Mild-to-Moderate Psoriasis, Second Edition

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SECOND EDITION

Dermatology about the book… Using a practical and problem-focused approach, this updated, full-color Second Edition of Mild-to-Moderate Psoriasis equips dermatologists, internists, family practitioners, and residents with a state-of-the-art guide to the clinical management of mild-tomoderate psoriasis.

about the editors... JOHN Y.M. KOO is Director of the University of California at San Francisco (UCSF) Medical Center Psoriasis and Skin Treatment Center, and Professor of Dermatology and ViceChairman of Department of Dermatology, UCSF Medical Center, San Francisco, California, USA. Dr. Koo received his M.D. degree from Harvard Medical School, Boston, Massachusetts, USA. Dr. Koo has been named on the list, “Best Doctors in America.” Dr. Koo is Board Certified in Psychiatry and Dermatology. He has published more than 300 articles and book chapters in the field of psoriasis. He is co-editor of the first edition of Mild-to-Moderate Psoriasis and the upcoming Moderate-to-Severe Psoriasis, Third Edition. CHAI SUE LEE is Director of the Psoriasis and Phototherapy Treatment Center in the Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA. Dr. Lee received her M.S. and M.D. degrees from the University of California, San Francisco, and the University of California, Berkeley Joint Degree Program, Berkeley, California, USA. Dr. Lee is author of numerous professional articles and book chapters, and was co-editor of the first edition of Mild-to-Moderate Psoriasis and Moderateto-Severe Psoriasis, Third Edition. MARK G. LEBWOHL is Professor of Dermatology and Chairman of the Department of Dermatology, the Mount Sinai School of Medicine, New York, New York, USA, and Chairman of the Medical Board of the National Psoriasis Foundation. Dr. Lebwohl received his M.D. from Harvard Medical School, Boston, Massachusetts, USA. Dr. Lebwohl is the founding editor of Psoriasis Forum and is on the editorial board of the Journal of the American Academy of Dermatology. He has authored or co-authored over 500 publications, including the first edition of Mild-to-Moderate Psoriasis and Moderate-to-Severe Psoriasis, Third Edition. Printed in the United States of America

H8860

Mild-to-Moderate

New to the Second Edition: • updates on calcipotriene, tazarotene, tars, anthralin, salicylic acid, and phototherapy • new treatment such as innovative formulations of topical corticosteroids, laser therapy and hydrogel patches • expanded coverage on scalp psoriasis

Mild-to-Moderate

Psoriasis

Written by an international team of key opinion leaders, this resource explores new treatments for the condition and provides clinicians with up-to-date management strategies for optimal patient management.

Koo • Lee • Lebwohl

Psoriasis

S E C ON D

E DI T ION

Edited by

John Y.M. Koo Chai Sue Lee Mark G. Lebwohl

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Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016  C

2009 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. overnment works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-8860-2 (Hardcover) International Standard Book Number-13: 978-1-4200-8860-1 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, eparate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data Mild-to-moderate psoriasis / edited by John Y. M. Koo, Chai Sue Lee, Mark G. Lebwohl. – 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4200-8860-1 (hardcover : alk. paper) ISBN-10: 1-4200-8860-2 (hardcover : alk. paper) 1. Psoriasis. I. Koo, John Y. M. II. Lee, Chai Sue. III. Lebwohl, Mark. [DNLM: 1. Psoriasis–therapy. WR 205 M641 2008] RL321.M552 2009 616.5 26–dc22 2008042837

For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Preface

The goal of this book is to provide state-of-the-art clinical management of mildto-moderate psoriasis written by an international array of key opinion leaders. The second edition highlights new treatments and treatment extensions that were not available when the first edition was published. Innovative coverage includes formulation of topical corticosteroids, topical vitamin D analogs, laser therapy, and hydrogel patches. Updates on the coverage of treatments covered include topical corticosteroids, calcipotriene, tazarotene, tars, anthralin, salicyclic acid, and phototherapy. There is a chapter highlighting recent advances in combination therapy. We have also included chapters on palmaoplantar psoriasis, scalp psoriasis, inverse psoriasis, and nail psoriasis because these are areas of the body that are frequently resistant to ordinary forms of therapy. The editors are hopeful that the comprehensive yet practical and problem-focused approach to the management of mild-to-moderate psoriasis makes this a reference that dermatologists, internists, family practitioners, and residents can turn to for the most updated guidance in taking care of patients with mild-to-moderate psoriasis. John Y. M. Koo Chai Sue Lee Mark G. Lebwohl

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Contents

Preface . . . . iii Contributors . . . . vii 1. Introduction to Mild-to-Moderate Psoriasis Mark G. Lebwohl 2. General Approach to Psoriasis Treatment Steven R. Feldman

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3. General Guidelines for Administration of Topical Agents in the Treatment of Mild-to-Moderate Psoriasis 11 Jashin J. Wu and Gerald D. Weinstein 4. Topical Corticosteroids 23 Jason Givan, Daniel Pearce, and Steven R. Feldman 5. Vitamin D3 Analogs Chai Sue Lee

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6. Fixed-Dose Corticosteroid/Calcipotriene Combination Therapy Chai Sue Lee and John Y. M. Koo

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7. Topical Tazarotene 71 Chai Sue Lee 8. Topical Calcineurin Inhibitors 83 Mark G. Lebwohl and Chrystal A. Landry 9. Treatment of Mild-to-Moderate Psoriasis with Coal Tar, Anthralin, Salicylic Acid, and Lactic Acid 91 Sarah Fitzmaurice, Emily Becker, Priya Sivanesan, and John Y. M. Koo 10. Phototherapy and Laser for the Treatment of Mild-to-Moderate Psoriasis 103 Iltefat Hamzavi and Holly A. Kerr v

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vi

Contents

11. Topical Sequential Therapy of Psoriasis 129 John Y. M. Koo, Thao U. Nguyen, and Shanthi M. Colaco 12. Combination Therapy 139 Thao U. Nguyen and Alice Gottlieb 13. New Developments in Topical Psoriasis Therapy 165 Shanthi M. Colaco, Sarah Fitzmaurice, Emily Becker, Lawrence C. C. Cheung, John Y. M. Koo, Chai Sue Lee, Priya Sivanesan, Farah Malick, and Julie A. Letsinger 14. Palmoplantar Psoriasis 183 Eliana Krulig and Kenneth B. Gordon 15. Scalp Psoriasis 197 Peter C. M. van de Kerkhof, Marloes M. Kleinpenning, and Rianne M. J. P. Gerritsen 16. Inverse Psoriasis 209 Robert A. Lee and Abby S. Van Voorhees 17. Psoriasis of the Nails 225 Gabriele B. Poindexter, Richard K. Scher, and Maithily A. Nendedkar-Thomas Index . . . . 249

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Contributors

Emily Becker Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A. Lawrence C. C. Cheung Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A. Shanthi M. Colaco Department of Dermatology, Columbia University, New York, New York, U.S.A. Steven R. Feldman Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Sarah Fitzmaurice Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A. Rianne M. J. P. Gerritsen Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands Jason Givan Department of Dermatology, Saint Louis University School of Medicine, St. Louis, Missouri, U.S.A. Kenneth B. Gordon Evanston Northwestern Healthcare and Northwestern University, Feinberg School of Medicine, Skokie, Illinois, U.S.A. Alice Gottlieb Department of Dermatology, Tufts Medical Center, Boston, Massachusetts, U.S.A. Iltefat Hamzavi Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A. Holly A. Kerr Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A. Marloes M. Kleinpenning Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands John Y. M. Koo Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A. vii

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Contributors

Eliana Krulig Evanston Northwestern Healthcare, Skokie, Illinois, U.S.A. Chrystal A. Landry Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A. Mark G. Lebwohl Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A. Chai Sue Lee Department of Dermatology, University of California Davis Medical Center, Sacramento, California, U.S.A. and Sacramento VA Medical Center, Mather, California, U.S.A. Robert A. Lee Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Julie A. Letsinger Department of Dermatology, Palo Alto Medical Foundation, Palo Alto, California, U.S.A. Farah Malick Department of Dermatology, Wayne State University, Dearborn, Michigan, U.S.A. Maithily A. Nendedkar-Thomas Reston, Virginia, U.S.A.

Professional Dermatology Care, PC,

Thao U. Nguyen Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A. Daniel Pearce Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Gabriele B. Poindexter Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, U.S.A. Richard K. Scher Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, U.S.A. Priya Sivanesan Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Peter C. M. van de Kerkhof Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands Abby S. Van Voorhees Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Gerald D. Weinstein Department of Dermatology, University of California Irvine, Irvine, California, U.S.A. Jashin J. Wu Kaiser Permanente, Los Angeles Medical Center, Department of Dermatology, Los Angeles, California, U.S.A.

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1 Introduction to Mild-to-Moderate Psoriasis Mark G. Lebwohl Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A.

The treatment of psoriasis has changed dramatically over the past five years with the emergence of biologic therapies primarily for moderate-to-severe disease. Nevertheless, topical therapy remains the most commonly prescribed treatment for psoriasis. The vast majority of patients have mild-to-moderate disease and are therefore reluctant to use systemic treatments. Surveys performed by the National Psoriasis Foundation (NPF) show that a large proportion of patients with disease affecting more than 10% of their body surface area (BSA) are treated with topical therapy alone. Moreover, the vast majority of patients treated with systemic agents including biologics require treatment with topical prescriptions as well. Successful therapy for biologic agents is measured by the Psoriasis Area and Severity Index (PASI) 75, i.e., 75% improvement in this measure of psoriasis severity. How is the other 25% treated? Most often, it is treated with topical therapy and occasionally with phototherapy. Many effective systemic therapies are slow. Alefacept is the best example, taking 12 weeks or longer to reach maximal effect. The most commonly prescribed biologic agent in the United States, etanercept, can take more than eight weeks for maximal effect and the same is true for efalizumab. Topical medications— particularly potent corticosteroids—can be quite fast, providing patients necessary relief while waiting for their systemic therapies to work. Many of the older systemic agents such as acitretin are also slow and provide only partial relief. Methotrexate is highly effective, but because methotrexate’s bone marrow and liver toxicity are 1

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dose related, it is safer to aim for partial clearance and treat residual disease with topical therapy or phototherapy. Similarly, cyclosporine’s nephrotoxicity is dose related, and it is therefore prudent to partially clear psoriasis and treat residual plaques with topical therapies. Since the first edition of Mild-to-Moderate Psoriasis, there has been considerable innovation in topical therapy and phototherapy. For the first time we have superpotent corticosteroids in spray, lotion, and shampoo formulations. Foam technology has improved so that there are several strengths of corticosteroids available in foams, and we now have emollient foams. While ointments are no longer the predominant branded therapy prescribed, the combination of betamethasone dipropionate ointment and calcipotriol in an ointment formulation has emerged as one of the most commonly prescribed psoriasis therapies and the first branded combination. This combination has most recently been introduced in a suspension that is marketed for the scalp. Dermatologists seldom consider hypothalamic-pituitary-adrenal (HPA) axis suppression, but pediatricians are quite concerned about this hormonal effect of corticosteroids. Formulations of two mid- to lower-potency corticosteroids, fluticasone propionate and hydrocortisone butyrate, have shown very little HPA-axis suppression in children and have been approved for pediatric use by the U.S. Food and Drug Administration. A superpotent corticosteroid, fluocinonide 0.1%, has also shown very little HPA-axis suppression in adults or children, but it is unlikely that this superpotent agent will be formally approved for pediatric use. Undoubtedly, we will continue to search for corticosteroids with improved benefit–risk ratios. There have been some innovations with corticosteroid-free agents. More elegant tar preparations have been introduced; anthralin still enjoys limited use; topical retinoids are highly effective, particularly in combination with other agents; and both topical retinoids and ammonium lactate have been shown to prevent corticosteroid-induced cutaneous atrophy. But the greatest innovation in noncorticosteroid topical therapy of psoriasis has come from vitamin D and its analogs. Calcipotriol, also known as calcipotriene in the United States, has been established as a staple of psoriasis therapy both alone and in combination with topical corticosteroids. A related topical agent, calcitriol, is gaining approval around the world. Data indicate that it is comparably effective to calcipotriol but may be less irritating on facial and intertriginous skin. Other vitamin D analogs that have been used for psoriasis include becocalcidiol, tacalcitol, and maxacalcitol. The topical calcineurin inhibitors, tacrolimus and pimecrolimus, are very useful for facial and intertriginous psoriasis, areas that are particularly prone to corticosteroid-induced atrophy and calcipotriol-induced irritation. Stronger formulations of topical calcineurin inhibitors have been studied for psoriasis, but it is not clear that they will ever reach the psoriasis market. In the area of phototherapy, innovation continues as well. Use of targeted phototherapy for isolated plaques of psoriasis is expanding. The excimer laser has become a well-established therapy for limited plaques of psoriasis, and is even effective for difficult-to-treat palm and sole psoriasis. A new device resembling a

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hairbrush with fiber optic cables that deliver ultraviolet B to the scalp has recently been introduced. Several attempts have also been made to find topical photosensitizers, but none has been as successful as psoralens. In the meantime, use of PUVA for psoriasis persists, particularly for dark-skinned patients who have a lower risk of skin cancer when treated with this modality. Undoubtedly, we will continue to look for the perfect treatment—a therapy that works for everyone and has no side effects. Until that time, we have a large array of topical therapies, light therapies, and systemic therapies to choose from that allow us to improve the quality of life of the vast majority of psoriasis patients.

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2 General Approach to Psoriasis Treatment Steven R. Feldman Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

INTRODUCTION Psoriasis is a complex disease to manage. It may present with wide-ranging severity affecting vastly different parts of the body. Very limited areas to very diffuse generalized disease can be present, and the character of the lesions may vary from minimal redness to thick scaly red plaques. The various presentations add to the complexity in choosing treatment. Adding to the complexity of the treatment is the availability of a host of different topical, phototherapy, and systemic treatment options. Matching the appropriate treatment with the presentation of the disease is an art. Adding to the complexity of this art is the fact that it is not just lesions that are being treated, but a patient, and patients’ responses to the lesions also vary considerably. Patients also differ in their concern about side effects and the way they tolerate different topical preparations. These variations can be dramatic. In nearly all patients, psoriasis impacts quality of life, including social interactions. The overall impact of psoriasis on quality of life—particularly the effect of psoriasis on social interactions—must also be addressed. Step I: Address Patients’ Psychosocial Needs The first step in managing all patients with psoriasis is to address their psychosocial needs. This is fundamental to effective psoriasis treatment. Addressing psychosocial issues helps to establish a strong working relationship between the physician 5

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and the patient. By doing so, patients are likely to be more compliant with treatment and should have better health outcomes. The first step to managing psychosocial needs is to sit within touching distance of the patient. While examining the lesions and talking to the patient, the physician should palpate lesions (with appropriate attention to cultural and patient preferences). While doing so the physician can remark, “Wow, these lesions are really thick.” The purpose of the palpation is not to determine the thickness of the lesions, but to communicate to patients that they are not untouchable. Patients with psoriasis feel isolated from others because of their disease and by touching the lesions the physician communicates to the patients that they should not be afraid of having contact with other people. Dr. J. Lamar Calloway, long-time dermatologist at Duke University, would communicate to patients that psoriasis is not an infectious condition; by taking the hand, he used to palpate the psoriasis and rub his own face with it. While sitting close to the patient, the physician should also proactively ask patients a few questions about their disease. These questions are not likely to change what the physician will prescribe, but they may change how the patient views the doctor, how the patient views the treatment, and ultimately how adherent the patient will be to the treatment recommendations. There are many things about psoriasis that are bothersome to patients and asking questions about a few of these helps communicate to the patient that the dermatologist understands the disease and what the patient is going through. One might ask if the itching has been bothersome, if past treatments have been messy or ineffective, or if psychosocial concerns have been an issue. Simply asking a few questions (and listening intently) helps further the bond between the physician and the patient. No health care provider has enough time to explain to patients everything they would like to know about psoriasis. All of us, however, have the time to encourage patients to join the National Psoriasis Foundation [or similar organizations in other countries, such as EUROPSO (www.europso.eu), or IFPA (www.ifpa-pso.org)]. The psoriasis foundation and other psoriasis support organizations provide numerous benefits to patients. First, these organizations help patients to feel less isolated. Second, the foundation helps educate patients about available treatment options. Third, the foundation encourages patients to be compliant with their dermatologists’ recommendations. If that were not enough, the psoriasis foundation also empowers patients to work toward a cure for the disease. The psoriasis foundation offers a variety of brochures that are very useful for educating patients about specific treatment options. The psoriasis foundation periodical for patients entitled “Psoriasis Advance” helps patients answer many of the psychosocial issues that physicians may not feel comfortable addressing; for example, what to do if the lifeguard says you cannot go in the pool, what to do when people point and ask questions, or other social situations. Communication among members is very supportive. Patients can be encouraged to join the psoriasis foundation by simply visiting the website (www.psoriasis.org), writing to the foundation (6600 SW 92nd Avenue, Suite 300, Portland, OR 97223–7195,

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U. S. A.), or calling(1–800-723–9166). Anyone can join, even without paying, although there is a recommended donation of $35 (to cover mailing costs). Step II: Categorization of Psoriasis Once psychosocial issues are addressed, further treatment planning is dependent on determining whether patients have relatively localized disease suitable for topical therapy or more extensive disease where phototherapy or systemic treatments will be used. This book focuses on the treatment of people with relatively localized disease. Formerly, the common categorization scheme of mild, moderate, and severe psoriasis has been used. These three categories do not correspond well to treatment decision making, however. Typically, one would hear categorizations of mild-to-moderate versus moderate-to-severe psoriasis for treatment purposes. Mild-to-moderate psoriasis tends to refer to patients with relatively localized psoriasis. The moderate-to-severe category tends to refer to the patient with more generalized disease or disease that is otherwise disabling. Treatment of this latter group has been covered in an excellent textbook entitled “Moderate-to-Severe Psoriasis” (1). This chapter and this book focus on the treatment of the patient with mild-to-moderate or localized psoriasis. GENERAL CONSIDERATIONS IN TREATMENT OF LOCALIZED PSORIASIS The treatment of localized psoriasis focuses on local treatments, predominately topical treatments, although certainly localized phototherapy and intralesional injection treatments are also used. When it comes to topical treatments, multiple agents are available including tar, anthralin, topical corticosteroids, topical vitamin D and vitamin A analoges, topical immunomodulators (tacrolimus and pimecrolimus), and keratolytics (such as salicylic acid). Whichever of these agents are chosen, a primary consideration determining patients’ outcomes will be patients’ adherence to the topical treatment regimen. When patients with psoriasis have been asked about their adherence to topical therapy, approximately 40% reported nonadherence (2,3). The reasons for poor adherence to treatment are manifold. Frustration with medication efficacy, inconvenience, and fear of side effects are among the most important reasons patients do not use their medication as directed. Other factors affecting patients’ use of medication include cost, the medication feeling unpleasant, unclear instructions, and directions that are too complicated (2). In a clinical trial that assessed adherence using both patient diaries and electronic monitors, psoriasis patients vastly overstated their true use of the treatment (4). A recent study of pharmacy records indicated that approximately 50% of prescribed psoriasis treatments were not even filled (5). It is clear that patients are not truthful with their doctors about their adherence to topical therapy. Topical therapy is time consuming and messy. Over time, use of topical therapy

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decreases. Chronic diseases like psoriasis are frustrating and wear on people over time. The treatment of these diseases, particularly topical therapy, can be frustrating too. Outcomes of localized psoriasis treatment can be improved by encouraging better adherence. There are a number of practical measures physicians can take to improve a patient’s use of their medication (6). First, as discussed above, physicians should establish a strong working relationship with the patient. The patient should also be involved in treatment decision making. Vehicles that the patients do not mind applying should be chosen. While it was commonly thought that ointments are more effective, new nonointment, less messy vehicles may be able to deliver active drugs just as well as traditional ointments, and better adherence with a nonmessy product may actually lead to greater efficacy than is seen with ointments. There is generally one vehicle that delivers topical therapy better than all the others—the vehicle that a particular patient is willing to use. Patients are also reluctant to apply topical therapy for long periods of time before they see improvement. Fast acting agents should be used, especially initially. The sequential therapy approach addresses this need. Sequential therapy consists of using stronger, faster acting but potentially more risky treatments early in the course of therapy and then transitioning to slower acting but safer treatments for the long-term maintenance of the disease. This approach has the advantage of helping patients see early in the course of therapy that treatments work, thereby improving patients’ compliance. The complexity of sequential treatment may make it more difficult for patients to adhere to treatment; giving patients clear, written instructions may help. Other approaches are to use the stronger topical agents such as clobetasol-containing topical corticosteroid products initially and then using them intermittently as needed to control the disease. Another way to help improve patients use of medication is to encourage patients to return to the office or at least contact the physician shortly after treatment has begun, for example, in one to two weeks. A long interval before a return visit may lead to poor compliance if the patient feels that it will be impossible to be adherent for that length of time. By seeing patients back in just a week, patients are more likely to use their medication over that week, thereby seeing the potential benefits the treatment offers. Once they have seen that the treatment actually works, they will use the treatment intermittently knowing that it will be effective for them. A short interval between initiation of treatment and the first return visit may be especially important for patients with scalp psoriasis, as use of topical scalp treatment regimens is exceedingly time consuming and difficult. Some patients have disease that is poorly responsive to all attempts at management with self-administered treatments. In these instances, the use of physician—administered treatments may be appropriate. Adherence can be assured with intralesional injection treatment. Office-based localized phototherapy, or even office-based application of topical agents, may be other helpful alternatives.

