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Fast Facts Pso

riasis

Fast Facts

Fourth edition

7 Epidemiology and pathophysiology

15 Clinical presentation

31 Differential diagnosis

38 General management approach

45 Topical therapy

65 Phototherapy and photochemotherapy

74 Systemic therapy

85 Receptor-targeted (biological) therapies

96 Psoriatic arthritis

112 Future trends

“This book reflects well the WHO’s current view of psoriasis as a chronic inflammatory condition with close links to the metabolic condition and a number of comorbidities. It

will be of great benefit in passing on new knowledge of psoriasis to health professionals, administrators and patient representatives around the world.”

Lars Ettarp, President, International Federation of Psoriasis Associations (IFPA) Fast Facts:

PsoriasisAlan Menter, Catherine Smith and Jonathan Barker

Fourth edition

© 2014 Health Press Ltd. www.fastfacts.com

Fast Facts

Fast Facts: Psoriasis Fourth edition

Alan Menter MD

Chair, Psoriasis Research Unit

Baylor Medical Center, Dallas, and

Clinical Professor, University of Texas

Southwestern Medical School

Dallas, USA

Catherine Smith MD FRCP

Professor of Dermatology and Therapeutics

St John’s Institute of Dermatology

Guy’s and St Thomas NHS Foundation Trust

London, UK

Jonathan Barker MD FRCP FRCPath

Professor of Medical Dermatology, and

Head of Department

St John’s Institute of Dermatology

King’s College, London, UK

Declaration of IndependenceThis book is as balanced and as practical as we can make it.Ideas for improvement are always welcome: [email protected]


Fast Facts: Psoriasis First published 2002; second edition 2004; third edition 2008, reprinted 2009, 2010 Fourth edition September 2014

Text © 2014 Alan Menter, Catherine Smith, Jonathan Barker © 2014 in this edition Health Press Limited

Health Press Limited, Elizabeth House, Queen Street, Abingdon, Oxford OX14 3LN, UK Tel: +44 (0)1235 523233 Fax: +44 (0)1235 523238

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Fast Facts is a trademark of Health Press Limited.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the express permission of the publisher.

The rights of Alan Menter, Catherine Smith and Jonathan Barker to be identified as the authors of this work have been asserted in accordance with the Copyright, Designs & Patents Act 1988 Sections 77 and 78.

The publisher and the authors have made every effort to ensure the accuracy of this book, but cannot accept responsibility for any errors or omissions.

For all drugs, please consult the product labeling approved in your country for prescribing information.

Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law.

A CIP record for this title is available from the British Library.

ISBN 978-1-908541-74-1

Menter A (Alan) Fast Facts: Psoriasis/ Alan Menter, Catherine Smith, Jonathan Barker

Medical illustrations by Dee McLean, London, UK. Typesetting by Thomas Bohm, User Design, UK. Printed by Latimer Trend & Company Limited, Plymouth, UK.

Text printed on biodegradable and recyclable paper manufactured using elemental chlorine free (ECF) wood pulp from well-managed forests.


Introduction 5

List of abbreviations 4

Epidemiology and pathophysiology 7

Clinical presentation 15

Differential diagnosis 31

General management approach 38

Topical therapy 45

Phototherapy and photochemotherapy 65

Systemic therapy 74

Receptor-targeted (biological) therapies 85

Psoriatic arthritis 96

Future trends 112

Useful resources 114

Index 116


4

List of abbreviations

APC: antigen-presenting cell

cAMP: cyclic adenosine monophosphate

COX: cyclooxygenase (inhibitor)

CRP: C-reactive protein

ESR: erythrocyte sedimentation rate

HIV: human immunodeficiency virus

HLA: human leukocyte antigen

ICAM1: intercellular adhesion molecule 1

Ig: immunoglobulin

IL: interleukin

LFA1: lymphocyte function-associated antigen 1

MED: minimal erythema dose; amount of radiation required to produce faint, but definite, erythema

NASH: non-alcoholic steatohepatitis

NSAID: non-steroidal anti-inflammatory drug

PASI: Psoriasis Area and Severity Index

PDE4: phosphodiesterase 4 (inhibitor)

PSORS1: psoriasis susceptibility locus

PUVA: photochemotherapy; combination of methoxsalen (psoralen), a photosensitizing drug, and long-wave ultraviolet A radiation

Th cell: T helper cell

TNFα: tumor necrosis factor α

TPMT: thiopurine methyltransferase

UV: ultraviolet (A and B) radiation


5

Introduction

Psoriasis is a common, chronic and disfiguring skin disease with

significant quality of life issues for every individual affected worldwide

(over 120 million). The significant growth in the number of patient

organizations around the world and the development of major new

biological agents are testimony to the increasing importance being

given to this common disorder.

