in the stratum corneum (Munro microab-
studies in the 1990s identified a locus termed pso- scesses). Eosinophils are not seen in psoriasis, un-
riasis susceptibility 1 (PSORS1) in the major histo- less the disease is drug induced.
compatibility complex (chromosome 6p21.3),
home of the HLA genes.2 Many HLA markers
have been associated with psoriasis, but HLA- T CELLS
Cw6 has constantly demonstrated the highest The role of T cells in psoriasis was first documented
relative risk for psoriasis in Caucasian popula- in the 1980s, and the last 30 years of scientific and
tions.3 HLA-Cw6 is also strongly associated with clinical research on psoriasis have further high-
early onset, guttate psoriasis, and psoriatic lighted their role in the pathophysiology of the dis-
arthritis. However, only about 10% of HLA-Cw6 ease. The latest biologic medications for psoriasis
carriers develop psoriasis and the PSORS1 may ac- target T-cell immune pathways, and their ability to
count for only one-third of the genetic liability to clear plaques underlines the importance of the
psoriasis.4 In recent years, additional genetic risk T-cell pathways these medications target.
variants have been identified for psoriasis, with In 1984, Dr Baker and colleagues6 were the
more than 60 genetic loci identified to date. These first to show a correlation between the eruption
findings confirm the polygenic nature of psoriasis of psoriatic skin lesions and the epidermal influx
and also its heterogeneity because most patients and activation of T cells. Subsequently, deletion
carry different combinations of these risk variants, of epidermal T cells was shown to predate resolu-
and this may influence clinical course of the dis- tion of psoriatic plaques in patients on photother-
ease as well as therapeutic responses. apy.7 In 1986, cyclosporine was shown to be
highly efficacious in treating psoriasis due to its
blockade of T-cell function.8 Ten years later in
DEVELOPMENT OF A LESION 1996, activated autologous T cells initiated psori-
Psoriasis is characterized clinically by red and scaly atic lesions when injected into uninvolved psori-
plaques sharply demarcated from normal skin. atic skin transplanted onto severe combined
Histologically, it is characterized by marked prolif- immunodeficient mice.9 This showed that T cells
eration of keratinocytes, altered epidermal differ- were sufficient to induce a psoriatic process.
entiation, and proliferation of endothelial cells More recently, using xenograft models where hu-
accompanied by an influx of a variety of inflamma- man skin is grafted onto immunodeficient mice,
tory cells. The development of a psoriatic lesion trafficking of T cells to the epidermis, particularly
is a complex and multicellular process that CD81 T cells, was shown to be critical for devel-
involves keratinocytes, T cells, dendritic cells, mac- opment of psoriatic plaques, highlighting the
rophages, mast cells, endothelial cells, and neutro- importance of these cells in psoriasis.
phils. Cytokines and growth factors initiate and Psoriatic lesions are typified by T helper 1 (Th1)
sustain inflammation in this process through path- polarized CD41 cells and T cytotoxic 1 (Tc1)
ways that involve cells of both the innate and the polarized CD81 T cells producing interferon
acquired immune systems. Initial pinhead-sized (IFN)-g, which is the dominant cytokine profile of
macular lesions show edema and mononuclear psoriatic lesions.10 IFN-g drives the production
cell infiltrates within the upper dermis. The over- of interleukin-12 (IL-12) and IL-23 by dendritic
lying epidermis becomes spongiotic, and there is cells. IL-23 supports and expands CD41 T cells,
a focal loss of the granular layer. As the plaque ma- and likely CD81 T cells, that produce IL-17 and/or
tures, the epidermis becomes thickened in the IL-22, whereas IL-12 promotes development of
Chapter 1 Overview of Psoriasis 3
Th1 and Tc1 cells. The secretion of IL-17 and IL-22 enzymes. These changes lead to histopathologic
by these cell types likely maintains the chronic findings that can be identified on microscopic ex-
inflammation in psoriasis,11,12 but the exact role amination and have been termed “histochemical
of IFN-g in this process is still unclear. T cells parakeratosis.”
also contribute to the production of tumor necro-
sis factor-a (TNF-a), but TNF-a is a potent proin-
flammatory cytokine, the main role of which may CLINICAL FINDINGS
be to amplify the effect of other cytokines, History
including IFN-g and TNF-a. Biologic medications In approaching a patient with psoriasis, it is impor-
targeted at inhibiting these inflammatory media- tant for the clinician to obtain a thorough personal,
tors, including TNF-a, IL-12/IL-23, and IL-17, family, and social history because it often will influ-
have shown great efficacy in treating psoriasis, ence the choice of therapeutic agent. Relevant in-
underlining the important role this molecule plays formation includes the age of onset of psoriasis
in driving the disease. and whether psoriasis is present in any close rela-
tives, because both a younger age of onset and
a positive family history have been associated
MACROPHAGES AND DENDRITIC CELLS with more widespread and recurrent disease.18
Macrophages are important phagocytic cells that In addition, the prior course of disease and fre-
reside under the basement membrane, adjacent quency of relapses should be recorded, because
to proliferating keratinocytes, and are important there is significant variability in the clinical presen-
in the early development of psoriatic lesions. tation of disease and the disease may change from
They express Factor XIIIa and secrete the chemo- one clinical phenotype to another (Box 1.1). In
kine MCP-1 (CCL2).13 They are an important source some patients, the disease frequently relapses,
of TNF-a, inducible nitric oxide synthase, and and this has been associated with more severe dis-
IL-23.13,14 It has been shown in mouse models ease with rapidly enlarging lesions covering signif-
that the selective elimination of macrophages leads icant portions of the body surface.19 Other
to prompt improvement of psoriatic lesions.15 patients have more chronic, slowly developing le-
Dendritic cells have an important role in both sions with only occasional recurrences.