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CONCLUSIONS Treating mild-to-moderate psoriasis (relatively localized psoriasis) can be frustrating for both the patient and the physician. Much of this frustration can be alleviated by addressing patients’ psychosocial concerns upfront. All patients with psoriasis should be encouraged to join the National Psoriasis Foundation or similar patient advocacy groups. These organizations help reduce patients’ isolation and increase their knowledge about treatments, ultimately resulting in approved adherence to the physician-recommended treatment regimen. Topical treatments are safe and effective for most patients with mild-tomoderate psoriasis. Getting patients to actually use the treatment is a critical component in maximizing topical treatment efficacy. Patients should be encouraged to participate in the treatment planning process, choosing vehicles and other treatment characteristics (such as dosing) that fit the patient’s lifestyle. Using rapidly acting agents initially and encouraging patients to come in for an early follow-up visit or other factors may help improve the compliance. The resulting improvement should help reduce the frustration of psoriasis on both the patient and the physician. ACKNOWLEDGMENTS Center for Dermatology Research is funded by a grant from Galderma Laboratories, L.P. Dr. Feldman has also received support from Abbott, Amgen, Astellas, Centocor, Genentech, Photomedex, Steifel, and Warner Chilcott. REFERENCES 1. Koo J, Lee CS, Lebwohl MG, et al. Moderate-to-Severe Psoriasis, 3rd ed. New York, NY: Informa Healthcare, 2009. 2. Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol 2006; 55:607–613. 3. Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol 1999; 41:581–583. 4. Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: Commonly used methods of measuring adherence to topical therapy overestimate actual use. J Am Acad Dermatol 2004; 51:212–216. 5. Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never redeemed: Primary nonadherence in an outpatient clinic. J Am Acad Dermatol 2008; 59:27–33. 6. Feldman SR. Practical Ways to Improve Patients’ Treatment Outcomes. Winston-Salem, NC: Medical Quality Enhancement Corporation, 2008.

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3 General Guidelines for Administration of Topical Agents in the Treatment of Mild-to-Moderate Psoriasis Jashin J. Wu Kaiser Permanente, Los Angeles Medical Center, Department of Dermatology, Los Angeles, California, U.S.A.

Gerald D. Weinstein Department of Dermatology, University of California Irvine, Irvine, California, U.S.A.

Psoriasis is a chronic inflammatory disorder of the skin that affects 2% of the world (1). It is one of the more commonly seen and treated diseases for the general dermatologist and amounting to approximately 2.3% to 10% of the office practice (2,3). In a survey of dermatologists who belong to the American Academy of Dermatology, approximately 70% of psoriasis patients were treated with topical therapies and 30% with phototherapy/systemic therapy (4). In another report, it is estimated that 75% of psoriasis patients have mild-to-moderate disease (as measured by 4 to ≤7; severe, >7 to ≤12). The modified PASI score (ranging from 0 to 12) was calculated as the sum of individual scores for erythema, induration, and scaling (each ranging from 0–4 and representing the spectrum of none to very severe). Each patient had bilaterally symmetric right- and left-sided body lesions chosen for comparison, one lesion to be treated with hydrogel and the other without hydrogel. Target lesions of mild severity were separated into group 1 or 2. For group 1, no study medications were applied and the hydrogel dressing was applied to one of the two target lesions twice daily, while the corresponding bilaterally symmetric lesion was untreated. Group 2 was treated twice daily with hydrocortisone cream 1.0% to a single target lesion and hydrocortisone cream 1.0% plus hydrogel to the bilaterally symmetric target lesion. Lesions of moderate severity were separated into groups 3, 4, and 5. Group 3 was treated twice daily with tacrolimus ointment

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Figure 2 Assignment of patients to treatment groups.

0.1% to one target lesion and tacrolimus ointment 0.1% plus hydrogel to the bilaterally symmetric target lesion. Group 4 was treated twice daily with triamcinolone cream 0.1% to a single target lesion and triamcinolone cream 0.1% plus hydrogel to the bilaterally symmetric target lesion. Similarly, group 5 was treated twice daily with calcipotriene cream 0.005% to a single target lesion and calcipotriene cream 0.005% plus hydrogel to the bilaterally symmetric target lesion. Corresponding bilaterally symmetric severe lesions were treated twice daily with a combination of halobetasol propionate cream 0.05% and calcipotriene cream 0.005% or the combination halobetasol propionate cream 0.05% and calcipotriene cream 0.005% plus hydrogel (group 6). Application of study medications and hydrogel dressings was done twice daily for eight weeks regardless of disease improvement. For psoriasis other than target lesions, patients were allowed to continue topical regimens instituted prior to study participation. Patients were evaluated at screening, baseline (day 0), and during treatment at weeks 2, 4, 6, and 8. At each visit, target lesions were photographed and assigned a modified PASI score by an unblinded investigator for each of the two target lesions. Patient satisfaction was determined via a brief voluntary questionnaire completed during the final visit. Safety was assessed based on the incidence of observed or elicited adverse events. The primary endpoint was a modified PASI score as described above for each target lesion at baseline (day 0), and weeks 2, 4, 6, and 8. Secondary

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endpoints were individual scores for erythema, induration, and scaling using a 5-point scale (0–4). A series of t-tests were performed within the six different treatment groups, comparing outcome variables with and without occlusive dressing. Statistical significance was based on resulting two-sided p-values of 0.05 or less. Last observation carried forward was used to impute missing data. Analyses were conducted on an intent-to-treat population (all subjects enrolled and receiving the occlusive dressing). Analyses on the per-protocol (PP) population were considered supportive of the ITT analyses. Subject data was included in PP analyses if they completed the eight-week evaluation without any noteworthy study protocol violations. A total of 131 patients were enrolled in the study and received at least one dose of study medication. Twenty-seven patients discontinued prematurely from the study. The most common reasons for early discontinuation were subject request (n = 12), lost to follow-up (n = 11), and adverse events (n = 4). The demographic and baseline characteristics between all treatment groups were statistically similar with respect to gender, race, and age. Baseline disease characteristics were statistically similar within mild, moderate, and severe treatment groups with respect to study outcomes. For all six treatment groups, the total modified PASI scores were significantly improved in the occluded arm when compared to the nonoccluded arm at the end of the treatment (Fig. 3). A statistically superior benefit was observed as early as week 2 (the first visit after baseline) and this benefit was maintained through the end of the treatment. Of the individual PASI components, induration and scaling, but not erythema, demonstrated statistically significant differences in favor of the occluded arm for all treatment groups. The ITT and PP populations led to similar conclusions concerning efficacy of the occluded arm compared to the nonoccluded arm (Fig. 4). The most common adverse events related to use of the hydrogel dressing were application site irritation, purpura, and pruritus (3.0%, 2.3%, and 1.5%, respectively). Application site irritation warranted discontinuation from the study in three cases (one subject in the triamcinolone group and two in the calcipotriene group). The final subject who was discontinued from the study following an adverse event was involved in a bicycle accident, judged to be unrelated to the study medication, in which the subject sustained a fractured humerus preventing dressing application. The single serious adverse event was a lacerated finger determined by the investigator to be unrelated to the study medication. Although the therapeutic mechanism of occlusion is not completely understood, it has been shown to restore defective barrier function and to normalize the epidermal calcium gradient in psoriatic plaques (25). Studies have demonstrated that occlusion also decreases epidermal mitotic activity in psoriatic plaques (26,27) and increases hydration of the stratum corneum thereby facilitating desquamation, preventing parakeratosis (28,29), and restoring the granular cell layer (26). Clinical studies have demonstrated the effectiveness of occlusion in the treatment of psoriasis (12–24); however, almost all of these studies have focused on the

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Figure 3 Groups 1 to 6 total PASI scores (intent-to-treat subjects).∗ p-Values calculated from a paired t-test with comparison between occluded mean and nonoccluded mean by visit. Last observation carried forward was used to impute missing scores.

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(B) Figure 4 Clinical treatment response. (A) Calcipotriene and halobetasol propionate with and without occlusion, both pre- and posttreatment. (B) Hydrogel/tacrolimus 0.1% ointment vs. tacrolimus 0.1% ointment alone.

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hydrocolloid dressing as an occlusion device. In clinical practice, adhesive tapes and plastic wraps are cumbersome to use while hydrocolloid dressings are limited by their high retail cost. An inexpensive, easy-to-use hydrogel dressing specifically designed for occlusion was developed to address these shortcomings. The results of this study demonstrate that this occlusive hydrogel dressing significantly enhances the efficacy of topical agents in plaque psoriasis. When interpreting these results, the reader should be aware of two limitations to this study. Most notably, this is an open-label study in which neither the patient nor the investigators were blinded to the use of occlusive hydrogel dressing. Visible skin changes cannot be masked by removing the dressing prior to study visits and a “placebo” dressing would have confounded study results. As a result, the PASI score assessment was performed in a nonblinded fashion. Furthermore, this study did not evaluate the relapse rate or the possible rebound of psoriasis at the end of eight weeks. However, there is some evidence in the existing literature to suggest that the relapse rate is similar, if not less common, with occlusion. In two studies examining the occlusion of topical clobetasol lotion with hydrocolloid dressings, one demonstrated a reduction in the relapse rate of psoriasis if the treatment was carried out to complete clinical and histologic remission (17), while the other study showed similar relapse rate (14). Most importantly, neither study showed any rebound of psoriasis. Nonetheless, this study is important for several reasons. First, a dressing containing hydrogel with much higher water content than that of traditional hydrocolloid has rarely been studied for occlusion of topical therapy. It is the high water content that allows hydrogel to be hydrating to the skin and can improve absorption of other topical agents secondary to this hydrating effect. Second, all previous clinical studies with occlusive use of hydrocolloid dressings have only focused on corticosteroids as the agent under occlusion. Third, the efficacy of combination therapy with halobetasol and calcipotriene under occlusion has not been extensively studied. This study demonstrates that hydrogel dressing occlusion can enhance the clinical efficacy of a range of topical steroids, tacrolimus, as well as combination halobetasol and calcipotriene, in the treatment of psoriasis. The impermeable urethane backing of hydrogel gives it a far superior advantage to other traditional occlusive wraps that are permeable to the agent they are trying to enhance. Similar to hydrocolloid dressings, the use of the hydrogel dressing was also effective as a monotherapy, without the addition of topical agents. Statistically significant differences were observed in all groups as early as the second week of treatment and sustained through week 8 of the study. The incidence of adverse events in this study is similar to the rates cited by other studies involving hydrocolloid dressing. It has been suggested that corticosteroids under occlusion are potentially more atrophogenic than corticosteroids without occlusion (30). In this study, no local adverse events such as skin atrophy, telangiectasias, or striae associated with the use of topical corticosteroids under hydrogel occlusion were observed. Nonetheless, it is very important to monitor patients closely for signs of skin atrophy and other cutaneous side effects when

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topical corticosteroids are used under occlusion. Rare localized irritation with the hydrogel dressing was seen most often in conjunction with calcipotriene, a medication that is known to have a higher incidence of irritation than topical corticosteroids (31). Finally, although the Koebner phenomenon has been observed with the use of hydrocolloid dressings, it was not observed in this study (20,23,24). The ability of the hydrogel dressing to enhance the efficacy of topical medications may have a wide range of applications. Moreover, the dressing may act as a physical barrier to discourage patients from excoriating skin lesions. Other skin conditions such as lichen simplex chronicus or prurigo nodularis are logical candidates. Future possibilities include infusing the hydrogel dressing with topical agents to further simplify therapy and encourage compliance. Recently, hydrogel was approved by the FDA as a device for the treatment of psoriasis alone. Its use to enhance other topical therapies is considered “off label” at this time. Hydrogel is anticipated to be available in one and a half to two years and will be marketed R under the name Envela . In summary, this study demonstrates that the hydrogel dressing can be safely used as a monotherapy and as an occlusive device to enhance the efficacy of topical medications including calcipotriene in the treatment of psoriasis. Further studies should be undertaken to examine the effect of hydrogel dressing occlusion on the relapse rate of psoriasis and its use in other dermatoses.

CONCLUSIONS Psoriasis is a chronic disease that requires long-term treatment. However, only 60% of patients are compliant with their therapy (32). There are several reasons why psoriasis patients are not compliant with their treatments. These reasons include treatment not working as well as expected, treatment may be too toxic, inconvenience of use, or association with rapid disease relapse (33). The new topical treatment options discussed in this chapter will hopefully improve patient compliance and patient satisfaction. Lastly, the development of hydrogel patches for use in occlusive enhancement of topical therapies of psoriasis may increase the efficacy of all topical agents.

REFERENCES 1. van de Kerkhof PC, Steegers-Theunissen RP, Kuipers MV. Evaluation of topical drug treatment in psoriasis. Dermatology 1998; 197:31–36. 2. Jemec GB, Ganslandt C, Ortonne JP, et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: A randomized, double-blind, controlled trial. J Am Acad Dermatol 2008; 59(3):455–463. 3. van de Kerkhof PC, de Hoop D, de Korte J, et al. Scalp psoriasis, clinical presentations and therapeutic management. Dermatology 1998; 197:326–334.

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4. Warner Chilcott. Taclonex scalp (calcipotriene 0.005% and betamethasone dipropionate 0.064%) pamphlet insert, May 2008. 5. Al Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psoriasis treatment. J Am Acad Dermatol 2000; 42:796–802. 6. Galderma. Clobex spray (clobetasol propionate 0.05%) pamphlet insert, September 2006. 7. Data on file, Galderma Laboratories, L.P. 8. Koo JYM, Menter A, Feldman SR, et al. The COBRA Trial: A large-scale communitybased trial on moderate and severe psoriasis. Cutis 2007; 80(suppl 5):3–40. 9. Connetics Corporation. Clobetasol propionate (foam) prescribing information. Palo Alto, CA: Connetics Corporation, January 2003. 10. Stoughton RB, Wullich K. Relation of application time to bioactivity of a potent topical glucocorticoid formulation. J Am Acad Dermatol 1990; 22:1038–1041. 11. Reygagne P, Mrowietz U, Decroix J, et al. Clobetasol propionate shampoo 0.05% and calcipotriol solution 0.005%: A randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatol Treat 2005; 16:31–36. 12. Shore RN. Clearing of psoriatic lesions after the application of tape. N Engl J Med 1985; 312:246. 13. Shore RN. Treatment of psoriasis with prolonged application of tape. J Am Acad Dermatol 1986; 15:540–542. 14. Volden G, Kragballe K, van De Kerkhof PC, et al. Remission and relapse of chronic plaque psoriasis treated once a week with clobetasol propionate occluded with a hydrocolloid dressing versus twice daily treatment with clobetasol propionate alone. J Dermatolog Treat 2001; 12:141–144. 15. van de Kerkhof PC, Chang A, van der Walle HB, et al. Weekly treatment of psoriasis with a hydrocolloid dressing in combination with triamcinolone acetonide. A controlled comparative study. Acta dermato-venereologica 1994; 74:143–146. 16. van Vlijmen-Willems IM, Chang A, Boezeman JB, et al. The immunohistochemical effect of a hydrocolloid occlusive dressing (DuoDERM E) in psoriasis vulgaris. Dermatology (Basel, Switzerland) 1993; 187:257–262. 17. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta dermato-venereologica 1992; 72:69–71. 18. Kragballe K, Larsen FG. A hydrocolloid occlusive dressing plus triamcinolone acetonide cream is superior to clobetasol cream in palmo-plantar pustulosis. Acta dermatovenereologica 1991; 71:540–542. 19. Wilkinson RD, Ohayon M. Therapeutic response to a dermatologic patch and betamethasone valerate 0.1 percent cream in the management of chronic plaques in psoriasis. Cutis 1990; 45:468–470. 20. Gottlieb AB, Staiano-Coico L, Cohen SR, et al. Occlusive hydrocolloid dressings decrease keratinocyte population growth fraction and clinical scale and skin thickness in active psoriatic plaques. J Dermatol Sci 1990; 1:93–96. 21. A trial of the Actiderm dermatological patch and topical corticosteroids in the treatment of psoriasis vulgaris. The Actiderm Multi-Center Study Group. Cutis 1990; 46:84–88. 22. Juhlin L. Treatment of psoriasis and other dermatoses with a single application of a corticosteroid left under a hydrocolloid occlusive dressing for one week. Acta dermatovenereologica 1989; 69:355–357. 23. David M, Lowe NJ. Psoriasis therapy: Comparative studies with a hydrocolloid dressing, plastic film occlusion, and triamcinolone acetonide cream. J Am Acad Dermatol 1989; 21:511–514.

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24. Friedman SJ. Management of psoriasis vulgaris with a hydrocolloid occlusive dressing. Arch Dermatol 1987; 123:1046–1052. 25. Hwang SM, Ahn SK, Menon GK, et al. Basis of occlusive therapy in psoriasis: Correcting defects in permeability barrier and calcium gradient. Int J Dermatol 2001; 40:223–231. 26. Fry L, Almeyda J, McMinn RM. Effect of plastic occlusive dressings on psoriatic epidermis. Br J Dermatol 1970; 82:458–462. 27. Fisher LB, Maibach HI. Physical occlusion controlling epidermal mitosis. J Invest Dermatol 1972; 59:106–108. 28. Rovee DT, Kurowsky CA, Labun J. Local wound environment and epidermal healing. Mitotic response. Arch Dermatol 1972; 106:330–334. 29. Van Scott EJ, Yu RJ. Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids. J Am Acad Dermatol 1984; 11:867–879. 30. Prawer SE, Katz HI. Guidelines for using superpotent topical steroids. Am Fam Physician 1990; 41:1531–1538. 31. Bruner CR, Feldman SR, Ventrapragada M, et al. A systematic review of adverse effects associated with topical treatments for psoriasis. Dermatol Online J 2003; 9:2. 32. Zaghloul SS, Good?eld JJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 2004; 140(4):408–414. 33. Krueger G, Koo J, Lebwohl M, et al. The impact of psoriasis on quality of life: Results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol 2001; 137(3):280–284.

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14 Palmoplantar Psoriasis Eliana Krulig Evanston Northwestern Healthcare, Skokie, Illinois, U.S.A.

Kenneth B. Gordon Evanston Northwestern Healthcare and Northwestern University, Feinberg School of Medicine, Skokie, Illinois, U.S.A.