Given the advances in genetics and immunology that have

furthered our understanding of the condition and resulted in

dramatically effective new treatments, psoriasis can no longer be

considered a mere ‘skin disease’. The disease called ‘Psoriasis’ has

a host of phenotypic variants, and multiple medical conditions have

been shown to be associated with the disease (see Chapter 2).

Cardiovascular disease is now more readily recognized as a

comorbidity of psoriasis, as are the consequences that this may have

for therapeutic intervention. An ongoing major issue of debate is

whether it is just patients with more extensive forms of psoriasis,

i.e. moderate to severe, who develop these comorbidities and a

potential shorter life span, or whether these comorbidities reach across

the whole spectrum of the disease.

We also need to answer the vexing questions as to why psoriatic

arthritis, which affects up to 30% of the psoriatic population, has its

onset approximately 10 years later than that of the skin manifestations

and why it has genetic, immunologic and therapeutic differences to

psoriasis.

Since the third edition, the main area of therapeutic advance

remains the receptor-targeted (biological) therapies, and the chapter

on these therapies has been updated to provide the latest developments

in this important area.

Receptor-targeted treatments have had a dramatic beneficial effect

on many patients with moderate and severe disease. These treatments

also have a key role in managing individuals with comorbidities such

as arthritis, cardiovascular disease and inflammatory bowel disease,

and in the future may have a role in switching off the systemic


6


inflammation associated with the disease that may in turn cause other

comorbidities.

Thus, looking forward – and of significant interest to researchers

and our readership – there is the potential to significantly improve the

quality of life of our patients and to reduce the full range of

comorbidities associated with psoriasis. It is thus essential that

dermatologists work closely with their primary care colleagues, as well

as specialists in cardiology, gastroenterology, rheumatology and

others, and maintain a central role in elucidating the complexity of

psoriasis.

This fourth edition of Fast Facts: Psoriasis is a well-illustrated, easy-

to-read yet comprehensive synopsis of the state of the art in psoriasis,

its pathogenesis and its management. We believe it is a valuable

resource for all health professionals involved in the care and treatment

of individuals with this problematic but increasingly treatable disease.

Acknowledgments. The authors thank Professor Philip Mease, Head

of Seattle Rheumatology Associates; Chief of Rheumatology Research,

Swedish Medical Center; and Clinical Professor, University of

Washington, Seattle, USA, for his chapter on psoriatic arthritis

(page 96).


7

EpidemiologyPsoriasis is a common chronic, disfiguring inflammatory skin disease

that affects up to 3% of the population. Several clinical variants exist

(see Chapter 2) of which chronic plaque psoriasis (psoriasis vulgaris) is

the most common form (85–90% of all cases).

Effects of ethnicity. Although all races are affected, there is

considerable interracial variation. For example, psoriasis is relatively

common in white people but appears to be very uncommon in

American Indians and in Japanese people. Prevalence appears to be

highest in Scandinavian countries and northern Europe.

Effects of gender and age. Men and women are affected equally. The

usual age of onset is 20–35 years, with 75% of all cases occurring for

the first time before 40 years of age. However, psoriasis can occur at

any age, including childhood (often signifying a more severe clinical

course) and old age.

Types of psoriasis. Two types of chronic plaque psoriasis have been

described, based on age of onset, association with human leukocyte

antigen (HLA) and disease course.

• TypeI,thecommonestform,occursinyoungadultswithahigh

probability of a positive family history. Affected individuals tend to

have more severe disease that runs a more irregular course.

• TypeIIhasapeakincidencebetween50and60yearsofage.In

these individuals, a positive family history is very uncommon and

the disease tends to be mild and localized.

Socioeconomic burden. Psoriasis severely affects a patient’s quality of

life in terms of both psychological and physical well-being. Studies

comparing psoriasis with other important chronic diseases have shown

that the impact of psoriasis on the patient’s quality of life is at least as

1 Epidemiology and pathophysiology


8


great as that of ischemic heart disease, diabetes and chronic

obstructive pulmonary disease. Psoriasis is therefore a disease of major

socioeconomic importance; in the USA alone, the annual cost to

society has been estimated at US$3.5 billion. Furthermore, there is

increasing evidence of an association between psoriasis and important

comorbidities including cardiovascular and psychiatric disease;

evidence suggests that patients with moderate and severe disease have

a high mortality due to cardiovascular events (see Chapter 2).