priming the adaptive immune response and The presence or absence of joint symptoms
inducing self-tolerance. Subtypes of dendritic should be recorded—such as painful, warm, or
cells, such as Langerhans cells, dermal dendritic swollen joints. Any of these complaints are con-
cells, and myeloid dendritic cells, help drive the cerning for psoriatic arthritis and prompt a more
Th1, Th17/Th22 polarization of psoriatic plaques. thorough evaluation. It is important to remember
In particular, myeloid dendritic cells help make that osteoarthritis is common and frequently co-
IL-12 and IL-23 cytokines that promote Th1 and exists with psoriasis.
Th17 differentiation and responses, respec-
tively.16 In a psoriatic plaque, myeloid dendritic
cells can be increased up to 30-fold as compared BOX 1.1
Clinical subtypes of psoriasis
with uninvolved skin and make up about 80% to
90% of the dendritic cells.17 Chronic plaque psoriasis (psoriasis vulgaris)
Psoriasis geographica
NEUTROPHILS Psoriasis gyrata
Although neutrophils are a common histopatho- Annular
logic finding in the upper epidermis of psoriatic Rupioid
lesions, they do not seem to a have a significant
role in lesional development in chronic plaque Ostraceous
psoriasis, although they have a key role in pustular Elephantine
variants of psoriasis. Guttate psoriasis (eruptive psoriasis)
Small plaque psoriasis
UNINVOLVED PSORIATIC SKIN Flexural (Inverse) psoriasis
Normal-appearing skin of patients with psoriasis Erythrodermic psoriasis
has been shown to have subclinical biochemical
changes that lead to subtle histologic findings. Sebopsoriasis
Lipid biosynthesis is predominantly affected with Napkin psoriasis
measurable changes in the levels, constitution of Linear psoriasis
phospholipids, free a-amino acids, and hydrolytic
4 Therapy for Severe Psoriasis
Psoriasis is associated with several comorbid- response is still unclear. There is a broad differen-
ities, including increased incidence of myocardial tial diagnosis for psoriasis that physicians should
infarction, stroke, and death, particularly in pa- consider (Table 1.1), and treatment failures may
tients with moderate-to-severe psoriasis.20–23 prompt a reconsideration of the diagnosis.
Psoriasis has been shown to be an independent
risk factor for cardiovascular disease,24,25 and it
is important to screen patients for other cardio- CUTANEOUS LESIONS
vascular risk factors in their social and medical his- Psoriasis Vulgaris
tories, because modification of these can help Psoriasis vulgaris, or chronic plaque psoriasis, is the
offset their increased risk. Cardiovascular risk fac- most common clinical manifestation of psoriasis,
tors include smoking status, diet, and any previ- affecting approximately 90% of psoriasis patients.
ous diagnoses of hypertension, diabetes, Psoriasis vulgaris is characterized by well-
dyslipidemia, or obesity. demarcated, erythematous, raised plaques with
Treatment history should also be recorded. white micaceous scale. Lesions vary in size from
Although the ability to predict treatment re- pinpoint papules to large plaques and tend to be
sponses to a given agent are still very limited, pa- symmetrically distributed on the scalp, postauricu-
tients that have been on previous biologics and lar skin, elbows, gluteal cleft, and knees. These le-
failed generally respond less well to other biologic sions produce significant amounts of scale and
agents, even when these are in a different removing the scale produces pinpoint bleeding
class. The nature of this decreased therapeutic (the Auspitz sign), which is a sign of the dilated
TABLE 1.1
Differential diagnosis of psoriasis
Psoriasis Vulgaris Guttate Erythrodermic Pustular
Common
Discoid/nummular eczema Pityriasis rosea Drug- Impetigo
Cutaneous T-cell lymphoma Pityriasis lichenoides induced Superficial candidiasis
(CTCL) chronica erythroderma Reactive arthritis
Tinea corporis Lichen planus Eczema syndrome
CTCL/Sézary Superficial folliculitis
syndrome
Pityriasis
rubra
pilaris
Consider
Pityriasis rubra pilaris Small plaque Pemphigus foliaceus
Seborrheic dermatitis parapsoriasis Immunoglobulin A
Subacute cutaneous lupus Pityriasis lichenoides pemphigus
erythematosus et varioliformis acuta Sneddon-Wilkinson
Erythrkeratoderma (either (PLEVA) disease (subcorneal
erythrokeratoderma variabi- Lichen planus pustular dermatosis)
lis and/or progressive sym- Drug eruption Migratory necrolytic
metric erythrokeratoderma) Secondary syphilis erythema
Hypertrophic lichen planus Transient neonatal pus-
Lichen simplex chronicus tular
Contact dermatitis melanosis
Chronic cutaneous lupus er- Acropustulosis of infancy
ythematosus/discoid lupus Acute generalized
erythematosus exanthematous
Hailey-Hailey disease (more pustulosis
flexural)
Intertrigo (flexures)
Candida infection (flexures)
Bowen disease/squamous
cell carcinoma in situ
Extramammary Paget
disease
Chapter 1 Overview of Psoriasis 5
capillaries below the epidermis and thinned supra- psoriatic papules across the upper trunk and
papillary plate. Disease presentation is impres- proximal extremities (Fig. 1.2). Guttate psoriasis
sively variable among patients, and the clinical typically presents in children, adolescents, and
findings can change quickly even within the same young adults. It is often preceded by a strepto-
patient. coccal throat infection, and less commonly, peri-
Psoriatic lesions can be induced by trauma, and anal strep infections, and more than half of
this is known as Koebnerization or the isomorphic patients will have molecular evidence of a recent
response. This phenomenon is more likely to occur streptococcal infection, such as an elevated anti-
when the disease is flaring and is an all-or-nothing streptolysin O, anti-DNase B, or streptozyme titer.