INTRODUCTION While patients with limited psoriasis usually suffer from a significant disease burden, those with involvement of the palms of the hands and soles of the feet, i.e., palmoplantar psoriasis, can be disabled to an even greater extent. Both cosmetically and physically, these patients have been shown to bear a greater burden of disease (1). Although the palms and soles represent only 4% of the total body surface area, the presence of psoriasis plaques with fissures and/or pustules in these areas can be painful, debilitating, and socially stigmatizing. These plaques can greatly interfere with a patient’s daily activities by impairing dexterity and mobility. Moreover, their location makes it difficult to avoid trauma and irritation, therefore preventing or delaying their successful healing. A publication by a task force of the American Academy of Dermatology specifically pointed out that disease limited to the palms and soles could be severe even though the total body surface area involved may be small (2). Surprisingly, with potential for such extensive disability associated with palmoplantar psoriasis, there has been remarkably little study into the incidence of this condition and even less investigation into its potential treatment. Psoriasis affects 1% to 3% of the population (3), but the pattern and incidence of the palmoplantar disease is still unclear. In a study of 3065 psoriatic patients in India, 17% had palm and/or sole involvement. From this group, 92% had plantar lesions and 56% 183

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palmar lesions. A possible role of occupational trauma/Koebner phenomena is suggested primarily because palmar lesions were predominantly in areas exposed to pressure. Furthermore, although it is usually a bilateral disease, it was noted that all patients with unilateral palmar lesions had them on their dominant hand, and these patients were involved in regular manual labor, supporting the hypothesis of the Koebner phenomena (4). In spite of the fact that in the past, some studies suggested that these lesions were not related to dermatophyte infection or contact sensitivity (5), a recent study reported statistically significant difference in the frequency of positive patch tests between a group of psoriasis patients with palmoplantar disease and patients without palm and sole involvement (6). Although this study has limited statistical power, other authors also report cases that exhibit an association between patch testing and palmoplantar pustulosis (7,8). One of the challenges in treating palmoplantar psoriasis is distinguishing it from other diseases that may affect the hands and feet. Palmoplantar psoriasis may appear as typical erythematous scaling plaques on the hands and feet similar to plaques elsewhere on the body, or the skin may develop a localized thickening and scaling (keratoderma). This thickened skin can develop deep fissures that are quite painful and can interfere with patients’ ability to walk or use their hands. The plaques are usually sharply demarcated with clinical apparent disease on the hands ending near wrist flexures and with involvement of the finger pads but only rarely involving the lateral aspects of the fingers. In most patients the disease is symmetrical. Nail pitting with normal-appearing paronychial skin is a classic finding. In addition, patients frequently have sterile pustules of the palms and soles and, unlike generalized pustular psoriasis, these deep-seated vesicles are chronic with the condition often lasting for years. The differential diagnosis of palmoplantar psoriasis is extensive and listed in Table 1. Most commonly, erythematous, hyperkeratotic conditions like chronic hand or foot dermatitis may be confused with palmoplantar disease. If this is the case, allergic contact dermatitis may be the underlying cause of the inflammatory condition. Notably, inflammatory fungal infection is an important aspect of the differential diagnosis of plantar disease. A potassium hydroxide preparation or Table 1 Differential Diagnosis of Palmoplantar Psoriasis Common disorders Chronic hand eczema Contact dermatitis Dermatophyte infection Uncommon disorders Acquired palmoplantar keratoderma Cutaneous T-cell lymphoma Keratoderma blennorrhagicum Pityriasis rubra pilaris Syphilis

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fungal culture can be performed to help distinguishing between a dermatophyte infection and psoriasis. The diagnosis of palmoplantar psoriasis is facilitated by the presence of psoriatic disease elsewhere on the body or by the presence of nail changes. A personal or family history of psoriasis may also be helpful. However, in isolation, it can be more difficult to differentiate from other mimickers. Though diagnosis of palmoplantar psoriasis is generally made based on clinical appearance, a skin biopsy may be helpful. The histologic appearance of palmoplantar psoriasis may be similar to typical psoriatic lesions but may have an increased number of neutrophilic pustules in the epidermis. A recent study that evaluated biopsies from either palmoplantar psoriasis or eczematous dermatitis patients concluded that many histologic features from those conditions tend to overlap. Blinded to the clinical diagnosis, investigators more specifically suggested that the detection of multiple parakeratotic foci, placed vertically, alternating with orthohyperkeratosis, could be considered in favor of palmoplantar psoriasis (9). All potential clues may be necessary in making the appropriate diagnosis, allowing for effective therapy of the patient’s condition. One condition in the differential diagnosis deserves special mention: palmoplantar pustulosis (PPP), including acrodermatitis continua of Hallopeau. This disease can appear clinically identical to palmoplantar psoriasis and is often categorized as a subset of the latter. PPP is strongly associated with cigarette smoking and autoimmune thyroid disease (10) and contrary to palmoplantar psoriasis, is rarely associated with koebnerization (11). While there is significant clinical and histologic similarity between the two conditions, current studies have found differences in the genetic susceptibility for each of them. PPP, for example, is not associated with high-risk loci of the psoriasis susceptibility 1 (PSORS1) locus in the major histocompatibility complex (MHC) locus of the genome. Moreover, it may respond differently to treatment (12). Thus, data concerning the treatment of palmoplantar psoriasis may not be applicable to PPP, and vice versa. TREATMENT As mentioned above, patients with palmoplantar psoriasis may have disease limited in extent but severe in its impact on their daily lives. Most studies of therapy for psoriasis have been concentrated on the most common form of the disease, chronic plaque type. Studies of topical therapy, phototherapy, and systemic therapy for palmoplantar psoriasis are often performed after the primary investigations of specific treatments for plaque psoriasis. These studies may not be well-designed placebo-controlled trials and are fraught with other potential confounding factors. For example, given the difficulty in distinguishing palmoplantar psoriasis from other conditions, the lack of solid diagnostic criteria hinders the selection of a consistent study population. Even more frustrating is that in studies of plaque psoriasis, data specific to palmoplantar disease is rarely captured. Thus, we are left with scattered studies and case reports to identify potential treatments that could have a great impact on patient welfare. We will classify the treatment of

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palmoplantar psoriasis into three basic categories: topical therapy, phototherapy, and systemic therapy. Many of these therapeutic regimes can be combined to achieve synergistic effects. Topical Therapy Protective Measures The most seemingly obvious intervention that can be of benefit for patients who suffer from palmoplantar psoriasis is shielding the lesions from harmful physical factors that can worsen the disease. Palmoplantar psoriasis patients have altered barrier function and may suffer from the Koebner phenomenon and, therefore, are at particular risk of aggravating their disease from trauma and exposure to noxious agents. Patients can benefit greatly from the instruction in avoiding irritation to their hands and feet. It is important that they avoid harsh cleansers and contact with chemicals and solvents as well as fruit and vegetable juices. These patients need to protect their hands from repeated wetting and drying by wearing protective gloves during activities such as washing dishes. Avoiding trauma during manual labor can also be of benefit. When doing ordinary daily housework, the avoidance of skin irritation can be partially accomplished by using protective cotton gloves. These simple instructions that can be discussed in just a few minutes during an office visit may have a significant impact on the efficacy of therapy for this disease. Emollients Another benign therapy that should always be included in a general plan for the treatment of palmoplantar psoriasis is proper lubrication of the skin. The use of emollients may help to maintain the barrier function of the skin, reduce the amount of fissuring in the palms and soles, and have a great impact on patient comfort. Applying oil or ointment-based preparations, such as petrolatum, frequently to the hands may help maintain barrier function. This therapeutic intervention, however, is often found to be difficult for patients who may find using greasy substances to the hands and feet an impediment to work or cosmetically unacceptable. In these cases, the use of other emollients can be attempted, but patients must be careful to avoid products with additives that may aggravate their condition. As a rule of thumb, compliance with the use of a suboptimal agent is likely superior to noncompliance with a more effective treatment. Topical Corticosteroids Similar to most other forms of psoriasis, topical corticosteroids are the mainstay of treatment. However, treatment of the palms and soles with these topical agents is complicated by a number of factors. As mentioned above, the application of topical substances to these areas is both an inconvenience in those who work with their hands or must use their feet consistently; that is everyone. Moreover, the thickness of the stratum corneum and the epidermis on the palms and soles inhibits the penetration of topical agents. In particular, agents that impact the dermal immune

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process may not be delivered to the appropriate layers of the skin in a sufficient amount to have significant impact on the disease. For this reason, treatment with more potent corticosteroids, occlusion, and combination with agents that induce exfoliation of the stratum corneum can be used (13). The thickness of the skin in the palms and soles allows for class I and class II high-potency corticosteroids to be used without fear of cutaneous atrophy in these areas. Moreover, these medications can be continued for a greater length of time than in other regions of the skin where there is lesser thickness of the epidermis. Importantly, care must be taken to ensure that skin other than the palms and soles, especially the dorsal hands and finger tips, is not treated, as this skin will be at risk of thinning. To increase efficacy of topical corticosteroids, nighttime occlusion or keratolytic agents are often employed (6). Occlusion can be accomplished through the use of plastics including gloves or wraps. Care should be taken to avoid contact allergy to these barriers, which can complicate the potential benefit of their use (14,15). Occlusion will increase the potency of the topical steroid by approximately 10-fold, and the occlusion itself will aid in the resolution of the psoriatic plaques. Because of the increased potency of topical medication when adding occlusive techniques, the use of class I corticosteroids is usually not recommended and patients should be carefully monitored for evidence of local side effects including skin atrophy (add Gomez vazquez and Vickers). The addition of keratolytic agents such as salicylic acid, urea, or lactic acid can reduce the hyperkeratosis associated with palmoplantar psoriasis and increase the penetration of the corticosteroid agents. A short clinical trial with 105 subjects with localized hyperkeratosis demonstrated that after 21 days of applying a cream gel with 30% urea, 2% salicylic acid, and 1% of lactic acid to the affected areas, in comparison to its vehicle, there was great improvement in hyperkeratosis, desquamation, and dryness/roughness (16). Topical Vitamin D Derivatives (Calcipotriene/Calcipotriol) Other topical agents in use for plaque psoriasis may also have a role in palmoplantar disease, but good quality data on their efficacy are not readily available. Calcipotriene has been reported to have some efficacy in a number of case reports and uncontrolled series in the literature (17). Nonetheless, there have been no reported placebo-controlled trials. In one randomized trial, calcipotriol used twice weekly under occlusion was compared to twice daily application in a six-week period (18). In this small study, occlusive therapy was equivalent to twice daily treatment (26% and 25% improvement in clinical score, respectively), potentially allowing for a tolerable protocol for the use of occlusive therapy for this disease. In a report from a large psoriasis treatment center in the United States, patients with palmoplantar psoriasis treated with topical vitamin D derivatives are almost always treated in combination with topical corticosteroids (19). Topical Retinoids Systemic retinoids have been used for the treatment of palmoplantar psoriasis for many years (see later). Thus, it has been assumed that application of antipsoriatic

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topical retinoids would also be beneficial. However, very little information is available in the literature about the use of topical retinoids in this condition. One patient with keratoderma blennorrhagicum, a condition with some clinical similarities to psoriasis, has been reported with a good response (20). Additionally, one large center has reported the use of topical tazarotene with qualitatively good responses when used in combination with topical corticosteroids, although no objective responses rates are reported (19). Clearly, further investigation is warranted. Topical Methotrexate Topical 0.25% methotrexate gel was shown not to be statistically significantly effective for palmoplantar psoriasis (21). In a 14-patient trial, there was an average of 40% improvement in the palms and 29% improvement in the soles of treated subjects. Unfortunately, it is not clear whether this trial was sufficiently powered to demonstrate therapeutic effects. One percent methotrexate gel in propylene glycol, used twice a day, was shown to give at least 50% improvement in 80% of palmar and 64% plantar psoriasis in a small series of 15 patients. This preparation is not readily available but could be of potential therapeutic benefit. Phototherapy Ultraviolet B Therapy (UVB) UVB phototherapy has been a standard therapy for psoriasis for decades. More recently, narrow-band UVB (NB-UVB) treatment has come into common usage. Like other treatments for palmoplantar psoriasis, data on its effectiveness is limited. In one open-label prospective study of NB-UVB therapy, 9 of 11 patients with refractory palmoplantar psoriasis responded to hand–foot UVB treatment. Additionally, one of the three patients with palmar plantar pustulosis had a good response to treatment (22). Though additional studies are unavailable, clinical experience suggests that NB-UVB is potentially a reasonable early intervention in the treatment of palmoplantar psoriasis. Topical Psoralen and Ultraviolet A (Topical PUVA) One of the unique aspects of treating palmoplantar psoriasis with phototherapy is the potential to apply the photosensitizing agent, methoxypsoralen, directly to the affected area without requiring systemic exposure to the drug. This can be applied as a cream or solution of psoralen or by soaking the affected area in a solution of the medication. This therapy avoids many of the complications and side effects associated with oral 8-methoxypsoralen (8-MOP). Topical PUVA therapy has probably been the most widely studied treatment for palmoplantar psoriasis and it has been demonstrated to be of great efficacy in treating patients for whom topical treatment has been unsuccessful. Both prospective and retrospective analyses of topical PUVA therapy have suggested efficacy of this modality (23–30). A great majority of patients had clinical improvement, with 40% to 63% of patients having clearing of their disease. The method of delivery

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of the photosensitizing agent in soak or cream form has been debated as well. In a study comparing bath and cream preparations of psoralen in a small number of patients, response rates were similar. Thus, topical PUVA seems to be an effective modality for patients with palmoplantar psoriasis. Directed Phototherapy Treatment of palmoplantar psoriasis with directed phototherapy, both of the laser and nonlaser varieties, has been reported. The 308-nm excimer laser has been suggested as an alternative to traditional phototherapy (31–33). This therapy can be administered with or without the addition of systemic retinoids. A pilot study demonstrated efficacy of a nonlaser 308-nm light source in palmar plantar pustulosis in a very limited number of patients (34). Another option in this class is the use of 5-aminolaevulinic acid photodynamic therapy. Case reports showed mild to marked improvement in PPP patients (35,36) but, like all aspects of palmoplantar psoriasis, further study is necessary to confirm the effectiveness of this therapeutic protocol. Systemic Therapy Systemic therapy for palmoplantar psoriasis can be used in patients who have severe disability at presentation or added to the regimen of those who have failed topical therapy. Retinoids Systemic retinoids have long been a staple of treatment for refractory palmoplantar disease. Much of the literature regarding retinoid use for this indication is with etretinate—a chemical precursor of the more readily available acitretin. A number of trials have demonstrated that etretinate as monotherapy has some efficacy when treating palmoplantar disease (37–39). This effect is significantly improved with the addition of photochemotherapy, a protocol that has been studied in controlled trials (40–42). Oral retinoids, with or without phototherapy, are frequently the first oral medication chosen for palmoplantar psoriasis (19). Importantly, due to the risks associated with teratogenicity, the FDA recommends that women of childbearing potential should not become pregnant for three years after taking acitretin. It is the opinion of the authors that this concern precludes the use of acitretin in this population. Methotrexate Systemic methotrexate is generally considered to be effective in palmoplantar psoriasis. Unfortunately, there is no significant literature to support this hypothesis. In a retrospective analysis, methotrexate has been reported to be used and effective in one large treatment center (19). The limitation of methotrexate use has been the side-effect profile associated with this medication. Before starting methotrexate,

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patients must be evaluated for baseline normal liver function, renal function, and bone marrow. Cyclosporine A Cyclosporine A (CyA) can be a very effective method for gaining rapid control of psoriatic disease and can be an effective bridge to other longer-term systemic therapies. CyA has been studied in a randomized, placebo-controlled trial with a dose of 2.5 mg/kg/day demonstrating response in 17 out of 19, while only 4 out of 15 patients on placebo showed benefit. Further study showed that doses as low as 0.25 mg/kg/day can be effective (43). Additional prospective analyses have verified the efficacy of CyA (44,45). It has been used effectively in both the United States and Europe (19,46). Systemic toxicities are the limiting factors in the use of CyA. CyA is an immunosuppressor and patients need to be evaluated for Hepatitis B and C, HIV, and TB prior to starting. Additionally, patients need regular monitoring of renal function and blood pressure while taking CyA (44,46). Biologic Therapies Recently, advances have been made regarding biologic therapy and palmoplantar psoriasis with several studies showing promising results. Efalizumab has been the front-runner among the biologics. Several case reports suggest that it may be effective in treating this form of psoriasis (47–49), including a positive therapeutic response experienced by a 14-year-old male (50). One of the most important trials recently completed is a 12-week, phase IV, randomized, double-blind, placebocontrolled study assessing the safety and efficacy of efalizumab for treatment of hand and foot psoriasis; 80 efalizumab-na¨ıve patients were randomized to receive either efalizumab 1 mg/kg/wk SC or placebo. The primary efficacy outcome measure was evaluated at day 84 (week 12) and 46.2% of the efalizumab-treated patients achieved a PGA of clear, almost clear, or mild versus 17.9% of placebotreated patients (51). The incidence of adverse events in patients treated with efalizumab was similar to those treated with placebo, which was consistent with the safety profile observed on previous phase III studies (52). Alefacept (53,54) and etanercept (55,56) have had published case reports suggesting efficacy. Importantly, patients who also suffer from psoriatic arthritis, anti-TNF- biologic therapies such as infliximab, adalimumab, and etanercept have been shown to halt the progression of their disease. For these patients, antiTNF- therapies should be a considered a first-line therapy (57). SUMMARY: A TREATMENT APPROACH FOR THERAPY OF PALMOPLANTAR PSORIASIS Given the limited data available on treating this condition, it is difficult to make evidence-based decisions for the appropriate therapy of palmoplantar psoriasis. Thus, treatment recommendations must be made on the basis of experience as well as the limited information in the literature. In the next section, suggestions are

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Initial presentation of palmoplantar psoraisis

Combination topical therapy with potent corticosteroids with either calcipotriol or tazarotene Insufficient response Phototherapy available

Phototherapy with topical PUVA or NB-UVB

Add acitretin if patient is not woman of child bearing potential

Phototherapy unavailable Male or post menopausal woman

Acitretin

Woman of childbearing potential

Methotrexate or biologic (anti-TNF if psoriatic arthritis is present)

Cyclosporine A

Figure 1 Possible treatment algorithm for palmoplantar psoriasis.

given based on the author’s treatment protocol for palmoplantar psoriasis, which is used in our psoriasis treatment center. This treatment philosophy is outlined in Figure 1. The approach to the patient with exclusively palmoplantar psoriasis is unique in that the disease is, by definition, local and limited. Thus, the use of topical therapies is sometimes more reasonable than in patients with extensive disease. In general, the authors begin with combination topical therapies, usually a potent topical corticosteroid used in combination with calcipotriol or tazarotene. If necessary, occlusion is added to increase efficacy. A treatment trial of at least six to eight weeks is needed for this means of treatment, although it is important to communicate with the patient to try to insure compliance with treatment. If topical therapy is insufficient, and the patient’s disease is still having a significant impact on daily life, the authors usually turn to phototherapy. They believe topical PUVA therapy to be more effective than NB-UVB, but many patients prefer

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the ease of avoiding the photosensitizing agent. They do not use systemic PUVA for localized palmoplantar disease, as application of the 8-MOP to these areas is readily available, and many of the systemic side effects of the oral medication are avoided with topical application. In male patients or postmenopausal females, they will often start acitretin prior to starting NB-UVB in order to maximize benefit. If phototherapy is not available or is inconvenient for the patient, the authors consider systemic treatment. In patients who are male or are female and postmenopausal, our first agent is acitretin. This agent may have significant benefit for palmoplantar disease, particularly of the pustular variety, and is generally well tolerated for extended periods. In women of childbearing potential, we generally prefer a biologic agent or methotrexate. With all medications in this population, special attention needs to be paid to the issue of pregnancy with at least three months off methotrexate and six weeks off a biologic therapy prior to conception. In patients with psoriatic arthritis, we generally prefer an anti-TNF agent. Cyclosporine is generally reserved for patients who have failed alternative therapy or require rapid resolution of their condition.