In the UK, although most patients with psoriasis have relatively

mild disease, evidence suggests that 30% require second-line treatment

(phototherapy or systemic medication) that involves referral to a

dermatologist and that perhaps 40% of all dermatology inpatients

have psoriasis. In the USA, where inpatient dermatology care is rarely

available, and at many institutions in the UK, specialized psoriasis day

centers have evolved for patients with moderate-to-severe disease. The

advent of new treatments has greatly improved the outlook for many

patients, particularly those with severe disease. Consequently, inpatient

episodes have been dramatically cut, with clear economic benefit.

Pathogenesis and pathophysiologyThe pathogenesis of psoriasis can be described in terms of three

inter-related phases (Figure 1.1):

• theinterplaybetweenenvironmentalandgeneticfactors

• theinteractionbetweeninnate/adaptiveimmunityandkey

inflammatory and epidermal cells

• changesintheepidermisanddermis,suchasexcessivegrowthand

failure of proper differentiation and proliferation and dilatation of

blood vessels, which lead to the development of the clinical

psoriatic plaque.

Genetics. In 1963, Gunnar Lomholt, a pioneer in the epidemiology of

psoriasis, stated in his classic thesis that the disease ‘is capricious and

refuses to part with its innermost secret’, but also wrote: ‘that psoriasis

is genetically conditioned is beyond doubt’. The validity of this

statement has been borne out by population and family studies and

research in twins, all of which suggest an important genetic


9

Epidemiology and pathophysiology

component to the disease. For example, in terms of types I and II

psoriasis (see page 7), approximately 80% of patients with type I

psoriasis are positive for the HLA-Cw6 gene, compared with only

20% of those with type II psoriasis. Approximately 30% of patients

with psoriasis will have a known family history of the disease.

In some families, psoriasis appears to behave like a Mendelian

autosomal dominant disease, whereas in other cases there is little or

no family history. It has been suggested that psoriasis may represent a

spectrum of diseases in which different genes, working either alone or

in concert (polygenic disease), are important in different families.

There have been a number of key genetic advances in recent years:

first, the chromosomal localization (on 6p21.3) of the major psoriasis

genetic locus, psoriasis susceptibility 1 (PSORS1), which contributes

up to 50% of the genetic risk; and secondly, the discovery of several

genes that, while conferring a low genetic risk, point to specific

biological pathways for the disease. To date, approximately 35 genetic

loci have been associated with psoriasis. Interesting candidate genes at

each of these loci cluster around specific biological pathways involved

in the epidermal barrier, innate immunity and adaptive immune

response. They suggest a key role for host defenses against microbes,

Primary event PBMCDC

Th1Th17

Environmental trigger

Innateimmunity

IL-12IL-23

Acquiredimmunity

PSORIASIS

PSORS1 TNFα

Figure 1.1 The interplay between environmental, genetic and

immunologic factors in lesional skin. Antigens may be environmental

antigens, superantigens or autoantigens. DC, dendritic cell; IL, interleukin;

PBMC, peripheral blood mononuclear cell; PSORS1, psoriasis susceptibility 1

gene; Th1/Th17, type 1/type 17 T helper cell; TNFα, tumor necrosis factor α.


10


which involve interferon. Intriguingly, these genetic findings indicate a

key role for tumor necrosis factor (TNF)α in disease pathogenesis,

thus supporting therapy targeted at TNF. Furthermore, when

combined with immunologic studies, they define the key T-cell subset

in psoriasis pathogenesis as T helper (Th)-17 cells (see below). This

explains the highly effective treatments designed to block Th17 cells or

prevent their differentiation through inhibition of interleukin (IL)-23

(see Chapter 8).

Environmental factors also play a key etiologic role. For example, in

60% of patients with guttate psoriasis (see page 18), the disease is

precipitated by systemic, usually upper respiratory tract, streptococcal

infection. Other important environmental factors include drugs,

particularly lithium and antimalarials, and physical or psychological

stress. Excessive alcohol intake is also associated with disease

deterioration and makes management more difficult.

Immunologic changes. Evidence that psoriasis is primarily an

immunologic disease comes from many different sources. In evolving

lesions, lymphocytes infiltrate the skin early, before epidermal and

other changes. Psoriasis is associated with certain HLA antigens,

particularly HLA-Cw6, which are cell-surface molecules critical to the

regulation of T-lymphocyte function. Experimentally, psoriasis can be

induced in non-lesional skin transplanted onto mice by injection of

lymphocytes from the same patient. Finally, psoriasis responds rapidly

to treatments designed to inhibit T-lymphocyte function, such as

ciclosporin (cyclosporine), as well as to specific biological agents

targeting key cytokines (IL17, TNFα, etc.) involved in its

immunopathogenesis.