response (meaning if psoriasis appears at one site Despite this association, antibiotics are not helpful
of injury then it will appear at all sites of injury). The in the treatment of guttate psoriasis and do not
isomorphic response typically appears 7 to 14 days alter the course of the disease.28 One-third to
after injury, and the lifetime prevalence of the phe- one-half of patients who develop guttate psoriasis
nomenon is estimated to be 25% to 75%.26 The will later develop chronic plaque psoriasis. As
isomorphic response is not specific to psoriasis. mentioned above, guttate psoriasis shows the
Historically, psoriasis vulgaris has been subclas- strongest association with HLA-Cw6.29
sified by the shape and scale of the plaques.
Today, the terms have little significance clinically, Inverse Psoriasis (Flexural Psoriasis)
but they connect the modern disease to its long Inverse, or flexural, psoriasis is distinguished by
history. Psoriasis geographica describes plaques psoriatic lesions appearing in the major skin folds,
that resemble a land map. Psoriasis gyrata consists such as in the axillae, inguinal creases, intergluteal
of confluent, connected plaques with a circinate cleft, umbilicus, and inframammary folds. Lesions
appearance. Rupioid lesions present in the shape are erythematous and sharply demarcated, with a
of a cone or limpet. Ostraceous plaques have a cir- glossy appearance and little to no scale. The
cular, hyperkeratotic concave lesion resembling an lesion may contain a central fissure. The sharp
oyster shell. Elephantine psoriasis refers to large, demarcation and glossy appearance help distin-
thick, scaly plaques on the lower extremities. guish the lesions from other diseases of the skin
Annular lesions have partial central clearing, giving folds. Sweating is decreased in affected areas
a ring-shaped appearance, and are associated and localized fungal or bacterial infections may
with a good prognosis because the annular shape be a trigger.
suggests clearing (Fig. 1.1). Finally, a hypopig-
mented ring on the periphery of an individual pla- Erythrodermic Psoriasis
que, or Woronoff ring, may be seen after Erythrodermic psoriasis is the generalized form of
treatment with UV radiation or topical steroids. disease and affects all body sites: face, trunk, ex-
Woronoff rings are thought to be caused by inhibi- tremities, hands, and feet. Erythema is more
tion of prostaglandin synthesis and are associated prominent and the scaling is finer, more superfi-
with lesional clearing and a good prognosis.27 cial and diffuse, as compared with psoriasis vulga-
ris. Patients lose their autonomic control of body
Guttate Psoriasis temperature and may present with systemic
Derived from the Latin gutta, “a drop,” guttate symptoms. They lose excessive heat from gener-
psoriasis is distinguished by the eruption of small alized vasodilation and so may shiver to try to
compensate. In warm climates, there is a risk for
hyperthermia because patients do not sweat
from their psoriatic lesions.30 The generalized
vasodilatation also puts patients at risk for high-
output cardiac failure, impaired hepatic and renal
function, and lower extremity edema. Erythroder-
mic psoriasis is thought to have 2 general presen-
tations: first, as a chronic form that is thought to
be a slow progression of psoriasis vulgaris
(Fig. 1.3). A second form is distinguished by its
sudden onset and may be a generalized Koebner
reaction to treatments such as phototherapy or
anthralin. Finally, other generalized forms of pso-
Fig. 1.1 Annular plaque psoriasis. There are well- riasis may give an appearance of erythrodermic
defined erythematous plaques with thick micaceous psoriasis as they heal, such as generalized pustular
scale on the periphery. psoriasis.