CONCLUSION Palmoplantar psoriasis can be limited in extent but have devastating impact on patients. Although it is often amenable to topical therapy, it is of great importance for the practitioner to be aware of the diminished quality of life associated with this condition and treat aggressively. Unfortunately, data on the efficacy of the various treatments available for palmoplantar psoriasis is limited and therapeutic decisions often need to be made on the basis of personal experience rather than evidence-based approaches.

REFERENCES 1. Pettey AA, Balkrishnan R, Rapp SR, et al. Patients with palmoplantar psoriasis have more physical disability and discomfort than patients with other forms of psoriasis: Implications for clinical practice. J Am Acad Dermatol 2003; 49(2):271–275. 2. Callen JP, Krueger GG, Lebwohl M, et al. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49(5):897–899. 3. van de Kerkhof PC. Consistent control of psoriasis by continuous long-term therapy: The promise of biological treatments. J Eur Acad Dermatol Venereol 2006; 20:639–650. 4. Kumar B, Saraswat A, Kaur I. Palmoplantar lesions in psoriasis: A study of 3065 patients. Acta Derm Venereol 2002; 82(3):192–195. 5. Fransson J, Storgards K, Hammar H. Palmoplantar lesions in psoriatic patients and their relation to inverse psoriasis, tinea infection and contact allergy. Acta Derm Venereol 1985; 64:218–223. 6. Caca-Biljanovska N, V’lckova-Laskoska M, Balabanova-Stefanova M, et al. Frequency of delayed-type hypersensitivity to contact allergens in palmo-plantar psoriasis. Prilozi 2005; 26(2):131–141.

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7. Ammoury A, El sayed F, Dhaybi R, et al. Palmoplantar pustulosis should not be considered as a variant of psoriasis. J Eur Acad Dermatol Venereol 2008; 22(3):392–393. 8. Yanagi T, Shimizu T, Abe R, et al. Zinc dental fillings and palmoplantar pustulosis. Lancet 2005; 366(9490):1050. 9. Aydin O, Engin B, Oguz O, et al. Non-pustular palmoplantar psoriasis: Is histologic differentiation from eczematous dermatitis possible? J Cutan Pathol 2008; 35(2):169– 173. 10. Eriksson MO, Hagforsen E, Lundin IP, et al. Palmoplantar pustulosis: A clinical and immunohistological study. Br J Dermatol 1998; 138(3):390–398. 11. Yamamoto T, Yokozeki H, Tsuboi R. Koebner’s phenomenon associated with palmoplantar pustulosis. J Eur Acad Dermatol Venereol 2007; 21(7):990–992. 12. Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol 2003; 120(4):627–632. 13. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992; 72(1):69–71. 14. Gomez Vazquez M, Fernandez-Redondo V, Totibio J. Corticosteroid iatrogenesis in a patient with palmoplantar psoriasis. J Eur Acad Dermatol Venereol 2004; 18(3): 370–371. 15. Vickers CF, Fristch WC. A hazard of plastic film therapy. Arch Dermatol 1963; 87:633– 636. 16. Coutanceau C, Carballido F, Le Maitre M. Clinical evaluation of the efficacy and the tolerance of a cream gel with 30% urea, 2% of salicylic acid, and 1% of lactic acid versus vehicle in subjects with localized hyperkeratosis. J Am Acad Dermatol 2008; 58(2):AB129. 17. Thiers BH. The use of topical calcipotriene/calcipotriol in conditions other than plaquetype psoriasis. J Am Acad Dermatol 1997; 37(3, pt 2):S69–S71; 5. 18. Duweb GA, Abuzariba O, Rahim M, et al. Occlusive versus nonocclusive calcipotriol ointment treatment for palmoplantar psoriasis. Int J Tissue React 2001; 23(2): 59–62. 19. Spuls PI, Hadi S, Rivera L, et al. Retrospective analysis of the treatment of psoriasis of the palms and soles. J Dermatolog Treat 2003; 14(suppl 2):21–25. 20. Lewis A, Nigro M, Rosen T. Treatment of keratoderma blennorrhagicum with tazarotene gel 0.1%. J Am Acad Dermatol 2000; 43(2, pt 2):400–402. 21. Kumar B, Sandhu K, Kaur I. Topical 0.25% methotrexate gel in a hydrogel base for palmoplantar psoriasis. J Dermatol 2004; 31(10):798–801. 22. Nordal EJ, Christensen OB. Treatment of chronic hand dermatoses with UVB-TL01. Acta Derm Venereol 2004; 84(4):302–304. 23. Agren-Jonsson S, Tegner E. PUVA therapy for palmoplantar pustulosis. Acta Derm Venereol 1985; 65(6):531–535. 24. Behrens S, von Kobyletzki G, Gruss C, et al. PUVA-bath photochemotherapy (PUVAsoak therapy) of recalcitrant dermatoses of the palms and soles. Photodermatol Photoimmunol Photomed 1999; 15(2):47–51. 25. Davis MD, McEvoy MT, el Azhary RA. Topical psoralen-ultraviolet A therapy for palmoplantar dermatoses: Experience with 35 consecutive patients. Mayo Clin Proc 1998; 73(5):407–411. 26. Grundmann-Kollmann M, Behrens S, Peter RU, et al. Treatment of severe recalcitrant dermatoses of the palms and soles with PUVA-bath versus PUVA-cream therapy. Photodermatol Photoimmunol Photomed 1999; 15(2):87–89.

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27. Hawk JL, Grice PL. The efficacy of localized PUVA therapy for chronic hand and foot dermatoses. Clin Exp Dermatol 1994; 19(6):479–482. 28. Layton AM, Sheehan-Dare R, Cunliffe WJ. A double-blind, placebo-controlled trial of topical PUVA in persistent palmoplantar pustulosis. Br J Dermatol 1991; 124(6):581– 584. 29. Schiener R, Gottlober P, Muller B, et al. PUVA-gel vs. PUVA-bath therapy for severe recalcitrant palmoplantar dermatoses. A randomized, single-blinded prospective study. Photodermatol Photoimmunol Photomed 2005; 21(2):62–67. 30. Taylor CR, Baron ED. Hand and foot PUVA soaks: An audit of the Massachusetts General Hospital’s experience from 1994 to 1998. Photodermatol Photoimmunol Photomed 1999; 15(5):188–192. 31. Gattu S, Rashid RM, Wu JJ. 308-nm excimer laser in psoriasis vulgaris, scalp psoriasis, and palmoplantar psoriasis. J Eur Acad Dermatol Venereol 2008 Aug 19. [Epub ahead of print] 32. Nistico SP, Saraceno R, Stefanescu S, et al. A 308-nm monochromatic excimer light in the treatment of palmoplantar psoriasis. J Eur Acad Dermatol Venereol 2006; 20(5):523–526. 33. Rivard J, Lim HW. The use of 308-nm excimer laser for dermatoses: Experience with 34 patients. J Drugs Dermatol 2006; 5(6):550–554. 34. Aubin F, Vigan M, Puzenat E, et al. Evaluation of a novel 308-nm monochromatic excimer light delivery system in dermatology: A pilot study in different chronic localized dermatoses. Br J Dermatol 2005; 152(1):99–103. 35. Kim JY, Kang HE, Lee ES, et al. Topical 5-aminolaevulinic acid photodynamic therapy for intractable palmoplantar psoriasis. J Dermatol 2007; 34(1):37–40. 36. Kim YC, Lee ES, Chung PS, et al. Recalcitrant palmoplantar pustular psoriasis successfully treated with topical 5-aminolaevulinic acid photodynamic therapy. Clin Exp Dermatol 2005; 30(6):723–724. 37. Thune P. Treatment of palmoplantar pustulosis with Tigason. Dermatologica 1982; 164(1):67–72. 38. White SI, Marks JM, Shuster S. Etretinate in pustular psoriasis of palms and soles. Br J Dermatol 1985; 113(5):581–585. 39. White SI, Puttick L, Marks JM. Low-dose etretinate in the maintenance of remission of palmoplantar pustular psoriasis. Br J Dermatol 1986; 115(5):577–582. 40. Rosen K, Mobacken H, Swanbeck G. PUVA, etretinate, and PUVA-etretinate therapy for pustulosis palmoplantaris. A placebo-controlled comparative trial. Arch Dermatol 1987; 123(7):885–889. 41. Lassus A, Lauharanta J, Eskelinen A. The effect of etretinate compared with different regimens of PUVA in the treatment of persistent palmoplantar pustulosis. Br J Dermatol 1985; 112(4):455–459. 42. Lawrence CM, Marks J, Parker S, et al. A comparison of PUVA-etretinate and PUVAplacebo for palmoplantar pustular psoriasis. Br J Dermatol 1984; 110(2):221–226. 43. Reitamo S, Erkko P, Remitz A, et al. Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study. Arch Dermatol 1993; 129(10):1273–1279. 44. Meinardi MM, de Rie MA, Bos JD. Oral cyclosporin A is effective in clearing persistent pustulosis palmaris et plantaris. Acta Derm Venereol 1990; 70(1):77–79. 45. Peter RU, Farber L, Wei J, et al. Low-dose cyclosporin A in palmoplantar psoriasis: Evaluation of efficacy and safety. J Eur Acad Dermatol Venereol 1994; 3(4):518–524.

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46. Meinardi MM, de Rie MA, Bos JD. Oral cyclosporin A in the treatment of psoriasis: An overview of studies performed in The Netherlands. Br J Dermatol 1990; 122(suppl 36):27–31. 47. Colsman A, Carrascosa JM, Ferrandiz C, et al. Successful treatment of recalcitrant palmoplantar psoriasis with efalizumab. J Eur Acad Dermatol Venereol 2008 Apr 10. [Epub ahead of print] 48. Cohen DJ, Scherschun L. Case reports: Practical experience with efalizumab in hand and foot psoriasis. J Drugs Dermatol 2007 6(12):1224–1230. 49. Fretzin S, Crowley J, Jones L, et al. Successful treatment of hand and foot psoriasis with efalizumab therapy. J Drugs Dermatol 2006; 5(9):838–846. 50. Conroy E. Positive therapeutic response to efalizumab by a pediatric patient with hand and foot psoriasis. J Am Acad Dermatol 2008; 58(2):AB130. 51. Leonardi C, Sobell J, Sofen H, et al. Phase IV study to evaluate the safety and efficacy of efalizumab for treatment of hand and foot psoriasis. J Am Acad Dermatol 2007; 56(2):AB48. 52. Papp KA, Bressinck R, Fretzin S, et al. Safety of efalizumab in adults with chronic moderate-to-severe plaque psoriasis: A phase IIIb, randomized, controlled trial. Int J Dermatol 2006; 45(5):605–614. 53. Myers W, Christiansen L, Gottlieb AB. Treatment of palmoplantar psoriasis with intramuscular alefacept. J Am Acad Dermatol 2005; 53(2)(suppl):s127–s129. 54. Prossick TA, Belsito DV. Alefacept in the treatment of recalcitrant palmoplantar and erythrodermic psoriasis. Cutis 2006; 78(3):178–180. 55. Weinberg JM. Successful treatment of recalcitrant palmoplantar psoriasis with etanercept. Cutis 2003; 72(5):396–398. 56. Ahmad K, Rogers S. Two years of experience with etanercept in recalcitrant psoriasis. Br J Dermatol 2007; 156(5):1010–1014. Epub 2007 May 4. 57. Mease PJ. Recent advances in the management of psoriatic arthritis. Curr Opin Rheumatol 2004; 16(4):366–370.

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15 Scalp Psoriasis Peter C. M. van de Kerkhof, Marloes M. Kleinpenning, and Rianne M. J. P. Gerritsen Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands

INTRODUCTION Psoriasis has the scalp as one of its predilection sites. Scalp psoriasis may seriously impair the quality of life. After a presentation of the epidemiologic aspects, clinical morphology, and differential diagnosis of scalp psoriasis, various classes of treatments will be presented. EPIDEMIOLOGY Involvement of the scalp is the most frequent manifestations of psoriasis. Indeed, 79% of Dutch patients with psoriasis indicated that the scalp was the most frequently affected area (1). In many patients psoriasis of the scalp is a major problem, in fact, 31% of patients with scalp psoriasis indicated that the condition is distressing (2). A questionnaire mailed to 6000 members of the Dutch Psoriasis Association revealed that in 57% of them scalp involvement is an important psychologic handicap (3). In fact, scalp psoriasis had existed for more than five years in 81% of the patients and in 48% of them, psoriasis covered more than half of the scalp. Visibility of the lesions and itch were the most annoying symptoms in 34% and 26%, respectively, of patients with scalp psoriasis.

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CLINICAL MORPHOLOGY The classical picture of scalp psoriasis is sharply demarcated erythematous plaques with white-silvery scales. The scales extend as sleaves around the hair, which picture is also described as “pseudoteigne amiantac´ee.” The lesions often expand onto the face, in particular in the hairline area. But also involvement of the retroauricular fold is often seen. Figure 1 illustrates the classical manifestations of scalp psoriasis. Scalp psoriasis may itch in most patients in some episodes at least. It is the traditional view that scalp psoriasis is not characterized by hair loss and not by atrophy of the skin. However, it has been shown that the number of telogen hair in trichograms of plucks of hair is increased (4). Scanning electron microscopy has revealed that hair of psoriatic patients show cuticular breakage and an abraded cuticular surface (5). Furthermore it is borne out of clinical praxis that long-lasting psoriatic plaques may cause alopecia cicatricialis (6–8). As scalp psoriasis may result in irreversible hair loss, it is important to convince the patient that active treatment is important not only for the immediate improvement of the condition but also for the long-term appearance of the patient.

Figure 1 Classical manifestations of scalp psoriasis. (A) Psoriasis of the scalp. (B) Scarring psoriatic alopecia. (C) Hairline psoriasis.

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DIFFERENTIAL DIAGNOSIS Scaling of the scalp may provide a challenge to the physician for adequate diagnosis and treatment. Classic psoriatic plaques elsewhere or classic manifestations of seborrheic dermatitis, lupus erythematosus, or lichen planopilaris may help the diagnosis. Therefore, inspection of the entire skin is important. The scalp lesions of psoriasis may strongly resemble seborrheic dermatitis, which is also a papulosquamous condition, however, with more yellow scalescrusts and preferential localization on upper trunk, face, and flexures. Fungal lesions may strongly resemble scalp psoriasis. Broken hair, pustulation, and prominent atrophy may increase suspicion that a fungus is involved. Lichen planus is characterized by violaceous papules in follicular arrangement resulting in atrophy. Lupus erythematodes is also characterized by atrophy and follicular hyperkeratoses. A group of 85 patients with scaling of the scalp (“pityriasis amiantacea”) were examined clinically, underwent histologic, bacteriologic, and mycological examinations (9). Psoriasis was confirmed in only 35.3% of cases. In 34.2% of them the diagnosis was seborrheic dermatitis or atopic dermatitis. In 12.9%, the diagnosis of tinea capitis was confirmed by potassium hydroxide preparation, fungal culture, and periodic-acid Schiff staining. Overgrowth of staphylococcus isolates was evident in 96.5% of the patients. In another study, patients who had been diagnosed as having scalp psoriasis proved to show colonization with malassezia species (10). M. globosa, M. slooffiae, and M. restricta were predominant species in 55%, 18%, and 10% of the patients. Therefore, in case of pityriasis amiantacea the differential diagnosis is broad, and in case the clinical picture is not conclusive, histologic examination and cultures may be indicated (11). In psoriasis of the scalp, overgrowth of malassezia species remains an important feature, which may be of therapeutic relevance.

GENERAL THERAPEUTIC ASPECTS A questionnaire mailed to patients of the Dutch society for Psoriasis (n = 922 responders) (3) revealed that 99.6% of patients used a topical corticosteroid for scalp psoriasis. For shampoos were used by 51% and calcipotriol treatment by 28% of the patients responding to the questionnaire. The majority of these patients used the treatment for prolonged periods of time; 72% of them had indicated that they had used treatments for more than eight weeks. Of particular importance is that the patients indicated that the formulation allowing a cosmetically acceptable treatment is of utmost importance. Although involvement of the scalp with psoriasis is frequent and the impairment of quality of life is important, few evidence-based data on treatment of scalp psoriasis are available.

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Table 1 Actual Frequency of Use of Various Treatments in Scalp Psoriasis (n = 922 patients)

Treatment

No. of patients

Corticosteroids Hydrocortisone cream Clobetasone cream Hydrocortisone butyrate cream Hydrocortisone butyrate lotion Hydrocortisone butyrate emulsion Triamcinolone cream Betamethasone valerate cream Betamethasone valerate emulsion Betamethasone valerate lotion Clobetasol cream Clobetasol lotion Betamethasone diproprionate hydrogel Betamethasone diproprionate cream Betamethasone diproprionate lotion Desoximethasone emulsion

13 14 32 16 18 28 65 19 125 106 101 26 37 72 292

Other treatments Calcipotriol ointment Coal tar shampoo UVB phototherapy Salicylic acid Other/unknowna

258 474 119 65 161

a Other/unknown

implies a series of alternative treatment approaches. Abbreviation: UVB, ultraviolet B.