Considerable progress has been made in identifying the precise

lymphocytes that cause the disease (see Genetics above). The antigens

– foreign or auto – to which these lymphocytes respond are currently

unknown, although potentially important lessons can be learnt from

Streptococcus-induced eruptive guttate psoriasis.

There has been an explosion of knowledge about immunopathogenetic

events in psoriasis. In great part, this has been led by advances in


31

3 Differential diagnosis

Although diagnosis is relatively straightforward, a number of other

dermatological entities may be confused with psoriasis (Table 3.1). A

careful medical and family history and physical examination, together

with laboratory findings, will usually reveal the correct diagnosis.

InfectionCandidiasis. In flexural areas, peripheral pustules are characteristic of

Candida infection. The presence of yeast and pseudohyphae in

Gram-stained microscopy specimens will confirm infection.

Tinea, or ringworm, is an infection caused by a dermatophyte fungus

and may sometimes be mistaken for psoriasis. Where diagnostic doubt

exists, appropriate mycological specimens (skin, hair and/or nail)

should be taken.

Tinea capitis is ringworm of the head. Although a minor degree of

hair thinning is not uncommon in established cases of psoriasis,

well-demarcated areas of hair loss (Figure 3.1) and signs such as the

TABLE 3.1

Differential diagnosis of psoriasis

• Candidiasis

• Tineainfection

• Syphilis(secondary)

• Eczema(atopicornummular)

• Contactdermatitis

• Drug-inducedrashes

• Lichenplanus

• SuperficialbasalcellcarcinomaandBowen’sdisease

• CutaneousT-celllymphoma(mycosisfungoides)

• Pityriasisrosea


32


‘black dots’ or fractured hair shafts characteristic of tinea infection are

highly unusual in psoriasis. In addition, tinea capitis seldom shows the

classic silvery scale of psoriasis.

Tinea corporis affects the body (Figure 3.2). Lack of symmetrical

lesions, presence of peripheral scale and central clearing are all more

characteristic of tinea than of psoriasis.

Tinea cruris affects the groin area, and is characterized by central

clearing with an advancing edge. The lesion has a non-silvery, fine

Figure 3.2 A patch of tinea corporis due to Microsporum canis. Note the

typical peripheral scale and relative central clearing.

Figure 3.1 A scalp infected with Trichophyton tonsurans, which is a

common cause of tinea capitis. Clinical signs vary from mild scaling to,

as here, marked alopecia and suppurative inflammation (kerion formation).


33

Differential diagnosis

scale, particularly at the periphery, and frequently extends more on the

left than the right side.

Tinea pedis is ringworm of the feet. In the vesicular form, clear

vesicles are noted (in contrast to the whitish-yellow pustule of

psoriasis; see Figure 2.6). In the ‘dry moccasin’ variety of tinea pedis, a

relative lack of symmetry is seen.

Tinea manum is ringworm of the hands. It presents as a fine

powdery scale, particularly involving the palms and palmar creases.

Again, it is usually asymmetrical.

Tinea unguium infection of the nails may be extremely difficult to

distinguish from psoriatic nail involvement, particularly in toenails.

Furthermore, patients with psoriatic nail disease are more likely than

individuals without pre-existing nail disease to have an associated

fungal infection. A search for nail pits and clinical evidence of

cutaneous psoriasis or tinea of the feet is important. Appropriate

cultures taken from the nails are often required to make the

diagnosis.

Secondary syphilis. The guttate (drop-like) forms of psoriasis may

mimic secondary syphilis. Therefore, it is important to search carefully

for a primary syphilitic lesion, together with associated

lymphadenopathy, mucosal lesions and palmar–plantar lesions with a

peripheral collarette of scale, which are characteristic of secondary

syphilis. If in doubt, serological testing for syphilis should be

considered.

Eczema/dermatitisDiscoid eczema. Individual patches are usually more pruritic, lack a

silvery scale and are less likely to show the more vivid, characteristic

purplish-red color of psoriasis (Figure 3.3).

Hand and foot eczema. Hyperkeratotic forms of eczema, particularly

in atopic patients, may be identical in appearance to psoriasis. Taking

a skin biopsy to differentiate it from psoriasis is rarely helpful. Clues

to the diagnosis include a history of atopy (hay fever and/or asthma),

a lack of psoriasis elsewhere on the body, and evidence of eczema


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