6 Therapy for Severe Psoriasis
Fig. 1.2 Erythrodermic psoriasis associated with HIV. (A) Cutaneous disease often worsens as a patient’s CD4 count
drops. (B) Thick micaceous scale. (C) There was confluent erythema and scale on the hands. Note the prominent oil
spots below the fingernails and swelling of the left fifth PIP joint. (D) There is confluent scale on the feet with subtle
erythema. Note the left third toe dactylitis, also known as a “sausage digit,” a manifestation of psoriatic arthritis.
Fig. 1.4 Pustular psoriasis. The patient shown in (A) and (B) demonstrates flaccid subcorneal pustules on an
erythematous base. Note the pus accumulating in the dependent half of the pustules. The patient shown in (C)
and (D) had pustules form an annular or circinate pattern with an erythematous center. This may resemble erythema
annulare centrifugum or impetigo herpetiformis.
The cause of attacks is unknown but possible trig- successfully include methotrexate, cyclosporine,
gering factors include infections, irritating topical infliximab,33 and systemic corticosteroids.34
treatments (provoking a Koebner phenomenon), Loss-of-function mutations in the IL36RN gene,
and withdrawal of systemic corticosteroids. encoding IL-36 receptor antagonist (IL-36ra), have
Generalized pustular psoriasis may have been found in patients with generalized pustular
life-threatening complications, including hypocal- psoriasis. IL-36ra is an anti-inflammatory cytokine
cemia, acute respiratory distress syndrome, that inhibits signaling of proinflammatory IL-36
bacterial superinfection leading to sepsis, and proteins (a, b, and g).35
dehydration.31,32 The severity of the disease
makes rapid control important, and therefore, Annular Pustular Psoriasis and Impetigo
medications with a rapid onset of action should Herpetiformis
be chosen. Drugs that have been used Annular pustular psoriasis is a rare form of pustu-
lar psoriasis that presents with pustules on an
erythematous ring. It may initially resemble gyrate
BOX 1.2 erythemas, such as erythema annulare centrifu-
Clinical subtypes of pustular psoriasis gum. It can present during pregnancy, typically
in the early third trimester, and is called impetigo
Generalized pustular psoriasis (von herpetiformis. There is significant risk for hypocal-
Zumbusch) cemia, and while the disease typically improves af-
Annular pustular psoriasis ter delivery, it may recur during subsequent
Impetigo herpetiformis pregnancies.31,36 There is often no personal or
family history of psoriasis.
Localized pustular psoriasis
Pustulosis palmaris et plantaris Localized Pustular Psoriasis Variants
Acrodermatitis continua (of Hallopeau) There are 2 main forms of localized pustular pso-
SAPHO (synovitis, acne, pustulosis, riasis: PPP and acrodermatitis continua (of Hallo-
hyperostosis, osteitis) peau). PPP is characterized by sterile pustules on
the palmoplantar surfaces with yellow-brown
8 Therapy for Severe Psoriasis
Napkin Psoriasis
Napkin psoriasis typically presents in the diaper arranged on the dorsal nail plate. Nail pitting is
(napkin) areas between the ages of 3 and 6 months caused by foci of parakeratosis at the proximal
with a red, confluent patch. Scattered small, red, nail matrix, which forms the dorsal nail plate,
papules with psoriatic white scale may appear a causing poor keratinization. Nail pitting is not
few days later on the rest of the body. It typically unique to psoriasis and can also be seen in alope-
responds readily to topical steroids and usually re- cia areata and other disorders. The nail pitting of
solves by 1 year of age. alopecia areata is typically thought to be more
linear than in psoriasis, although this is not always
Linear Psoriasis the case. Other findings of nail matrix disease
Linear psoriasis is a rare form of the disease that include leukonychia, a result of disease in the mid-
typically presents as a linear plaque on an extrem- portion of the nail matrix, and widespread disease
ity or dermatome of the trunk. There may be an leads to crumbling of the nail plate.
underlying nevus, such as an inflammatory linear Oil drops are translucent red-yellow discolor-
verrucous epidermal nevus (ILVEN). Separating ations on the nail bed, below the nail plate. They
linear psoriasis and ILVEN into distinct diseases are a result of psoriasiform hyperplasia, parakera-
is controversial.38 tosis, and microvascular changes of the nail bed
and trapping of neutrophils under the nail plate.39
Unlike nail pits, oil drops on the nail bed are a
RELATED PHYSICAL FINDINGS unique finding of psoriasis. Other nail bed findings
Nail Findings with psoriasis include splinter hemorrhages, from
Nail involvement is common in psoriasis and is capillary bleeding at thinned suprapapillary plates,
seen in up to 40% of psoriasis patients.18 It in- onycholysis, and subungual hyperkeratosis. These
creases with age, extent of disease, duration of findings are not as specific to psoriasis. Anonychia,
disease, and presence of psoriatic arthritis. Find- complete loss of nails, is common in acrodermati-
ings are classified as either evidence of nail matrix tis continua, but nail findings are not typically seen
or nail bed disease (Box 1.3). Nail matrix disease in other localized variants of pustular psoriasis.