SHAMPOOS Shampoos are used as a vehicle for active treatment principles. Although no doubleblind studies are available on the efficacy of tar shampoos, the usage of tar shampoo is a popular approach under patients suffering from scalp psoriasis. Open studies indicated that shampoos containing 2% to 10% coal tar may be effective in psoriasis (12,13). Some reservation on the usage of coal tar shampoos is justified as the secretion of 10-hydroxy pyrene in urine is increased in patients using tar shampoo, indicating resorption of hydrocarbons through the skin (14). Zinc pyrithion shampoos are well appreciated. But again, no double-blind studies are available to substantiate their efficacy. In open studies, scalp psoriasis proved to respond to zinc pyrithion shampoos in concentrations between 1% and 2% (14–16). More recently, clobetasol propionate shampoo 0.05% was reported to be a new option for the treatment of patients with moderate-to-severe scalp

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psoriasis (17). In a multicenter, randomized, vehicle-controlled, double-masked and parallel-group study, clobetasol propionate shampoo was compared against the corresponding vehicle shampoo in patients with moderate-to-severe scalp psoriasis during a four-week treatment. A total of 143 patients were treated. Clobetasol shampoo was significantly more effective as compared to the vehicle shampoo with the same safety profile. Clobetasol propionate 0.05% shampoo was compared with a 1% tar shampoo in 162 patients with scalp psoriasis. In this multicenter, randomized study, clobetasol propionate shampoo was more effective (18). In another comparative study in 151 patients, clobetasol shampoo was more effective as compared to 0.005% calcipotriol solution over a four-week period (19). DESCALING OF THE SCALP Debridement of the scalp by an automatized shampooing and debridement machine has been shown to empower markedly the response to antipsoriatic treatments (20). Salicylic acid 5% to 10% has been shown to have a marked keratolytic effect. Salicylic acid is formulated in an ointment, which can be washed off easily. Application of salicylic acid ointments is done for a few days, before active treatment principles are used. An alternative for salicylic acid is urea that can be used in concentrations of up to 40% (21). COAL TAR AND DITHRANOL Coal tar may be indicated for itchy psoriasis. However, the unpleasant smell of coal tar is a limitation. Coal tar solution (5–20%) can be formulated in a lotion or added to a topical corticosteroid preparation. Dithranol is another time-honored principle. Dithranol 0.1% to 3% is manufactured in various formulations. The treatment is started at a low concentration and increased stepwise, aimed at preserving a minimal degree of irritation. Dithranol treatment of the scalp may cause temporary discoloration of the hair. In an open study, dithranol in a cream formulation caused 58% reduction of the modified PASI for the scalp during an eight-week treatment (22). The application of dithranol in scalp psoriasis has been improved by manufacturing dithranol into detergens [(Silix wash oil N (PacosGmbH, Halle, Germany)]. An emulsifying oil base (helianthus annulus, octyl cocoate, PEG-40, sorbitan peroleate, PEG-40 hydrogenated castor oil, trideceth-9, propylparaben, BHT, ascorbyl palmitate, glyceryl stearate, glyceryl oleate, and citric acid) and crystalline monoglycerides (Micanol Bioglan, Giessen, Germany) have been shown to be suitable vehicles for dithranol treatment of scalp psoriasis (23). IMIDAZOLE ANTIFUNGALS As scalp psoriasis is accompanied by an overgrowth of pityrosporon, an antifungal treatment seems to be a rationalistic approach. The outcome of various studies on

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topical and systemic antifungal treatments is contradictory (24–27). However, in treatment-resistant manifestations, a reduction of pityrosporon overgrowth may be effective in improving the condition. TOPICAL CORTICOSTEROIDS Topical corticosteroids are frequently used in scalp psoriasis. From an epidemiologic survey we know that topical corticosteroids are used by the majority of patients for more than eight weeks (3). In scalp psoriasis, the formulation is relevant in particular with respect to the cosmetic appearance. A cream or lotion is preferred over an ointment, although an ointment provides the better bioavailability. More recently, a foam vehicle became available. The advantage of the foam is that it spreads in the hair until it reaches the scalp, where it melts. The total coverage area for 100 g of foam was comparable to the coverage area of 100 g of traditional vehicles (28). In a comparative study against standard treatment (corticosteroids lotion or vitamin D3 treatments), betamethasone-17-valerate in foam was more effective, resulting in clearing or nearly clearing in 88% of the patients (29). In another study, it was shown that once daily application of betamethasone-17-valerate in the foam vehicle was as effective as twice daily application of the standard treatment (30). The average sign scores (erythema + induration + scaling) reduced from 8.1 to 3.9 and from 7.7 to 3.0 during a four-week head-to-head study (31). In a comparative study of clobetasol propionate foam 0.05% against clobetasol cream, the decrease of PASI during a two-week study was 41% against 31%. Patients using foam had a significantly greater increase in quality of life parameters and had spent less time applying their medication (31). Another innovation is an oil preparation of fluocinolone acitonide 0.01% combined with an emollient in the vehicle. In a randomized, double-blind, vehicle-controlled study in 89 patients, it was found that the oil containing this medium-strength corticosteroid was substantially more effective as compared to the vehicle (32). Side effects of topical corticosteroids on the scalp are limited. In case the facial areas are exposed to the steroids, perioral dermatitis may develop. It may be relevant, however, that topical corticosteroids may suppress hair growth (33) and that the skin of the scalp is by far more permeable to topical corticosteroids than most other regions of the skin (34). The efficacy and safety ratio of topical corticosteroids may be enhanced by applying corticosteroid preparations intermittently for two or three days per week. Furthermore, the addition of salicylic acid may increase the bioavailability of topical corticosteroids considerably thus enhancing efficacy. Plastic occlusion (for example, a shower cap) may be helpful in enhancing the efficacy of corticosteroid. However, penetration may be enhanced considerably. Zinc pyrithione spray has been used in combination with a topical corticosteroid. In a double-blind study, the added value of zinc pyrithione could not be shown (35). Combination treatments with vitamin D3 analoges, the topical retinoid tazarotene (36), and UVB phototherapy are important options for effective and safe control of scalp psoriasis.

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VITAMIN D3 ANALOGES Calcipotriol, calcitriol, and tacalcitol are well-established, first-line treatments of psoriasis. Calcipotriol lotion has become a mainstay in the topical treatment of scalp psoriasis. More recently, tacalcitol has become available in several countries. In a double-blind comparative study during four weeks, calcipotriol lotion proved to be effective, although less effective as compared to betamethasone lotion (37). In 73% to 75% of the patients treated with betamethasone, a marked improvement or clearing was observed and in 57% to 58% of the calcipotrioltreated patients such an improvement was seen. The majority of the patients were treated for another six weeks with calcipotriol lotion in an open-label phase that resulted in a marked improvement in 82.6% of the patients. In this respect, it should be noted that optimal efficacy with calcipotriol lotion requires eight weeks, whereas a potent topical corticosteroid already results in maximum efficacy after two to three weeks. In another comparative study (open-label) during six weeks, both treatments were equally effective (38). The combined use of calcipotriol ointment (80–100 g/wk) and calcipotriol lotion (30–50 mL/wk) proved to be safe, without affecting the indices of calcium metabolism or bone turnover (39). In 202 patients the long-term efficacy and safety of twice daily calcipotriol lotion was studied. By week 28 the total sign score had reduced from 5.9 to 2.5. Facial irritation was observed in 91 out of 276 events and no significant changes of systemic calcium metabolism have been observed (40). In a multicenter prospective observational cohort (fewer than 3396 patients) treated with calcipotriol lotion twice daily over an eight-week period, the following observations were made (41): (i) In the total cohort, the scalp severity index reduced from 18.4 to 5.6. (ii) In 80%, the improvement was rated as good to very good. (iii) In those patients who were treated only with calcipotriol lotion without additional treatments, the scalp severity index decreased from 16.0 to 4.9 in eight-week treatment. More recently tacalcitol in an emulsion has become available in various countries. Once daily tacalcitol emulsion proved to be effective and safe in a double-blind, placebo-controlled study. After an eight-week treatment, the median sum score had decreased by 53% in the tacalcitol group with 80% of the patients showing marked improvement to clearing (42). Local adverse reactions were transient and uncommon and systemic calcium metabolism was not affected. Topical vitamin D3 treatment can be combined with topical corticosteroids. An elegant, effective, and safe strategy is once daily application of a topical corticosteroid during weekend days and once or twice daily a vitamin D3 analoge during weekdays (43). Recently, a large program of phase II studies has been completed evaluating the efficacy and safety of a gel formulation containing calcipotriol and betamethasone dipropionate. This two compound formulation had a faster improvement and more impressive efficacy as compared to the monocomponent formulations (44).

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PHOTOTHERAPY Phototherapy, although effective in plaque psoriasis, has limited applications in scalp psoriasis as the hair prevents adequate UV exposure of the skin surface. The UVB/fiber optic comb has been shown in a pilot study in fewer than 14 patients to improve the treated sides well above the untreated sides (45). The 308-nm excimer laser has also been investigated with respect to efficacy in the treatment of scalp psoriasis. In a study in fewer than 13 patients, excimer laser–treated sides improved well above untreated sides (46). A challenging development is photodynamic therapy (47). Application of aminolevulinic acid results in intracellular accumulation of protoporphyrin IX that can be activated by visible light to produce reactive oxygen species and free radicals. This process has an antipsoriatic potential. Visible light penetrates better through keratin structures as compared to ultraviolet light and may well improve phototherapy of scalp psoriasis. SYSTEMIC TREATMENTS In general, scalp psoriasis can be managed by a topical treatment. In case topical treatments are not effective and phototherapy does not provide an adequate solution, a systemic treatment may be indicated. Cyclosporin is a very effective antipsoriatic treatment, which can be used up to one or two years for reason of cumulative toxicity. Methotrexate, fumarates, and acitretin may provide a satisfactorily long-term control. TREATMENT STRATEGIES IN SCALP PSORIASIS A spectrum of treatments is available for the management of scalp psoriasis. However, few double-blind, placebo-controlled studies and double-blind controlled studies against active comparators are available. Guidelines on the treatment of scalp psoriasis are largely based on the open studies as described above and on expert opinions. In this section we will integrate the available knowledge into treatment recommendations for scalp psoriasis. The first phase is active descaling. In case of mild scaling, regular shampooing is an option. Application of salicylic acid 5% to 10% or urea up to 40% in a wash-off ointment may enhance descaling. An automatic shampooing machine may help at day-care centers for efficient descaling. The second phase is active clearing treatment. The first-line approach is a vitamin D3 lotion or emulsion once a day and a superpotent topical corticosteroid in a vehicle that is well accepted by the patient once a day. If this approach is not effective after eight weeks or not appreciated for reason of intolerance, a superpotent topical corticosteroid may be combined with UVB therapy. In order to optimize phototherapy of the scalp, a hair blower or a UVB fiber comb can be used. Another alternative for the second phase is dithranol and tar-based treatments at a

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day-care center. If all these approaches are not effective, cultures for Malassezia should be taken and a systemic antifungal treatment can be started. In case all these treatments are not effective, a systemic antipsoriatic treatment should be considered with methotrexate, fumarates, cyclosporine, or acitretin. The third phase of treatment is stabilization with a vitamin D3 analog on weekdays (once or twice daily) and a superpotent topical corticosteroid once daily during the weekend. In case a vitamin D3 analog is not tolerated, one may restrict to intermittent applications of the corticosteroid only. The fourth phase is the maintenance phase. For this phase, a vitamin D3 analog is the preferred treatment either once or twice daily. A tar shampoo may further support this phase. CONCLUSION Scalp psoriasis is a frequently occurring condition, which may impair quality of life considerably. A spectrum of treatments for this condition is available, although few double-blind comparative studies support the efficacy of these treatments. Treatment phases comprise I, descaling; II, clearing; III, stabilization; and IV, maintenance. REFERENCES 1. van de Kerkhof PCM, Steegers-Theunissen RPM, Kuipers MV. Evaluation of topical drug treatment in psoriasis. Dermatology 1998; 197:31–36. 2. Poyner TF, Fell PJ. Frequency of patients with plaque psoriasis who had not consulted their doctor in the past year. Br J Clin Res 1995; 6:201–207. 3. van de Kerkhof PCM, de Hoop D, de Korte J, et al. Scalp psoriasis, clinical presentations and therapeutic management. Dermatology 1998; 197:326–334. 4. Schoorl WJ, Baar HJ, van de Kerkhof PCM. The hair root pattern in psoriasis of the scalp. Acta Derm Venereol 1992; 72:141–142. 5. Plozzer C, Coletti C, Kokelj F, et al. Scanning electron microscopy study of hair shaft disorders in psoriasis. Acta Derm Venereol Suppl 2000:9–11. 6. van de Kerkhof PCM, Chang A. Scarring alopecia and psoriasis. Br J Dermatol 1992; 126:524–525. 7. Schuster S. Psoriatic alopecia. Br J Dermatol 1992; 87:73–77. 8. Bardazzi F, Fanti PA, Orlandi C, et al. Psoriatic scarring alopecia: Observations in four patients. Int J Dermatol 1999; 38:765–768. 9. Abdel-Hamid IA, Agha SA, Moustafa YM, et al. Pityriasis amiantacea: A clinical and etiopathologic study of 85 patients. Int J Dermatol 2003; 42:260–264. 10. Conti Diaz IA, Civila E, Veiga R. The importance of microscopic examination in the management of desquamative disease of the scalp. Mycopathologica 2002; 153:71–75. 11. Prohic A. Identification of Malassezia species isolated from scalp skin of patients with psoriasis and healthy subjects. Acta Dermatovenerol Croat 2003; 11:10–16. 12. Olansky S. Whole coal tar shampoo: A therapeutic hair repair system. Cutis 1980; 25:99–104.

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13. Lowe NJ, Breeding JH, Wortzmann MS. New coal tar extract and coal tar shampoos. Arch Dermatol 1982; 118:487–489. 14. Jongeneelen FJ, Bos RP, Azion RBM. Biological monitoring of polycyclic aromatic hydrocarbons: Metabolites in urine. Scand J Work Environ Health 1986; 12:137–143. 15. Snijder FH, Beuhler EV, Winek CL. Safety evaluation of zinc-2-pyridine-thiol 1-ozide in a shampoo formulation. Toxicol Appl Pharmacol 1965; 7:425–437. 16. Orentreich N. A clinical evaluation of two shampoos in the treatment of psoriasis. J Soc Cosmet Chem 1972; 23:189–194. 17. Jarrat M, Breneman D, Gottlieb AB, et al. Clobetasol propionate shampoo 0.05%: A new option to treat patients with moderate to severe scalp psoriasis. J Drugs Dermatol 2004; 3:367–373. 18. Griffiths CEM, Finlay AY, Fleming CJ, et al. A randomized, investigator-masked clinical evaluation of the efficacy and safety of clobetasol propionate 0.05% shampoo and tar blend 1% shampoo in the treatment of moderate to severe scalp psoriasis. J. Dermatolog Treat 2006; 17:90–95. 19. Reygagne P, Mrowietz U, Decroix J, et al. Clobetasol propionate shampoo 0.05% and calcipotriol solution 0.005%: A randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatol 1999; 38:628–632. 20. King L Jr, Webb B, Zanolli M. Experience in treating recalcitrant scalp psoriasis with auton shampooing and debridement. J Am Acad Dermatol 1999; 41:638–651. 21. Shemer A, Nathansohn N, Kaplan B, et al. Treatment of scalp seborrhoeic dermatitis and psoriasis with an ointment of 40% urea and 1% bifonazole. Int J Dermatol 2000; 39:532–534. 22. Prins M, Swinkels OQJ, Bertholet B, et al. Dithranol short contact treatment of scalp psoriasis. J Derm Treat 1999; 10:13–17. 23. Wulff-Woesten A, Ohlendorf D, Henz BM, et al. Dithranol in an emulsifying oil base (bio-wash-oil) for the treatment of psoriasis of the scalp. Skin Pharmacol Physiol 2004; 17:91–97. 24. Farr PM, Krause LB, Marks JM, et al. Response of scalp psoriasis to oral ketoconazole. Lancet 1985; 8461(II):921–922. 25. Faergemann J. Treatment of sebopsoriasis with itraconaxole. Mykosen 1985; 28:612– 618. 26. Rosenberg EW, Belew PW, Skinner RB. Treatment of psoriasis with antimicrobial agents. Semin Dermatol 1985; 4:307–311. 27. Jury CS, Hugh McL, Shankland GS, et al. A randomized, placebo-controlled trial of oral itraconazole in scalp psoriasis. J Dermatol Treat 2000; 11:85–89. 28. Feldman SR, Sangha N, Setaluri V. Topical corticosteroid in foam vehicle offers comparable covered compared with traditional vehicles. J Am Acad Dermatol 2000; 42:1017– 1020. 29. Andreassi L, Giannetti A, Milani, et al. Efficacy of betamethasone valerate mousse in comparison with standard therapies on scalp psoriasis: An open, multicentre, randomized, controlled, cross-over study on 241 patients. Br J Dermatol 2003; 148:134–138. 30. Feldman SR, Ravis SM, Fleischer AB Jr, et al. Betamethasone valerate in foam vehicle is effective with both daily and twice a day dosing: A single-blind, open-label study of the treatment of scalp psoriasis. J Cutan Med Surg 2001; 5:386–389. 31. Bergstrom KG, Arambula K, Kimball AB. Medication formulation affects quality of life: A randomized single-blind study of clobetasol propionate foam 0.05%

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44. 45. 46. 47.

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comparison with a combined program of clobetasol cream 0.05% and solution 0.05% for the treatment of psoriasis. Cutis 2003; 72:407–411. Pauporte M, Maibach H, Lowe N. Fluocinolone acetonide topical oil for scalp psoriasis. J Dermatolog Treat 2004; 15:360–364. Robertson D, Maibach H. Topical corticosteroids. Semin Dermatol 1983; 2:238–249. Feldman RJ, Maibach HI. Penetration of 14-C hydrocortisone through normal skin, the effect of stripping and occlusion. Arch Dermatol 1965; 91:661–666. Housman TS, Keil KA, Mellen BG, et al. The use of 0.25% zinc pyrithione spray does not enhance the efficacy of clobetasol propionate 0.05% foam in the treatment of psoriasis. J Am Acad Dermatol 2003; 49:79–82. Gollnick HP, Finzi AF, Marks R, et al. Optimizing the use of tazarotene in clinical practice: Consensus statement from the European advisory panel for tazarotene (Zorac TM). Dermatology 1999; 199:40–46. Klaber MR, Hutchinson PE, Pedvisleftick, et al. Comparative effects of calcipotriol solution 50 mg/mL in the treatment of scalp psoriasis. Br J Dermatol 1994; 131:678– 683. Duweb GA, Abuzariba O, Rahim M, et al. Scalp psoriasis: Topical calcipotriol 50 micrograms/g/mL solution vs. Betamethasone valerate 1% lotion. Int J Clin Pharmacol Res 2000; 20:65–68. van de Kerkhof PCM, Green C, Hamberg KJ, et al. Safety and efficacy of combined high-dose treatment with calcipotriol ointment and solution in patients with psoriasis. Dermatology 2002; 204:214–221. Barnes L, Altmeyer P, Forstrom L, et al. Long-term treatment of psoriasis with calcipotriol scalp solution and cream. Eur J Dermatol 2000; 10:199–204. Thaci D, Daiber W, Boehncke WH, et al. Calcipotriol solution for the treatment of scalp psoriasis: Evaluation of efficacy, safety and acceptance in 3396 patients. Dermatology 2001; 203:153–156. Ruzicka T, Trompke C. Treatment of scalp psoriasis. An effective and safe tacalcitol emulsion. Hautarzt 2004; 55:165–170. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobetasol ointment in the long-term of psoriasis: Effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. Papp K, Berth-Jones J, Kragballe K, et al. Scalp psoriasis: A Review of current topical treatment options. J Eur Acad Dermatol Venereol 2007; 21:1151–1160. Taneja A, Racette A, Gourgouliatos Z, et al. Broad-band UVB fiber-optic comb for the treatment of scalp psoriasis: A pilot study. Int J Dermatol 2004; 43:462–467. Taylor CR, Racette AL. A 308 nm excimer laser for the treatment of scalp psoriasis. Lasers Surg Med 2004; 34:136–140. Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: An overview. Am J Clin Dermatol 2003; 4:699–708.

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16 Inverse Psoriasis Robert A. Lee and Abby S. Van Voorhees Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION Psoriasis is commonly described as a chronic relapsing disease characterized by erythematous well-circumscribed plaques with thick, silvery scale and a predilection for the extensor surfaces of the extremities, lower back, and umbilical area (1–3). Yet the morphology and presentation of cutaneous lesions can vary considerably and can be divided into subtypes, including chronic plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, generalized pustular psoriasis, pustular palmar and plantar psoriasis, and inverse psoriasis (2). Moreover, these subtypes are not mutually exclusive with one type evolving into another over time. Inverse psoriasis is also known as flexural or intertriginous psoriasis because of its selective involvement of skin folds such as the axillae, groin, inframammary folds, navel, gluteal crease as well as the palms, soles, and nails. Because of its particular localization, inverse psoriasis has clinical impact out of proportion to the total body surface area affected and poses unique therapeutic challenges.

EPIDEMIOLOGY In the United States, psoriasis affects approximately 2.2% to 2.5% of the general population. Inverse psoriasis accounts for roughly 2% to 6% of these cases (4,5). The male-to-female ratio is approximately equal. The age of onset has a bimodal distribution with the first peak at 22.5 years of age and second peak at 55 years of age (6). 209

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Psoriasis appears to demonstrate a polygenic mode of inheritance. Approximately one-third of the patients with psoriasis also have a relative with the disease. Incidence of monozygotic twins exhibit a 65% rate of concordance opposed to 30% for dizygotic twins. Certain major histocompatibility complex types (HLA-Cw6, HLA-B57, HLA-DR7) (7,8) are associated with a higher incidence of psoriasis with some corresponding to specific clinical patterns: pustular type (HLA-B27), guttate type (HLA-B13 and HLA-B17), palmoplantar pustulosis (HLA-B8, HLABw35, HLA-Cw7, HLA-DR3) (9). No HLA type has been specifically associated with inverse psoriasis.

CLINICAL PRESENTATION Inverse psoriasis often appears as glossy, sharply demarcated erythematous plaques with little to no scale (Fig. 1). Often lesions are moist and can be fissured. Characteristic histopathology is identical for psoriasis vulgaris and inverse psoriasis, and includes regular acanthosis, club-shaped dermal papillae, focally absent granular layer, focal parakeratosis, elongated and tortuous capillaries, and collections of neutrophils in the epidermis (10). The effect of psoriasis on a patient is multidimensional, including the physical, social, and psychologic health of the person. Overall clinical severity of

Figure 1 Patient with inverse psoriasis involving the intergluteal fold.

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psoriasis, as assessed by the psoriasis area and severity index (PASI), and duration of psoriasis may not always be related directly to health-related qualityof-life measures (11). Patients with psoriasis often ascribe a substantial negative effect on their quality of life (12). The psychosocial effects of psoriasis on patients may be profound resulting in considerable stigmatization, social isolation, and discrimination. Eighty-four percent of patients with psoriasis expressed difficulties in establishing social contacts and relationships and stated that this was the worst aspect of their psoriasis. Psoriasis patients also had reduction in physical and mental functioning comparable to that seen in cancer, arthritis, hypertension, heart disease, diabetes, and depression (13). While approximately 40% of patients report that psoriasis negatively affected their sexual activity and enjoyment, no study has been performed to specifically address the impact of inverse psoriasis (14). For inverse psoriasis, the extent of skin involvement may not be a reliable guide to disability. By the same token, the presence of psoriasis on the face may contribute to depression. As a consequence, patients should be assessed using a holistic approach that considers physical and psychologic measures (15).

ETIOLOGY The pathogenesis of psoriasis is not well understood. The presence of numerous immune cells in psoriatic lesions implies an important role in disease progression and maintenance through secretion of various inflammatory cytokines. Also, hyperproliferation of keratinocytes is observed (3). Often there is an inciting insult such as infection, medication (Table 1) (15–17), or trauma (Koebner phenomenon). While fungal infections have often been associated with inverse psoriasis, a recent study comparing untreated patients, topical steroid–treated patients, and control patients shows no evidence of Candida infection (18,19).

Table 1 Drugs that Exacerbate Psoriasis Antimalarials Lithium -Blockers NSAIDs Trazadone Interferon-alpha Terbenifine ACE inhibitors Gemfibrizil Tetracycline Penicillin

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Table 2 Differential Diagnosis of Inverse Psoriasis Intertrigo Seborrheic dermatitis Erythrasma Cutaneous candidiasis Contact dermatitis Darier disease Bowen disease Extramammary Paget disease Mycosis fungoides Acrodermatitis enteropathica Radiation dermatitis Glucagonoma syndrome Epidermolysis bullosa Histiocytosis X Acanthosis nigricans Axillary granular parakeratosis Confluent and reticulated papillomatosis

DIFFERENTIAL DIAGNOSIS Inverse psoriasis can be a difficult diagnosis in the intertriginous areas because lesions often lack the characteristic silvery scale seen in plaque-type psoriasis (Table 2). The lesions are generally deep red, smooth, even glistening with a welldemarcated edge. Friction, heat, and moisture in these areas are thought to induce psoriasis as a Koebner phenomenon. Pustules or papules extending beyond the border suggest secondary Candida infection. Intertrigo, erythrasma, and seborrheic dermatitis may be indistinguishable in some cases. MANAGEMENT Topical Corticosteroids Corticosteroids persist as the mainstay for topical treatment. Topical corticosteroids are categorized by the Stoughton–Cornell classification system based on the vasoconstriction of small blood vessels in the upper dermis. This system ranges from the super potent class I steroids to the weaker class VII steroids. They are believed to reduce inflammation by reducing inflammatory cells and cytokines, including IL-1, IL-2, IFN- , TNF-, and GM-CSF (20–22). Topical corticosteroids have side effects that limit their long-term use in the treatment of psoriasis. Common side effects can occur locally at the site of prolonged topical corticosteroid application, resulting in skin atrophy, irreversible striae, and telangiectasias. These findings are most often seen when high-potency corticosteroids are used on the face and intertriginous areas for prolonged periods of time. Because of the thinness of intertriginous psoriasis lesions and possible

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occlusion in these areas, they are even more sensitive to topical corticosteroids. An open-label study of 20 patients applying fluticasone proprionate 0.005% (class III) twice a day for two weeks followed by twice weekly application for 10 weeks demonstrated greater than 75% clearance in 95% of facial and intertriginous lesions compared to 35% of nonfacial, nonintertriginous lesions (23). There was no evidence of skin atrophy after 10 weeks. Long-term studies have not been done for inverse psoriasis. Tachyphylaxis is also a common phenomenon with prolonged use (24). Pulse therapy has been shown to prevent tachyphylaxis in psoriasis vulgaris but has not been studied for inverse psoriasis. Rarely, the hypothalamic-pituitaryadrenal (HPA) axis can be suppressed in cases of widespread use. Topical Vitamin D Analogs Calcipotriene is a synthetic analog to calcitriol (1,25-dihydroxyvitamin D3 ) and binds to the vitamin D receptor found in keratinocytes, halting proliferation, and causing terminal differentiation. It also inhibits production of IL-2, IL-6, IFN- , and GM-CSF by T cells. Because it is not associated with skin atrophy, calcipotriene has potential advantages when used in intertriginous areas (25). For psoriasis vulgaris, calcipotriene has been shown to be as effective as a class II corticosteroid. In a randomized, double-blind study with 114 subjects, mean scores of scaling and plaque elevation in calcipotriene-treated subjects were significantly lower by week 2 than in the fluocinonide-treated subjects and continued to be significantly lower through week 6 (26). Calcipotriene can also be used in conjunction with topical corticosteroids to extend the duration of remissions while minimizing the adverse effects of chronic steroid use. In a randomized, doubleblind study of 44 patients, 76% of patients using a combination of calcipotriene twice a day on weekdays and a class I corticosteroid twice a day on weekends were able to maintain remission at six months of treatment compared to 40% using a class I corticosteroid steroid twice a day on weekends and vehicle twice a day on weekdays (27). There have been no randomized control studies studying the efficacy of calcipotriene for inverse psoriasis. In an open, uncontrolled trial, 10 or 12 patients with inverse psoriasis showed clinically significant improvement by six weeks of treatment (28). However, calcipotriene can cause irritant contact dermatitis, particularly on the face and in intertriginous sites. Dilution of calcipotriene with petrolatum or the addition of a topical steroid may prevent the irritant contact dermatitis. Rarely, hypercalcemia can occur but is always associated with excess use over large surface area (29). Topical Retinoids Tazarotene has multiple effects on keratinocyte differentiation and proliferation, and inflammation processes that contribute to psoriasis. There are two classes of nuclear retinoid receptors that have been identified: the retinoic acid receptor (RAR) and retinoid X receptor (RXR) (30). Tazarotene selectively binds to RAR.

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The function of these RAR and RXR is not well understood in skin. In animal models, topical tazarotene blocks induction of ornithine decarboxylase activity, which is associated with cell proliferation and expression. In vitro skin models and cell cultures also demonstrate that tazarotene suppresses epidermal hyperproliferation. In a randomized, double-blind, placebo-controlled study involving 324 plaque psoriasis patients using tazarotene gel 0.1% or 0.05% applied once a day for three months demonstrated clearance in 63% and 50% of cases, respectively, compared to 30% of the vehicle (31). There have been no randomized control studies studying the efficacy of tazoratene for inverse psoriasis. Generally, tazarotene is most effective for reducing plaque thickness. Since intertriginous psoriasis tends to have thin plaques and significant local irritation of tazarotene can be seen, it is not commonly used for intertriginous areas but may be effective on the face. Common side effects from local application include irritation, pruritus, erythema, stinging, and desquamation (32). Short contact with tazarotene minimizes the local irritation on the skin, which is especially applicable to intertriginous areas. Topical Immunomodulators Immunosuppression in the treatment of psoriasis can be achieved by inhibition of cytokine production, which is essential in the development of psoriasis (33). Tacrolimus, a lipophilic agent produced by Streptomyces tsukubaensis, exhibits similar in vivo and in vitro biologic characteristics to cyclosporine A. Furthermore, it is more potent than cyclosporine A. Inhibition of calcineurin blocks the activity of NF-AT (nuclear factor of activated T cells), which in turn suppresses IL-2 production as well as T-cell response. Both systemically and topically, tacrolimus inhibits T-cell infiltration and skin reddening, and levels of IL-2 receptors decrease during treatment. There is also inhibition of keratinocyte proliferation induced by EGF, TGF-, or IL-6 through influence on the keratinocyte cell cycle at G0/1 phases and dose-dependent inhibition of IL-8, which is elevated in psoriatic plaques. Tacrolimus has a lower molecular weight and therefore a much better skin penetrant than cyclosporine. Therefore, it can be used topically. Adverse events include burning, heat sensation, itching, and erythema. In contrast to topical corticosteroids, there is no influence on collagen biosynthesis and therefore no skin atrophy. As psoriatic plaques on the trunk and the extremities can be thick, topical tacrolimus formulations are only minimally effective in treating these lesions (34). However, several open-labeled trials indicating topical tacrolimus might be effective for intertriginous lesions (35,36). A randomized, double-blind, vehiclecontrolled study of inverse psoriasis with 167 patients using 0.1% tacrolimus showed 65.2% of the tacrolimus ointment group and 31.5% of the vehicle were 90% clear by eight weeks (37). None of the patients had skin atrophy, telangiectasias, or striae during the eight-week study. Recent studies have also confirmed its effectiveness in the pediatric setting (38,39).

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Pimecrolimus also belongs to the macrolide group of immunomodulators. Compared to tacrolimus, it is 20 times more lipophilic and has a lower permeation potential through the skin. A 57 patient, randomized, double-blind, vehiclecontrolled trial studying inverse psoriasis showed that 82% of the pimecrolimus group and 41% of the vehicle were 90% clear by eight weeks (40). A direct comparison of topical 1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone demonstrated pimecrolimus to be the least effective of the three in treating inverse psoriasis but clearly superior to vehicle alone (41). However, topical tacrolimus and pimecrolimus should be used with caution due to the potential of rare but serious adverse events (42–44). Use of systemic tacrolimus has been shown to be associated with both lymphoid and nonlymphoid malignancies in the posttransplant setting (45,46). Topical tacrolimus has been implicated in squamous cell carcinoma of the penis (47). Oral pimecrolimus has been associated with development of lymphoma in monkey models (48). In mouse models, topical tacrolimus have been shown to accelerate the development of squamous cell carcinomas (49). In March 2005, the FDA issued a public health advisory for topical pimecrolimus reporting 10 cases of cancer-related adverse events including lymphoma, basal cell carcinoma, and squamous cell carcinoma (48). At the same time, an advisory was also issued for topical tacrolimus reporting 19 cases linking it with cancer-related adverse events, including lymphomas, squamous cell carcinoma, and malignant melanoma (48). However, no long-term studies are yet available to evaluate the risk of topical formulations in humans. Therefore, prolonged use over large areas of the body should be used with caution. Topical Anthralin and Tar Anthralin and tar can be moderately irritating, and can stain skin and clothing. They are generally not well tolerated in intertriginous areas and are not widely used in the treatment of inverse psoriasis having been replaced with better tolerated topical agents (21). Botulinum Toxin A single case series reported the use of botulinum toxin to treat inverse psoriasis. Thirteen out of fifteen patients appeared to respond favorably as early as two weeks after treatment with a durable response through the 12-week follow up period. No adverse reactions were reported. The mechanism is unclear, but it is thought to involve the decrease of sweating and thereby maceration in the area. The involvement of neuropeptides as mediators of inflammation may also play a role (50). Light Therapy Ultraviolet light causes DNA damage to cutaneous tissue and thereby can inhibit cell proliferation (2). Specifically, it appears to target cutaneous immune cells and

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reduce the production of inflammatory cytokines important in psoriasis pathogenesis. It is widely used in the treatment of psoriasis vulgaris (21). Broadband UVB (BB-UVB) and narrowband UVB (NB-UVB) can be used to treat plaque psoriasis. NB-UVB is generally more effective than BB-UVB in treating psoriasis but has the disadvantage of producing more severe and longerlasting burns than BB-UVB. The long-term effect of NB-UVB on carcinogenesis in plaque psoriasis remains unknown. Its overall safety is generally believed to be better than PUVA (psoralen plus UVA) (51). Genitalia are often shielded due to the possible increased risk of carcinogenesis. Typical UVB light units are designed to treat large surface areas and generally do not reach intertriginous areas because of body habitus and positioning of the patient. A recent study using NB-UVB specifically for intertriginous areas in Asian patients demonstrated significant improvement in 41 out of 48 patients. Side effects were limited to darkening of the skin and pruritus, which are resolved after stopping the treatments (52). Smaller handheld units are promising alternatives to allow better targeting of occluded areas such as the axilla and inframammary folds. Specific studies addressing the efficacy and safety of BB-UVB and NB-UVB in inverse psoriasis have not been done. PUVA is commonly employed for widespread and resistant psoriasis. Psoralen, 8-methoxypsoralen, causes the formation of pyrimidine dimers that lead to cross-linkage of DNA strands and genomic instability and apoptosis. In a randomized trial involving 100 patients comparing NB-UVB with PUVA given twice weekly, 88% of patients were cleared with PUVA compared with 63% with NBUVB (53). Also PUVA-treated patients required significantly fewer treatments and had almost three times the remission rate at six months after treatment. The potential side effects of PUVA include an increased incidence of squamous cell carcinoma (54), basal cell carcinoma, and possibly malignant melanoma (55). The genitalia are usually shielded during UVA exposure because of the risk of developing carcinoma in that region. PUVA is not commonly used for inverse psoriasis because of the tendency for intertriginous skin to burn, the risk of carcinogenesis, and the technical difficulty of delivering UV light to the intertriginous areas. No studies using PUVA specifically for inverse psoriasis have been performed. Targeted ultraviolet light therapy, which allows for sparing of uninvolved skin, has recently been considered. In a preliminary case report, a single inverse psoriasis patient using the excimer laser (308 nm) obtained 90% improvement of her lesions after three weeks of treatment (56). Excimer light therapy has also been reported to be effective in conjunction with topical tacrolimus (57). Further studies are necessary to better demonstrate the efficacy and safety of this modality. The disadvantages of this approach include cost, limited availability, risk of burning, and unknown risk of carcinogenesis. Methotrexate Methotrexate is a synthetic analoge of folic acid and a competitive inhibitor of the enzyme dihydrofolate reductase (58). The inhibition of thymidylate synthesis

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appears to be the most important effect exerted by methotrexate, which results in inhibition of DNA synthesis and arrest of cell division in the S-phase. T and B cells are preferentially targeted and thereby inhibit the elaboration of inflammatory cytokines. Methotrexate also suppresses epidermal cell division in psoriasis. Methotrexate is indicated in patients with moderate-to-severe psoriasis and is indicated when other treatment modalities have failed (59,60). It is most appropriately used for patients with plaque psoriasis with more than 10% body surface involvement, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, and more localized, recalcitrant psoriasis. Because of its distribution, inverse psoriasis can be much more debilitating than the total body surface area might suggest. In which case, intervention with methotrexate can be considered. A randomized, single-blinded controlled trial comparing cyclosporine and methotrexate involving 88 patients with psoriasis vulgaris showed no significant difference in effectiveness or side effects between the two drugs. Sixty percent in the methotrexate group compared to 71% in the cyclosporine group achieved at least 75% clinical improvement over the 16 weeks of the study (61). Also, the time needed to reach an almost complete remission and a partial remission did not differ significantly between the groups. No specific studies for the use of methotrexate in inverse psoriasis have been performed. Methotrexate is contraindicated in patients who have renal impairment, persistent abnormalities in liver function enzymes, pregnancy, hepatitis, frequent alcohol usage, and myelosuppression (62). Common side effects associated with methotrexate include nausea and vomiting. Ulcerative stomatitis, pulmonary fibrosis, bone marrow suppression, and induction of lymphoma have also been described. The most serious long-term adverse effect associated with methotrexate is the induction of hepatotoxicity. The liver biopsy is the most definitive test for ascertaining whether fibrotic changes in the liver are present during methotrexate therapy. Cyclosporine Cyclosporine is an immunosuppressive agent derived from the fungus Tolypocladium inflatum Gams. Cyclosporine is used to prevent allograft rejection and is FDA approved for the treatment of psoriasis. Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activation. Cyclosporine binds to cyclophilins, which then complexes to inhibit the enzyme, calcineurin, a calcium-activated phosphatase. Calcineurin inhibition, in turn, results in the inhibition of the transcription factor NF-AT, which is important for inflammatory cytokine expression (63). Cyclosporine is indicated for the treatment of severe plaque psoriasis in patients who are not immunocompromised (64). In addition, cyclosporine is effective in treating various forms of psoriasis, which have been recalcitrant to other modalities. When used as monotherapy, cyclosporine can induce rapid clearance of plaques in a large majority of patients with attainment of 60% to 80% reduction

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at 8 to 12 weeks, respectively. Its use for inverse psoriasis has not been specifically studied (61,63). Nephrotoxicity is the main adverse effect of cyclosporine therapy (62). Acute renal toxicity is dose-dependent and reversible upon lowering the dosage or discontinuation of the drug. Other common side effects include gastrointestinal symptoms such as nausea, vomiting, anorexia, and diarrhea. Hypertension, headache, myalgias, arthralgias, paresthesias, hyperesthesia, influenza-like symptoms, and fatigue are not uncommon. Dermatologic side effects include hypertrichosis and gingival hypertrophy. Cyclosporine has been associated with the induction of various lymphoproliferative disorders in transplant patients. In contrast, an increase incidence of nonmelanoma skin cancer has not been observed in psoriatic patients treated with cyclosporine, presumably because of much shorter courses of therapy with lower doses that have been utilized. Biologic Agents Psoriasis is thought to involve a complex pattern of overexpressed Th1 cytokines such as IL-2, -6, -8 or IFN- , and TNF- (65). In particular, TNF- is involved in the activation of NF-B, a transcription factor that regulates the expression of cytokines such as IL-6, IL-8, and CSF. It also induces the expression of ICAM-1 and vascular cell adhesion molecule type 1 (VCAM-1) on endothelial cells and keratinocytes, where both are involved in trafficking lymphocytes to inflammatory lesions. TNF- also stimulates migration of Langerhans’ cells to lymph nodes and enhances capability to present antigens to primed T cells. Several agents targeting specific steps in the immunopathogenesis of psoriasis are now available in clinical practice (66). Etanercept is a recombinant soluble fusion protein consisting of two identical chains of the TNF- receptor fused with the Fc portion of human IgG1 . It is functioning as a competitive inhibitor for binding of TNF- at its receptor. Inflammatory cytokines such as tumor necrosis factor (TNF) have been implicated in the pathogenesis of psoriasis. In randomized, double-blind study, 672 plaque psoriasis patients either received placebo or etanercept subcutaneously at 25 mg once weekly, 25 mg twice weekly, or 50 mg twice weekly. At 12 weeks, 14%, 34%, and 49% of patients, respectively, demonstrated a 75% reduction in severity compared to 4% of patients receiving placebo (67). In another randomized, doubleblind, placebo-controlled study, 148 plaque psoriasis patients receiving placebo or etanercept 25 mg, subcutaneously twice weekly, 30% of the etanercept-treated patients demonstrated 75% severity reduction as compared to 1% of the patients in the placebo group at 12 weeks (68). Infliximab is a human-mouse monoclonal chimeric antibody against the TNF- molecules. Adalimumab is a humanized monoclonal antibody against the TNF- molecules. Both bind to soluble and membrane bound TNF leading to cell lysis. In a randomized, double-blind study, 33 patients with plaque psoriasis received intravenous placebo, infliximab 5 mg/kg, at weeks 0, 2, and 6. At

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10 weeks, 82% of patients in the infliximab 5 mg/kg had a 75% improvement in the PASI scores compared to 18% of patients in the placebo group (69). Longterm studies seemed to indicate that continuous therapy is superior to intermittent therapy with infliximab at 5 mg/kg given every 8 weeks showing a PASI 75 of 78% at 26 weeks and a PASI 75 of 55% at 50 weeks (70). Loss of long-term efficacy appears to correlate with a progressive reduction of serum infliximab concentrations to undetectable levels. This could be related to the dosing regimen as well as the development of neutralizing antibodies (71). A large randomized control study of 1212 patients using adalimumab revealed 68% achieving a PASI 75 at week 12 compared to 5% of patient taking placebo. Loss of response was seen at much higher rate among responders who were reassigned to a placebo group compared to those who continued on the medications (5% vs. 28%) (72). This strongly suggests that continued adalimumab therapy is required to maintain a response. Alefacept is a fusion protein composed of the leukocyte function–associated antigen (LFA)-3 with the Fc portion of human IgG and binds to CD2 on T cells to block costimulation by antigen presenting cells. In a randomized, placebocontrolled, double-blind study, 229 patients with plaque psoriasis received intravenous alefacept (0.025, 0.075, or 0.150 mg/kg of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks (73). Two weeks after the treatment, 21%, 33%, and 31% of the patients in the three alefacept groups, respectively, had a 75% improvement in the PASI scores compared to 10% of patients in the placebo group. Twelve weeks after treatment, 33%, 31%, and 19% of the patients in the three alefacept groups, respectively, had a 75% improvement in the PASI scores compared to 11% of the patients in the placebo group at 12 weeks. Efalizumab is a humanized monoclonal anti-CD11a antibody that binds to the CD11a portion of human LFA-1 and blocks the LFA-1/intercellular adhesion molecule (ICAM) interaction, thus blocking costimulation and T-cell migration. In a randomized, placebo-controlled, double-blind study, 597 subjects with plaque psoriasis received subcutaneous efalizumab 1 mg/kg, efalizumab 2 mg/kg, or placebo weekly. At week 12, 22% of patients who received efalizumab 1 mg/kg and 28% of patients who received efalizumab 2 mg/kg demonstrated 75% response as compared with 5% of patients who received placebo (74). At present, there are no published data specifically addressing the effectiveness of the various biologics for the treatment of inverse psoriasis. CONCLUSION Inverse psoriasis is a common, chronic relapsing, potentially debilitating disease that belies proportion to the total body surface area affected. Careful attention needs to be paid to the patient in assessing the true impact of the disease as well as designing an individualized treatment regimen that thoughtfully addresses the challenges of treating these areas of the body.