leads to pitting, onychorrhexis, Beau lines, leuko- Nail changes are important to note clinically
nychia, and thinning of the nail plate. Nail bed dis- because they have been associated with increased
ease leads to findings of oil drops (or “salmon risk for psoriatic arthritis.
patches”), subungual hyperkeratosis, and splinter
hemorrhages. Fingernails are more often affected
than toenails, and nail involvement may cause PSORIATIC ARTHRITIS
pain and restrictions on activities of daily life. Psoriatic arthritis occurs in 5% to 30% of pa-
Nail pitting is one of the most common nail tients with cutaneous psoriasis, and its preva-
findings with psoriasis. Typically, there are single lence may be underestimated.40 Cutaneous
or multiple 0.5- to 2.0-mm pits irregularly disease typically precedes the joint disease by
Chapter 1 Overview of Psoriasis 9
about 10 to 12 years, but about 10% to 15% of Many patients with psoriasis manifest altered
patients with psoriatic arthritis present without lipid profiles with elevated levels of high-density li-
skin findings. Diagnosis is difficult to establish poproteins, altered cholesterol-triglyceride ratios
because there is no serologic marker, and the in very low-density lipoprotein particles, and
radiographic hallmark, erosive changes, may elevated plasma apolipoprotein-A1 concentra-
occur years after the initial periarticular inflam- tions.43 These alterations in lipids may contribute
mation. Classic findings include asymmetric to the increased cardiovascular risk for psoriasis
involvement of both the distal (DIP) and prox- patients. Other risk factors of cardiovascular dis-
imal (PIP) interphalangeal joints, seen in about ease should be considered and appropriate labo-
40% of patients.41 In contrast to rheumatoid ratory tests ordered, because patients with
arthritis, involvement of the metacarpophalan- psoriasis are predisposed to cardiovascular dis-
geal joints is rare. Prolonged disease in the PIP ease (see later discussion). General markers of sys-
and DIP of a single digit can lead to swelling temic inflammation, such as C-reactive protein and
(dactylitis) and the appearance of a “sausage” erythrocyte sedimentation rate, are elevated in a
digit. Enthesitis, or inflammation at the insertion minority of patients with chronic plaque psoriasis
site of tendons into bones, is also a common and may suggest the presence of psoriatic arthritis.
finding in psoriatic arthritis and is seen in
approximately 20% of patients with psoriatic
arthritis.42 Arthritis mutilans is the most severe COMPLICATIONS
form of psoriatic arthritis with extensive joint Psoriatic patients have increased morbidity and
damage and bone resorption and is seen in mortality from cardiovascular disease, which cor-
5% of patients.41 Early diagnosis of psoriatic relates with the severity and length of disease.44
arthritis alters the treatment approach for a Younger patients with psoriasis are at particular
patient, as the physician should consider sys- risk, because a large population-based cohort
temic or biologic medications to prevent life- study using the UK General Practice Research
changing morbidity from arthritic changes, Database found that 30-year-olds with severe
even when cutaneous disease is limited. psoriasis had a relative risk of myocardial infarc-
tion of 3.10 as compared with healthy controls.21
Other large epidemiology studies have shown
LABORATORY TESTS that patients with psoriasis are 2.9-fold more likely
Most patients can be diagnosed based on their to have a diagnosis of metabolic syndrome—
clinical history and features alone. However, histo- which is defined by having 3 of 5 risk factors for
pathologic examination can be helpful to estab- cardiovascular disease, including obesity, hyper-
lish the diagnosis in difficult cases. The typical triglyceridemia, low high-density lipoprotein, hy-
histopathologic features of chronic plaque psoria- pertension, or diabetes. Psoriasis patients had
sis and guttate psoriasis have been discussed pre- increased rates of hypertension (35.6% in psoriatic
viously (see “Development of Lesions”). patients vs 20.6% in controls), and hyperlipidemia
Pustular psoriasis is distinguished on histopa- (29% vs 17.1%).45 Psoriasis is thought to be an in-
thology by the presence of neutrophils migrating dependent risk factor for the development of
from dilated vessels and pooling in the upper metabolic syndrome because psoriasis patients
epidermis, within the upper Malpighian layer have increased odds of having hypertension
below the stratum corneum. In newer lesions, even after controlling for age, sex, smoking sta-
there may be mild acanthosis, whereas older le- tus, and other variables.46 There is an increased
sions have more typical psoriasiform hyperplasia. prevalence of rheumatoid arthritis (prevalence ra-
There are no serum markers that are specific tio [PR] 3.8), Crohn disease (PR 2.1), and ulcerative
for psoriasis and regularly used to establish a colitis (PR 2.0) in patients with psoriasis.45 There is
diagnosis. Laboratory workup is typically aimed an increased risk of both Hodgkin lymphoma and
at ruling out other disease processes in the differ- cutaneous T-cell lymphoma in psoriasis, particu-
ential diagnosis, such as checking an antinuclear larly in patients with severe disease.47
antibody to test for connective tissue disease. The psychological impact of psoriasis on
Nonetheless, it can be important to check serum patients is profound. Cutaneous disease leads
markers in patients with severe disease to assess to concerns about appearance, lowered self-
for systemic complications. Patients may have a esteem, social rejection, guilt, embarrassment,