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62. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001; 45:649–661; quiz 662–644. 63. Ho VC. The use of ciclosporin in psoriasis: A clinical review. Br J Dermatol 2004; 150(suppl 67):1–10. 64. Laburte C, Grossman R, Abi-Rached J, et al. Efficacy and safety of oral cyclosporin A (CyA; Sandimmun) for long-term treatment of chronic severe plaque psoriasis. Br J Dermatol 1994; 130:366–375. 65. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002; 46:1–23; quiz 23–26. 66. Kipnis CD, Myers WA, Opeola M, et al. Biologic treatments for psoriasis. J Am Acad Dermatol 2005; 52:671–682. 67. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349:2014–2022. 68. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 2003; 139:1627–1632; discussion 1632. 69. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomised trial. Lancet 2001; 357:1842–1847. 70. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol 2007; 56:31.e1–15. 71. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicentre, double-blind trial. Lancet 2005; 366:1367–1374. 72. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58:106– 115. 73. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345:248–255. 74. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349:2004–2013.

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17 Psoriasis of the Nails Gabriele B. Poindexter and Richard K. Scher Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, U.S.A.

Maithily A. Nendedkar-Thomas Professional Dermatology Care, PC, Reston, Virginia, U.S.A.

INTRODUCTION Nail psoriasis is a relatively common and often misdiagnosed disorder affecting millions of people worldwide. An epidemiologic study of psoriasis conducted 10 years ago reported that approximately 7 million people in the United States, or roughly 2.6% of the population were affected (1). While the number of people with psoriasis in the United States has undoubtedly increased, the percentage affected likely remains the same. Not everyone who develops psoriasis will have nail changes. Indeed, no more than half of those patients who have cutaneous psoriasis will have associated nail psoriasis (2). There is a much tighter association of nail disease in patients who have psoriatic arthritis. About 63% to 83% patients who develop psoriatic arthritis will have nail changes as the first external indicator of joint disease (3). Heeding the early visual clues can prevent the development of severe, debilitating permanent joint destruction (3). There are numerous types of psoriatic nail changes, some of which are more closely associated with arthropathy than others. Nail psoriasis without joint or skin involvement can occur and presents a diagnostic challenge. Due to the morphologic similarities, isolated nail psoriasis is most frequently mistaken for onychomycosis (4,5). The psychosocial impact and functional impairment of severe multinail psoriasis cannot be understated (6). It is often a source of embarrassment for psoriasis patients who try to disguise their fingernails under coats of nail polish or hide 225

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their toenails under the safety of socks (7). This is especially true in patients who have concomitant onychomycosis due to psoriasis-induced nail injury (8). Additionally, psoriasis has now been found to be associated with an increased risk of cardiovascular disease, making the diagnosis of isolated nail psoriasis significant for long-term risk stratification (9). This chapter will review the various manifestations of nail psoriasis, its associations, mimicking conditions, as well as objective means of measuring nail alterations. Furthermore, therapeutic options for this challenging disease will also be explored. MANIFESTATIONS OF NAIL PSORIASIS Psoriatic nail changes have various manifestations depending on the location of the disease within the nail unit (Fig. 1) (10). The largest portion of the nail unit is the nail plate, derived from the nail matrix, which is carefully protected under the proximal nail fold. There are two portions of nail matrix also known as the nail “growth center.” The distal matrix forms the ventral portion of the nail plate and the proximal matrix forms the dorsal part. In addition to the plate and matrices, the nail unit is composed of the nail bed and its anchoring portion surrounded by the nail folds, which include the cuticle adjacent to the proximal nail fold. The most distal part of the nail unit is the hyponychium. The final component of the nail Proximal nail fold

Nail plate Onychodermal band

Nail matrix

Hyponychium Distal phalanx

Nail plate Nail bed Proximal nail fold Matrix

Figure 1 The nail unit.

Onychodermal band Lateral nail fold Cuticle Distal phalanx

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unit is the distal phalanx beneath the nail structures. Changes in this joint element become evident as psoriatic arthritis (11). Alterations in nail unit organization occur in a limited number of sites: nail matrix, nail bed, proximal nail fold, and hyponychium (2,11) (Table 1). When the nail matrix is involved then pitting and leukonychia commonly occur (Fig. 2). Pitting is a phenomenon attributed to an abnormality in the maturation and keratinization of the proximal nail matrix (12). Pitting is the most common nail lesion found in psoriasis (13). The histopathology is the same as classic psoriasis but on a much smaller scale. The “pits” are actually produced by small foci of hyperproliferative parakeratotic cells. Just like in classic psoriasis, the overexuberant cell turnover leads to a build up of parakeratotic proximal matrix cells pressing against the dorsal nail plate (11). Zaias’ landmark study demonstrated that as the nail plate grows out, the poorly adherent parakeratotic cells desquamate from the surface of the nail plate (11) leaving an indentation as clinical evidence of their former activity (14). The nail pits’ depth and shape depend upon the extent and duration that the parakeratotic cells remain in place before becoming dislodged. This is a direct indicator of disease activity (2). While pitting may be seen in other disorders, the large size, irregular shape, and random distribution of the pits are the hallmark of fingernail psoriasis (11). Interestingly, nail pitting is infrequently seen on toenails (15). One possible mechanism to account for nail pitting in fingernails rather than toenails can be attributed to the varying growth rates of finger versus toenails. In toenails, the growth rate is much slower and therefore, the parakeratotic focus and the nail plate may grow out towards the hyponychium together (2). This would account for the lack of pitting and the marked increase in subungual hyperkeratosis as the key manifestation of toenail psoriasis. Subungual hyperkeratosis is analogous to thick plaque psoriasis on the skin and results from the deposition and collection of cells under the nail plate, which have not undergone desquamation (16). Like psoriasis elsewhere on the body, the hyponychial skin is subject to the Koebner phenomenon. Therefore, severe hyponychial involvement leading to subungual hyperkeratosis is more common in toenails because they are subject to more traumas than finger nails (11). Beau’s lines are horizontal indentations in the nail plate due to temporary arrest of matrix growth during a period of inflammation (11). Onychomadesis is due to severe disease leading to separation of the nail plate from the proximal nail fold (11). Trachyonychia is due to proximal matrix disease that manifests as roughened or “sandpaper” nails (17). Crumbling is a more severe form of trachyonychia and pitting. The whitish chalky plaque overlying the bed occurs when the entire matrix is involved for such a long duration that parakeratotic cells outnumber normal cells. Thus, the psoriatic changes are so severe that there is no semblance of normal cell structure remaining upon which cells can adhere (11). Red spots in the lunula are seen when the distal matrix is affected (2). When the nail bed alone is affected then “oil spots” (18), nail bed hyperkeratosis, and

Nail bed, mid-distal matrix

Splinter hemorrhages

Splinter hemorrhages Silvery classic plaques

Chronic paronychia

Proximal nail fold

228

Trachyonychia Crumbling (due to total matrix involvement for a long duration)

Onychomadesis

Hyperkeratosis

Subungual hyperkeratosis (when severe, this is the likely cause of onycholysis)

Nail bed and hyponychium

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Red spots in the lanula Crumbling (all matrix)

Onycholysis due to distal separation of the two structures progressing proximally

Nail bed and plate

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Beau’s lines

Oil spots

Nail bed only

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Nail matrix, proximal involvement

Nail unit psoriasis location

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Table 1 Clinical Manifestation of Nail Psoriasis Based on Location of Psoriatic Change in the Nail Unit

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Figure 2 Pitting in nail psoriasis

splinter hemorrhages (19) are common. Oil spots also known as “salmon patches” refer to a yellow-orange discoloration due to psoriasis of the nail bed (Fig. 3) (20). Leukonychia is caused by mid-matrix disease. The whitish areas are likely due to adherent foci of parakeratotic cells that cannot be dislodged. Onycholysis is a distinct phenomenon that results from separation of the nail bed from the plate (Fig. 4). The separation begins distally and progresses proximally towards the matrix. The plate appears whitish rather than yellow because air becomes trapped underneath it. It is usually surrounded by a reddish hue (11) and is distinguished from true leukonychia by location. Leukonychia is usually seen on the proximal portion of the plate whereas onycholysis appears whitish distally. Splinter hemorrhages are due to trauma and are analogous to the Auspitz sign associated with cutaneous psoriasis (11). Proximal nail fold plaques are marked by classic cutaneous psoriasis with silvery scales over a red base (2). This may appear as chronic paronychia (12). Nail bed psoriasis in conjunction with hyponychial

Figure 3 Oil spot in nail psoriasis.

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Figure 4 Onycholysis in nail psoriasis.

involvement leads to subungual hyperkeratosis and ultimately crumbling of the nail plate (21). While there are numerous manifestations of nail psoriasis, very few are characteristic of psoriasis alone. The classic oil spot is the most diagnostic lesion (20), followed by random fingernail pitting and subungual hyperkeratosis, respectively (14). Extensive onychodystrophy with painful pustules and loss of the nail plate is usually due to a more severe and distinct type of nail psoriasis known as acrodermatitis continua of Hallopeau (12). While most manifestations of nail psoriasis do not lead to scarring, pustular psoriasis remains the exception. Fortunately, this debilitating disorder is rare and often isolated to a single digit (15). Unfortunately, despite several treatment options described in the literature, successful eradication of the disorder prior to anonychia and scarring remains poor (22). Some success was found with oral retinoids and topical calcipotriol but relapses occurred (23). ASSOCIATION WITH PSORIATIC ARTHRITIS The most common signs of fingernail psoriasis are pitting and oil spots, with fingernail subungual hyperkeratosis being the most common sign associated with psoriatic arthritis (24). Moll and Wright originally classified psoriatic arthritis into five types based on clinical features (25). Type I refers to primarily distal interphalangeal (DIP) bone and joint erosion, which radiographically presents as the classic “pencil in cup deformity.” It affects approximately 5% of all patients. The rarest is type II, also known as arthritis mutilans, which presents as a severe mutilating arthritis that can have ocular involvement. Type III manifests as a symmetric polyarthritis that affects the small joints of the hands and feet and the large joints of the legs, such as the hips and knees. Type IV is the most common type, affecting approximately 70% of those patients who present with psoriatic arthritis. Asymmetric oligoarthritis is the hallmark of this type of psoriatic arthritis. It affects the same joints as type III, and may or may not present with DIP joint involvement. Type V is distinguished by axial disease that affects the spine and sacroiliac joints. It

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usually presents with ankylosing spondylitis. Of all the psoriatic arthritis types, this one is the least associated with nail disease. In addition to the five types of arthritis classically associated with psoriasis, pustulosis palmoplantaris with osteoarthritis sterno-clavicularis and psoriatic onycho-pachydermo-periostitis are now linked to psoriatic arthritis (26). The major distinguishing characteristic of the most common form of psoriatic arthritis, type IV, is that unlike rheumatoid arthritis, it usually presents with asymmetric joint disease. Furthermore, enthesopathy is unique to psoriatic arthritis; it is not seen in rheumatoid arthritis (27). Symptoms include joint pain, stiffness, and enthesitis (inflammation at the tendon insertion points) leading to “sausage digits” and joint deformation (28). It is classified as a seronegative, inflammatory arthropathy, meaning rheumatoid factor is usually negative. Much like cutaneous psoriasis, it waxes and wanes unpredictably (29). Many studies have established that patients with psoriatic DIP joint disease are highly likely to have associated psoriatic nail changes in the same digit (30,31). Furthermore, even if arthritic changes are not clinically evident, radiographic changes may be seen in the DIP joint of the same fingertip that has visible psoriatic nail disease (32). More recently, studies show that the distal phalynx bone is the most affected by adjacent nail involvement, with worsening nail disease correlating with worsening bony destruction. Additionally, it is theorized that DIP involvement may be the end result of this process (33,34). One study sought to determine if psoriatic nail alteration can be used as an independent predictor of psoriatic arthritis, regardless of the type (35). The study looked specifically at patients with the various types of psoriatic arthritis and found that 83% had clinically evident nail disease. As predicted, those patients with DIP involvement had more severe nail damage. Likewise, the severity of nail psoriasis is directly correlated with the severity of the enthesitis and skin psoriasis. The arthritis also tends to be progressive and unremitting in those patients. However, dactylitis and axial disease were not associated with nail disease. In fact, the lesser the nail involvement, the more likely the patient was to have the human leukocyte antigen (HLA)-B27 genetic haplotype, which is associated with axial rather than DIP joint disease (29). More severe nail involvement correlates with more severe joint disease with increased numbers of tender and swollen joints, especially the DIP. Additionally, one study found that scalp severity also correlates positively with the number of swollen joints, deformed joints, dactylitis, and DIP involvement. This suggests that not only nail involvement, but possibly scalp involvement can also predict psoriatic joint involvement (3). ASSOCIATED GENETIC HAPLOTYPES While the exact pathogenesis of nail psoriasis remains unclear, certain key HLA subtypes are known to be associated with certain psoriatic types (Table 2) (29,36,37). However, genetic factors alone cannot account for the occurrence of

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Table 2 Key Genetic Haplotypes Associated with Psoriatic Arthritis and Nail Disease Major histocompatibility class I type HLA B27 and HLA-Cw2

HLA-Cw6

HLA-Cw6 negative

HLA-B13 and HLA-B57 (B17)

Later onset; less nail disease; strong association with axial disease. If early onset, then linked to pediatric spondyloarthropathy, but still has a poor association with nail disease

Earlier onset; nail disease but less dystrophy than if Cw6 negative

Stronger association with dystrophic nails than if Cw6 positive

If more severe skin disease, then joint or nail disease

psoriasis. Environmental and immunologic factors most certainly play a role in its inception. NAIL PSORIASIS: CHILDHOOD VS. ADULT ONSET Characterizations of childhood psoriasis versus adult psoriasis are numerous and varied. A recent study from Kuwait examining the epidemiology of childhood psoriasis in 201 patients found that girls tend to develop psoriasis at an earlier age than boys with a female-to-male ratio of 1.42:1 (38). Of those patients, 38% had nail involvement. Nail pitting was the most common manifestation (62%), followed by onycholysis (30%), subungual hyperkeratosis (13%), and discoloration of nail plate (8%) (38). Various studies from around the world have had conflicting findings (39,40). This is likely based on varying genetic haplotypes and immunosusceptibility patterns to infectious disease that predispose to the development of psoriasis (41). A study from India found more males with childhood psoriasis (42), while a Denmark study found a female preponderance with childhood onset psoriasis (43). An Australian study found that the mean onset of psoriasis in children was less than five years of age (44), whereas most studies note onset to be between the ages of 5 and 14 (39–43). However, despite some contradictory data, certain generalities may be made regarding childhood versus adult onset nail psoriasis. Most patients, regardless of gender, develop psoriasis after the age of 20 as adults (45). When a familial history of psoriasis is found in association with juvenile-onset psoriasis, the disease course is inevitably more severe (46), more strongly associated with psoriatic arthritis (47), and more likely to display nail changes (6). Childhood onset of nail psoriasis is

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commonly precipitated by trauma or infectious disease (42,43,48). Also, the later the onset of cutaneous psoriasis, the less often concomitant fingernail or toenail psoriasis occurs. This is especially true for toenail psoriasis (49). Although rare, when a child presents with nail alteration as the sole manifestation of psoriasis, an evaluation for juvenile psoriatic arthritis should be considered (50).

DIAGNOSTIC CHALLENGE: ISOLATED NAIL PSORIASIS AND ITS IMPERSONATORS Onychomycosis The most common misdiagnosis for psoriatic nail disease is onychomycosis (2). It is easy to see why this occurs, especially if subungual hyperkeratosis is the primary feature in an isolated nail. Onychomycosis can occur concomitantly in psoriatic nails as well with a prevalence of 13% to 30% of patients with nail psoriasis (51,52). For this reason, it is prudent to perform a potassium hydroxide (KOH) wet mount, culture, or nail clipping for a periodic-acid-Schiff (PAS) stain to ensure there is no superimposed onychomycosis. Treatment of the overlying onychomycosis often causes diminution of the hyperkeratosis, allowing the more characteristic psoriatic changes such as oil spots to be revealed. Onychomycosis does not usually cause psoriatic nail changes, but rather each condition may worsen the other (53,54). This is often difficult to eradicate. It is especially true if the superimposed infection is due to molds rather than dermatophytes (54).

Allergic Contact Dermatitis in One Nail Typically, most patients with ungual contact dermatitis also have some other skin site involved, which helps to confirm the diagnosis, although it may be confined to one digit. It is most commonly due to nail trauma (55) or nail cosmetics (56). Like most diagnostic dilemmas, a thorough history and examination usually helps to ascertain the correct diagnosis.

Drug Reactions Onycholysis is often seen in patients taking phototoxic drugs such as antibiotics (57). However, drug-induced onycholysis may occur with no associated cutaneous photosensitivity. Beau’s lines and onychomadesis are the most common abnormality associated with drug reactions (58). When they are also associated with onycholysis, the clinical picture can clearly mimic psoriasis (59). A careful evaluation of the history of the lesions should identify the likely culprit. Psoriatic nail changes typically have a slower onset than those due to a drug reaction, which can often be sudden and explosive.