decreased serum albumin, secondary to the nega- emptiness, sexual problems, and impairment of
tive nitrogen balance from the turnover of their professional ability (Fig. 1.5). These stressors
skin, or elevated uric acid, increasing their risk lead to higher rates of anxiety, depression, and sui-
for developing gouty arthritis. cidal ideation in psoriasis patients than in the
10 Therapy for Severe Psoriasis
categories of treatment: topical therapies, photo- treatment available (Box 1.4). Topical treatments
therapy, oral medications, and biologic medica- are often inexpensive and efficacious and have an
tions (Table 1.2). This chapter covers topical excellent safety profile. Despite these benefits,
treatments at depth but leaves the other modal- 40% of patients report being noncompliant with
ities for the remainder of this book. their topical treatments because they feel these
In formulating a treatment regimen, the clini- treatments are time-consuming and cosmetically
cian must balance the patient’s goals with the unacceptable.58 Cosmetic considerations are
measurable severity of the disease, patient- particularly important, and physicians should pre-
specific factors (such as psoriatic arthritis, preg- scribe a medication as both a cream, to be used
nancy, or a history of malignancy), and limits set during the day, and a more potent ointment, to
by payors. There is no cure for psoriasis, and treat- be used at night. It is important to give a sufficient
ment can be frustrating, with many patients volume of medication for the patient to treat their
reporting their treatment regimens being ineffec- skin lesions appropriately, and 400 g of a topical
tive. With the advent of highly effective biologics agent is required to entirely cover an average
and the high level of treatment responses sized adult twice daily for 1 week.
achieved with these drugs, patient’s expectations
have grown. Therefore, these feelings are only
likely to grow. CORTICOSTEROIDS
As patients will use these medications for Topical corticosteroids are commonly first-line
years, safety is also a major concern and deserves therapy in mild-to-moderate psoriasis and on sen-
a frank discussion with patients. New treatments, sitive skin, such as the flexures and genitalia.
which can be highly efficacious, often have the These medications work by causing nuclear trans-
shortest safety record. Furthermore, although location of glucocorticoid receptors, leading to a
some treatments are safe for continuous use, wide variety of effects. Patients typically see
others have cumulative toxicity that limits their improvement with 2 to 4 weeks of daily treatment
use. Treatments may lose efficacy over time either and then can taper to a maintenance phase of
through a process called tachyphylaxis, which is applying the creams only 2 to 3 days per week.
mostly limited to topical treatments, through the Long-term daily use of topical corticosteroids
development of neutralizing antibodies to a may cause skin atrophy, telangiectasias, stretch
particular biologic agent, or possibly through marks, and adrenal suppression (from systemic
the changing nature of inflammatory responses absorption). With long-term use, these agents
in psoriatic skin, requiring the change or the addi- lose their efficacy, and patients should be
tion of other modalities. Physicians must individu- switched to an alternative formulation. Upon
alize a treatment regimen to the patient and, if discontinuation of a topical steroid, a patient’s
there is disease progression, progression of dis- disease may rebound.59 Topical corticosteroids
ease will likely have to use treatments in combina- are inexpensive, effective, and safe, when used
tion to achieve long-term control. appropriately; therefore, they should be a part
of every patient’s treatment plan.
TOPICAL THERAPIES
Most patients with psoriasis are treated initially VITAMIN D3 AND ANALOGUES
with topical treatments, and these medications The topical vitamin D preparations that are
can be used safely with nearly every other commercially available for the treatment of skin
TABLE 1.2
Treatments for psoriasis
Topical Phototherapy Systemic Biologics
Corticosteroids Narrowband UVB Cyclosporine TNF-a inhibitors
Vitamin D analogues (310–331 NM) Methotrexate Etanercept
Tazarotene Broadband UVB Acitretin Humira
Salicylic acid PUVA Fumaric acid esters Infliximab
Calcineurin inhibitors (for Excimer laser (308 NM) (available in Germany IL-12/IL-23
inverse psoriasis) but not the US or UK) inhibitor
Apremilast Ustekinumab
IL-17 inhibitor
Secukinumab
Ixekizumab
12 Therapy for Severe Psoriasis
BOX 1.6
Biologic therapies
TNF-a inhibitors
Etanercept
Adalimumab
Infliximab
IL-12/IL-23 p40 subunit inhibitor
Ustekinumab
IL-17 inhibitor
Secukinumab
Fig. 1.6 Lentigines from ultraviolet treatment of psori-
asis. Chronic damage from the ultraviolet treatment of Ixekizumab
these psoriatic patches has led to the formation of len-
tigines bilaterally. There is also epidermal atrophy,
likely from chronic use of topical steroids. A closer that they have an excellent safety profile. This is
view of the lentigines and epidermal atrophy (inset). an exciting time for the treatment of psoriasis
with multiple classes of biologics available:
particularly squamous cell carcinoma (Fig. 1.6).65 TNF-a inhibitors, anti-p40 (IL-12/IL-23 antago-
In the 1980s, narrow band UVB (311–313 nm) nists), IL-17 inhibitors, and the promise of new
was developed and shown to be efficacious. Since anti-p19 inhibitors (selective for IL-23) on the hori-
that time, phototherapy has proven to be a safe, zon. These medications are changing the treat-
effective treatment for psoriasis that does not ment of patients with psoriasis and improving
cause immunosuppression. clinical outcomes.
10. Uyemura K, Yamamura M, Fivenson DF, et al. The severe psoriasis and severe atopic dermatitis. Am
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mediated response. J Invest Dermatol 1993;101(5): estimate of severe psoriasis on major cardiovascular
701–5. events. Am J Med 2011;124(8):775.e1-6.
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Invest 2009;119(12):3573–85. A systematic review of treatments for guttate psori-
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et al. A subpopulation of CD163-positive macro- 29. Mallon E, Bunce M, Savoie H, et al. HLA-C and gut-
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14. Wang H, Peters T, Kess D, et al. Activated macro- Br J Dermatol 1969;81(2):119–24.
phages are essential in a murine model for T cell- 31. Zelickson BD, Muller SA. Generalized pustular pso-
mediated chronic psoriasiform skin inflammation. riasis. A review of 63 cases. Arch Dermatol 1991;
J Clin Invest 2006;116(8):2105–14. 127(9):1339–45.
15. Stratis A, Pasparakis M, Rupec RA, et al. Patho- 32. Abou-Samra T, Constantin JM, Amarger S, et al.
genic role for skin macrophages in a mouse Generalized pustular psoriasis complicated by
model of keratinocyte-induced psoriasis-like acute respiratory distress syndrome. Br J Dermatol
skin inflammation. J Clin Invest 2006;116(8): 2004;150(2):353–6.
2094–104. 33. Varma R, Cantrell W, Elmets C, et al. Infliximab for
16. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, the treatment of severe pustular psoriasis: 6 years
et al. Psoriasis is characterized by accumulation of later. J Eur Acad Dermatol Venereol 2008;22(10):
immunostimulatory and Th1/Th17 cell-polarizing 1253–4.
myeloid dendritic cells. J Invest Dermatol 2009; 34. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeu-
129(1):79–88. tic guidelines for the treatment of generalized pus-
17. Zaba LC, Krueger JG, Lowes MA. Resident and “in- tular psoriasis (GPP) based on a proposed
flammatory” dendritic cells in human skin. J Invest classification of disease severity. Arch Dermatol
Dermatol 2009;129(2):302–8. Res 2003;295(Suppl 1):S43–54.
18. Gudjonsson JE, Karason A, Runarsdottir EH, et al. 35. Marrakchi S, Guigue P, Renshaw BR, et al. Inter-
Distinct clinical differences between HLA-Cw*0602 leukin-36-receptor antagonist deficiency and
positive and negative psoriasis patients–an analysis generalized pustular psoriasis. N Engl J Med 2011;
of 1019 HLA-C- and HLA-B-typed patients. J Invest 365(7):620–8.
Dermatol 2006;126(4):740–5. 36. Oumeish OY, Parish JL. Impetigo herpetiformis.
19. Christophers E. Psoriasis–epidemiology and clinical Clin Dermatol 2006;24(2):101–4.
spectrum. Clin Exp Dermatol 2001;26(4):314–20. 37. Michaelsson G, Gustafsson K, Hagforsen E. The
20. Wu JJ, Choi YM, Bebchuk JD. Risk of myocardial psoriasis variant palmoplantar pustulosis can be
infarction in psoriasis patients: a retrospective improved after cessation of smoking. J Am Acad
cohort study. J Dermatolog Treat 2015;26(3):230–4. Dermatol 2006;54(4):737–8.
21. Gelfand JM, Neimann AL, Shin DB, et al. Risk of 38. Happle R. Linear psoriasis and ILVEN: is lumping or
myocardial infarction in patients with psoriasis. splitting appropriate? Dermatology 2006;212(2):
JAMA 2006;296(14):1735–41. 101–2.
22. Gelfand JM, Troxel AB, Lewis JD, et al. The risk of 39. Kvedar JC, Baden HP. Nail changes in cutaneous
mortality in patients with psoriasis: results from a disease. Semin Dermatol 1991;10(1):65–70.
population-based study. Arch Dermatol 2007; 40. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J
143(12):1493–9. Med 2009;361(5):496–509.
23. Gelfand JM, Dommasch ED, Shin DB, et al. The risk 41. Reich K, Kruger K, Mossner R, et al. Epidemiology
of stroke in patients with psoriasis. J Invest Derma- and clinical pattern of psoriatic arthritis in Germany:
tol 2009;129(10):2411–8. a prospective interdisciplinary epidemiological
24. Hjuler KF, Bottcher M, Vestergaard C, et al. study of 1511 patients with plaque-type psoriasis.
Increased prevalence of coronary artery disease in Br J Dermatol 2009;160(5):1040–7.
Chapter 1 Overview of Psoriasis 15
42. Radtke MA, Reich K, Blome C, et al. Prevalence and 54. Vittorio Luigi De Socio G, Simonetti S, Stagni G.
clinical features of psoriatic arthritis and joint com- Clinical improvement of psoriasis in an AIDS patient
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German national survey. J Eur Acad Dermatol Vene- therapy. Scand J Infect Dis 2006;38(1):74–5.
reol 2009;23(6):683–91. 55. O’Brien M, Koo J. The mechanism of lithium and
43. Mallbris L, Granath F, Hamsten A, et al. Psoriasis is beta-blocking agents in inducing and exacerbating
associated with lipid abnormalities at the onset psoriasis. J Drugs Dermatol 2006;5(5):426–32.
of skin disease. J Am Acad Dermatol 2006;54(4): 56. Famenini S, Wu JJ. Infliximab-induced psoriasis in
614–21. treatment of Crohn’s disease-associated ankylosing
44. Mallbris L, Akre O, Granath F, et al. Increased risk spondylitis: case report and review of 142 cases.
for cardiovascular mortality in psoriasis inpatients J Drugs Dermatol 2013;12(8):939–43.
but not in outpatients. Eur J Epidemiol 2004;19(3): 57. Ko JM, Gottlieb AB, Kerbleski JF. Induction and
225–30. exacerbation of psoriasis with TNF-blockade ther-
45. Augustin M, Reich K, Glaeske G, et al. Co-morbidity apy: a review and analysis of 127 cases.
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pertension: a case-control study. Acta Derm Vene- 59. Menter A, Korman NJ, Elmets CA, et al. Guidelines
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48. Gupta MA, Gupta AK, Watteel GN. Early onset (< 643–59.
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137 patients. Acta Derm Venereol 1996;76(6):464–6. 1997;37(3 Pt 2):S53–4.
49. Krueger G, Koo J, Lebwohl M, et al. The impact of 61. Hecker D, Worsley J, Yueh G, et al. Interactions be-
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50. Herron MD, Hinckley M, Hoffman MS, et al. Impact tacrolimus is not effective in chronic plaque psori-
of obesity and smoking on psoriasis presentation asis. A pilot study. Arch Dermatol 1998;134(9):
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51. Telfer NR, Chalmers RJ, Whale K, et al. The role of cream 1% in the treatment of intertriginous psoria-
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CHAPTER 2
Ultraviolet B Phototherapy
Sandra Pena, BS, Dane Hill, MD, Steven R. Feldman, MD, PhD
KEYWORDS
Phototherapy Narrowband UV-B UV therapy Psoriasis Excimer laser
KEY POINTS
Phototherapy with UV light can be used in the treatment of several cutaneous disorders.
Phototherapy is an efficacious treatment option in the management of psoriasis and should be a
first therapy considered in patients with moderate-to-severe plaque psoriasis.
Narrowband UV-B is used as the first-line phototherapy treatment option for moderate-to-severe
psoriasis due to its clinical efficacy and mild side-effect profile.
Targeted UV-B therapy phototherapy and employment of excimer lasers are excellent options for
patients with more limited disease, although there are now reports of use for extensive disease.
TARGETED PHOTOTHERAPY
Targeted phototherapy is a method of photother-
apy in which only affected areas of skin are treated. TABLE 2.2
Various devices can be used to deliver focused Ultraviolet B phototherapy indications
UV-B radiation on skin lesions while sparing unin-
Common Less Common
volved skin. These devices include high fluence
devices, like the excimer laser and flash lamp, Psoriasis Acquired perforating
and lower output devices, like UV-B light-emitting Vitiligo dermatosis
Atopic dermatitis Chronic urticaria
diodes.16 Introduced in 1997, the 308-nm excimer
Mycosis fungoides Cutaneous graft-
laser contains an unstable mixture of xenon and Pruritus (associated versus-host disease
chloride, which form “excited dimmers.” It is the with renal disease, Polymorphous light
dissociation of these dimers that produces the polycythemia vera) eruption
monochromatic wavelength, which is transmitted Cutaneous
via a fiber-optic cable to the lesion.17 The excimer mastocytosis
laser allows for targeted therapy that spares unin- Granuloma annulare
volved skin, especially in areas that are otherwise Lichen planus
difficult to treat, like the scalp, hands, and feet.17 Lichen simplex
In addition, it can generate high fluencies of chronicus
Lymphomatoid
UV-B, resulting in faster clearing and fewer expo-
papulosis
sures.18 Although the excimer laser is not suitable Parapsoriasis
for large body surface areas because the treat- Pityriasis lichenoides
ment may be considerably resource intensive Pityriasis rosea
and lengthy, the availability of more powerful UV Pityriasis rubra pilaris
emitting devices (and aggressive treatment proto- Seborrheic dermatitis
col) is extending the range of area that can be From Walker D, Jacobe H. Phototherapy in the age of bi-
treated.7,19 Although targeted treatment has ologics. Semin Cutan Med Surg 2011;30(4):196; with
generally been used for mild, localized psoriasis, permission.
Chapter 2 UV-B Phototherapy 19