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Linear Verrucous Epidermal Nevus Linear psoriasis is a rare entity whose existence has been questioned (60). It is difficult to distinguish from linear verrucous epidermal nevus, although it is likely a true condition that has been well described in the literature (60,61). Biopsy alone may not confirm the diagnosis because histologic features may overlap (62,63). Therefore, when only an isolated nail is the presenting sign, unless other presenting signs of psoriasis become manifest, it may be impossible to discriminate between the two conditions (64). Lichen Striatus This is an interesting disorder that is also commonly confused with linear epidermal nevus and linear psoriasis. It is more commonly seen in children on an isolated nail. The characteristic finding is linear trachyonychia and dystrophy of the nail plate with partial pterygium formation and then spontaneous resolution (65). It does not present with pitting or onycholysis. Parakeratosis Pustulosa This disorder is seen only in children. It presents with occasional isolated fingertip scaling and erythema in either the thumb or index finger. It may be a variant of psoriasis. Nail changes are always present and include onycholysis and hyperkeratosis on only one side of the nail. Typically, children have spontaneous resolution of the disorder by the time they reach puberty. However, some may later manifest widespread cutaneous psoriasis after they reach adulthood (12). Squamous Cell Carcinoma Albeit rare, there have been reports of squamous cell carcinoma (SCC) arising in psoriatic nails (66–68). There is only one report of SCC arising in a psoriatic nail bed (59). Interestingly, this man had an exophytic verrucous plaque arising from a psoriatic thumbnail that became progressively larger over a four-month period. Finally, pain prompted the patient to report it to his physician. Because it had progressed substantially, the terminal phalanx required amputation. Histologic examination of the amputated digit revealed well-differentiated SCC with erosion through the dermis and into the bone. The important feature of this case is that there was a delay in diagnosis because both the patient and the physician assumed that the excess hyperkeratosis was due to worsening psoriasis. DIAGNOSTIC PROCEDURE: THE NAIL BIOPSY Numerous excellent textbooks (2,69,70) describe the appropriate method for punch biopsy of the nail bed versus the nail matrix (71). It is a simple straightforward procedure that is safely and routinely performed in the office setting. With difficult or challenging cases, the biopsy can be invaluable in ascertaining the cause of the

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nail abnormality as it can help distinguish between neoplasms, infections such as dermatophyte, and inflammatory conditions including psoriasis. On occasion, both the nail bed and the matrix require biopsy simultaneously. In this case a longitudinal biopsy may be appropriate (72). MEASUREMENT OF SEVERITY: THE NAIL PSORIASIS SEVERITY INDEX It is important to have an objective scale with which to measure disease severity. The Psoriasis Area and Severity Index (PASI) is used primarily for cutaneous psoriasis but does not adequately measure nail disease activity. Therefore, the Nail Psoriasis Severity Index (NAPSI) was developed to objectively quantify the severity of nail disease in a reproducible manner (73). It was also designed to assess efficacy of drug therapy for different manifestations of nail psoriasis (e.g., pitting vs. subungual hyperkeratosis). Using NAPSI, the nail is divided into four quadrants, each of which is then graded based on the presence or absence of nail matrix or nail bed disease. The highest score possible for each fingernail is 8 for a total of 80. If toenails are included, then the maximum total number increases to 160 (Tables 3 and 4). The sum of the scores is calculated and used to judge the severity of nail psoriasis. Not included in this grading system are proximal nail fold psoriasis, pustular psoriasis, and psoriatic arthritis. Other methods have also been proposed but we find NAPSI the most complete and useful (74–76). Table 3 NAPSI Scoring System NAPSI scoring systema

Nail matrixb

Nail bedc

Total scored

0 1

None Present in 1 quadrant

None Present in 1 quadrant

2

Present in 2 quadrants

Present in 2 quadrants

3

Present in 3 quadrants

Present in 3 quadrants

4

Present in 4 quadrants

Present in 4 quadrants

0 Possible points: 1 or 2 Enter score: Possible points: 2 or 4 Enter score: Possible points: 3 or 6 Enter score: Possible points: 4 or 8 Enter score:

a For

each nail, score the points as shown in the column. means evidence of any: (1) pitting, (2) leukonychia, (3) red spots in the lunula, or (4) crumbling. c This means evidence of any: (1) onycholysis, (2) splinter hemorrhages, (3) subungual hyperkeratosis, or (4) oil spots/salmon patch. d There is a minimum of 0 and a maximum of 8 points awarded for each nail: 4 possible points for evidence of matrix disease and 4 possible points evidence of nail bed disease. Abbreviation: NAPSI, Nail Psoriasis Severity Index. b This

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Table 4 NAPSI Scoring Table Nail scoring table—compile the score for each nail Nail 1 Nail 5 Nail 9 Final score total:

Nail 2 Nail 6 Nail 10

Nail 3 Nail 7

Nail 4 Nail 8

Note: Minimum score is zero and maximum score is 80. Abbreviation: NAPSI, Nail Psoriasis Severity Index.

TREATMENT OPTIONS AND COMPLICATIONS FROM THERAPY There are numerous treatments for nail psoriasis. This tends to be a chronic, persistent condition and since the nail grows slowly, numerous months of treatment are required in many cases to see the results. Topical medications are theoretically ideal since they have the advantage of direct application of the medication to the affected area without the risk of systemic side effects or drug interactions with systemic medications or the pain of intralesional injections. Nevertheless, the low permeability of the nail plate creates difficulties in topical drug therapy (77). Currently, the drugs used for psoriatic nail disease are usually classified as follows: steroids, biologic agents, retinoids, and other miscellaneous therapies such as chemotherapy or phototherapy. Each therapeutic class will be discussed in detail (Table 5).

Table 5 Therapeutic Options for Nail Psoriasis Topical

Intralesional Oral

Subcutaneous or intravenous

Radiation Combinations

Corticosteroids Calcipotriol Tazarotene 5-Fluorouracil Cyclosporine Anthralin Corticosteroids Acitretin & isotretinoin Cyclosporine Sulfasalazine Etanercept, infliximab, adalimumab Alefacept Efalizumab PUVA Topical corticosteroid & topical calcipotriol Topical corticosteroid & topical salicylic acid Oral cyslosporine and topical corticosteroid

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Steroids and Steroid-Like Drugs The high potency topical steroids are likely the most utilized form of therapy for nail psoriasis. Typically, a high potency corticosteroid ointment such as clobetasol is applied to both the nail plate and proximal nail fold nightly (78). Clobetasol nail lacquer alone or in combination with a vitamin D3 analog has been studied as well (79–81), but is not readily available. Topical corticosteroids are relatively inexpensive, readily available, and are easy to apply without concern for systemic side effects or pain. Nevertheless, both steroid atrophy of the nail fold and tachyphylaxis can occur with prolonged use. There have been a few reports of a “disappearing digit” after extreme prolonged use as well (82). Penetration of the topical corticosteroid alone is a problem and seems to result in marginal efficacy. When combined with salicylic acid ointment, efficacy for topical corticosteroids increases for reduction of hyperkeratosis and nail thickness (83). The most effective of all steroids for nail matrix psoriasis appears to be the triamcinolone acetonide (TAC) (2.5–10 mg/mL) injection administered into the proximal and/or lateral nail fold every month for six months. Some dermatologists prefer using a ring block for anesthesia prior to the injection (84). However, in our experience, dilution of the TAC with 1% lidocaine and application of anesthetic refrigerant spray prior to rapid injection minimizes patient discomfort and increases tolerability. One report found that 0.4 mL of 10 mg/mL TAC injected intralesionally into the nail bed and nail matrix worked best for subungual hyperkeratosis, ridging, and thickening while only moderate results were obtained for pitting and onycholysis (84). Another studies have found good results with injection only into the proximal nail fold (85,86). The major complications from this therapy are pain, hemorrhage under the nail plate (2), and steroid-induced atrophy or hypopigmentation of the skin and subcutaneous tissues (87). However, in our experience, careful injection at the inflammatory psoriatic site with small amounts at a concentration of 2.5 mg/mL of steroid does not cause major atrophy. As an added positive side effect, patients report that associated painful DIP joint arthritis seems to diminish with repeated injections. Calcipotriene (Dovonex) is a vitamin D3 analog that binds to a similar steroid receptor in the skin. The cream and ointment forms have been studied in comparison to a topical steroid for use in the treatment of nail psoriasis and both were just as effective in decreasing hyperkeratosis (83). Additionally, one case series found calcipotriol to be helpful in pustular psoriasis of the nails, both for regression of lesions and prevention of relapse (23). Calcipotriene may be most effective in treating subungual hyperkeratosis, onycholysis, and discoloration (88). However, the ideal use of calcipotriene appears to be in combination with other oral agents such as cyclosporine (89) or even topical steroids (90). Combination therapies seem to be more effective at producing clinical improvement in nail psoriasis. Additionally, with this medication, there are no injections, no risk of atrophy, tachyphylaxis or hemorrhage, and patients experience minimal side effects.

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Biologic Agents There are several biologic agents available to combat cutaneous psoriasis. While many studies focus on plaque-type psoriasis and psoriatic arthritis with varying degrees of success (91–93), very little reproducible scientific information exists with regard to biologic agents improving nail psoriasis. Almost all of the biologic agents target either tumor necrosis factor-alpha (TNF-) or T cells. TNF- is a cytokine required for cell-mediated inflammation (94). The key cell in the inflammatory milieu is the activated T cell (95). The rationale for use of biologics is that they are designed to diminish TNF- or inhibit T-cell activity, which, in turn, appears to decrease the inflammatory, destructive component of psoriasis resulting in clinical improvement in disease. These medications can be loosely grouped as TNF- inhibitors (etanercept, adalimumab, and infliximab) and T cell modulators (alefacept and efalizumab). Etanercept (Enbrel) is a TNF- receptor antibody fusion protein, which acts like a soluble TNF- receptor that competitively binds free TNF- and is administered subcutaneously one to –two times a week (96). The TNF- molecule becomes biologically inactive. Infliximab (Remicade) is a chimeric mouse/human monoclonal antibody against TNF-. It also binds to TNF- and blocks its function. It is administered IV once every two months (97). The human monoclonal antibody, adalimumab (Humira), is also an antibody against TNF- and is administered subcutaneously every two weeks (94). While adalimumab and infliximab are structurally distinct from etanercept and have a discrete mechanism of action, the end result is similar. All three drugs bind TNF-, blocking its ability to bind to its receptor and thereby reducing localized inflammation (94). These three biologic agents are all FDA approved for the treatment of psoriasis and are all pregnancy category B. Of these, etanercept and infliximab have been reported specifically for the treatment of nail psoriasis. There is one case of rapid improvement and cure of nail psoriasis with etanercept (98). Infliximab has been studied in more detail for psoriasis. A recent double-blind placebo-controlled study of infliximab found marked and sustained nail improvement in onycholysis, splinter hemorrhages, oil drop discoloration, and hyperkeratosis. Clearance of psoriasis in the target nail was achieved in about 50% patients by week 50 (99). While the TNF- inhibitors have shown success in treating psoriasis and nail psoriasis, the cost is prohibitive for many patients. Additionally, any active chronic infection such as tuberculosis or hepatitis B is a contraindication to therapy (100). The possibility of increasing the risk of lymphoma with the use of the medication is also debated in the literature (100). Relative contraindications to therapy include heart failure, prior malignancies, and family or personal history of systemic lupus or multiple sclerosis (100). Recently, there have been reports of a paradoxical phenomenon occurring with all three of these mediations as well, which is the induction of psoriasis, including nail psoriasis by TNF- inhibitors (101). Alefacept (Amevive) is a human recombinant fusion protein composed of LFA-3 with Fc portion of IgG. Alefecept binds to T cells at the CD2 receptor

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and prevents T-cell activation and induces apoptosis (102). It is approved by the FDA for the treatment of psoriasis, administered intramuscularly weekly and is pregnancy category B. CD4 count must be monitored while patients are on this drug. A few small case series on the use of alefacept for psoriatic nails have shown variable results with marked to minimal improvement (103–105). One report found that it worked better for nail matrix disease (50% improvement at 24 weeks) than nail bed disease (103). Efalizumab (Raptiva) is a humanized monoclonal antibody against the CD11 portion of the LFA-1 molecule on T cells. This prevents binding to ICAM on the antigen-presenting cell and prevents T cell from migrating to the skin (106). Because it does not actually destroy the activated pathogenic T cells like alefacept, the psoriasis can actually worsen upon cessation of the drug due to a sudden influx of T cells into the skin. Efalizumab is FDA approved for the treatment of psoriasis, is administered subcutaneously weekly, platelets must be monitored during therapy, and it is pregnancy category C. Currently, no articles have studied specifically the treatment of nail psoriasis with efalizumab. A newer class of biologic therapy in development is the human monoclonal antibody to IL12/23, such as the medications ABT-874 and ustekinumab. This antibody binds to the p40 subunit, which is shared by both IL12 and IL23, which are overexpressed in psoriatic lesions. The function of these two cytokines is then neutralized. These medications are in clinical trials and may be effective at treating psoriasis but currently no studies evaluating their effect on psoriatic nail disease have been conducted (107–110). Retinoids Tazarotene (Tazorac) 0.1% gel is a topical retinoid whose active metabolite tazarotenic acid binds with high affinity to the gamma subunit of the retinoic acid receptors (RARs) in the skin and nails. The RAR- is the predominate type of RAR in the epidermis (111). Topical tazarotene impairs keratinocyte proliferation and inflammation, which may be one of the mechanisms for onycholysis. One study from Columbia University demonstrated that tazarotene under occlusion appears to reduce onycholysis and also improve the appearance of pitting (112). A subsequent study confirmed this finding (113). A recent double-blind comparison trial of tazarotene cream 0.1% versus clobetasol 0.05% cream found marked improvement in both groups in pitting, hyperkeratosis, onycholysis, and salmon patches with regression after therapy stopped (114). All studies found that the drug was well tolerated; repeated use caused minimal irritation. Acitretin (Soriatane) and isotretinoin (Accutane, Sotret, Claravis, Amnesteem) are systemic retinoids that are more effective when combined with phototherapy, either UVB or PUVA (115,116). Acitretin is the treatment of choice for pustular psoriasis but is less effective against plaque psoriasis (117). There is one report of near total clearance of severe nail psoriasis with acitretin (118). Another report compared low-dose short-term cyclosporine with etretinate and found

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significant alleviation of nail involvement in both the groups (119). Although these are impressive results, oral retinoids are not the best choice for isolated nail psoriasis given the sytemic side effects of hyperlipidemia, hyperostosis, and the localized side effects xerosis and periungual pyogenic granulomas (120). One major limitation of both the topical and systemic retinoid is that they are both pregnancy category X. Oral or Topical Chemotherapy and Keratolytic Agents Cyclosporine (Gengraf, Neoral, Sandimmune) is well established as an effective oral immunosuppressive agent for the treatment of generalized psoriasis as well as nail psoriasis (119,121). While being highly effective, the systemic side effects make it less than ideal for long-term therapy or for isolated nail disease. Side effects include hypertension, renal insufficiency, increased risk of skin cancers, and elevated lipids. It is also pregnancy category C. It is rarely used topically because it is a relatively large, highly lipophilic molecule that is unable to permeate the nail plate. Unlike the skin and GI tract, which have lipid permeable membranes, the nail plate is actually more of a concentrated hydrogel (121). Therefore, small hydrophilic molecules preferentially diffuse through the structure to the nail bed. This is the reason gels (e.g., Tazarotene 0.1% gel rather than cream) or other waterbased preparations are needed when choosing a topical agent for nail psoriasis. Cyclosporine cannot dissolve in water; so one study used a 70% maize-oil–dissolved oral cyclosporine solution applied to the nail plate versus a maize-oil–only vehicle (122). This method was effective in improving nail psoriasis. The key feature of this study is that the vehicle can alter the efficacy of a drug because it is unable to penetrate the nail plate. Numerous case series have shown that daily topical 1% to 5% 5-fluorouracil (Efudex) is effective for the treatment of psoriatic nails with improved pitting, subungual hyperkeratosis, onycholysis, and oil spots (123,124). Fluorouracil is a chemotherapeutic agent that inhibits the enzyme thymidylate synthetase, which leads to a decrease in cellular proliferation. It appears that using the low-dose formulation of the drug in a delayed nail penetration vehicle such as urea and propylene glycol enhances penetration (125). Like most agents that interfere with DNA synthesis, it is pregnancy category X. Most of the studies with the drug have shown localized irritation with occlusive dressings as the most serious adverse effect. However, there is one report of transient rhabdomyolysis occurring after the use of topical 5-fluorouracil (126). There are no reports of isolated nail psoriasis treated with methotrexate. Like fluorouracil, it inhibits DNA synthesis but the exact mechanism for blocking inflammation is still unknown. Because it is an immunosuppressive agent like cyclosporine, it is difficult to justify use of this agent for isolated nail psoriasis except if there is severe impairment of digit function. It is pregnancy category X. Sulfasalazine (Azulfidine) is a sulfonamide that is used to treat psoriatic arthritis. There is one case report of improvement in nail psoriasis with its use

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(127). However, in this report the patient had previously been treated with acitretin for 12 months. Like most oral medications, the benefit of the drug for isolated nail psoriasis must outweigh the potential side effects and it is pregnancy category class B. Topical anthralin is not usually a first-line medication due to the risk of long-term pigmentation of the nail plate. However, it has been used with moderate success for refractory nail psoriasis with improvement in onycholysis, pachyonychia, and pitting (128). In this study, the authors were careful to ensure that the anthralin was washed away after 30 minutes of contact followed by application of 10% triethanolamine to prevent pigmentation. Phototherapy PUVA has been reported to be effective for all the different manifestations of nail psoriasis except for pitting (129,130). Presumably, this is due to the inability of the light to penetrate the proximal nail fold skin sufficiently to affect matrix normalization. The major drawback of this therapy is the risk of severe PUVA burns with overexposure. There are no studies evaluating the efficacy of narrowband UVB in the treatment of nail psoriasis. However, one study evaluated the usefulness of 308 nm eximer light and found no benefit (131). Grenz ray therapy has been used with moderate success to treat psoriatic nails. In a Swedish study, moderate control was obtained using grenz ray on one hand compared to the other hand, which was untreated and acted as a control (132). This is no longer a practical therapy for office dermatology, but it may be an option for patients who require therapy for refractory nail psoriasis. Radiotherapy appears to have little curative benefit for nail psoriasis, but did decrease the thickness of the nail plate (130). This perhaps could be used as a method for preparing the nails for one of the topical occlusive therapies, but the concern for radiation adverse effects render it impractical. Compared to classic cutaneous psoriasis, nail psoriasis is a poorly studied entity. The reasons for this are multifactorial. It is commonly misdiagnosed or diagnosis is delayed because it mimics numerous other disorders. Once a proper diagnosis is made, it is often difficult to treat. Traditional systemic therapies show inconsistent benefit for nail psoriasis. The most promising of all therapies are the newer biologic agents such as infliximab. No doubt the elusive definitive treatment has yet to be developed. Meanwhile for isolated nail psoriasis, the best treatment remains simple intralesional corticosteroids. REFERENCES 1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 1996; 14(3):485–496. 2. Rich P, Scher R. Nail Manifestations in Cutaneous Disease. An Atlas of Diseases of the Nail. Parthenon Publishing Group, Inc., 2003:51–54.

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chronic plaque psoriasis: Results of a randomized, placebo-controlled, phase 2 trial. Arch Dermatol 2008; 144(2):200–207. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356(6):580–592. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371(9625):1665–1674. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371(9625):1675–1684. Van Laborde S, Scher RK. Developments in the treatment of nail psoriasis, melanonychia striata, and onychomycosis. A review of the literature. Dermatol Clin 2000; 18(1):37–46. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernail psoriasis: A double-blind, randomized, vehicle-controlled study. Cutis 2001; 68(5):355– 358. Bianchi L, Soda R, Diluvio L, et al. Tazarotene 0.1% gel for psoriasis of the fingernails and toenails: An open, prospective study. Br J Dermatol 2003; 149(1):207–209. Rigopoulos D, Gregoriou S, Katsambas A. Treatment of psoriatic nails with tazarotene cream 0.1% vs. clobetasol propionate 0.05% cream: A double-blind study. Acta Derm Venereol 2007; 87(2):167–168. Roenigk RK, Gibstine C, Roenigk HH Jr. Oral isotretinoin followed by psoralens and ultraviolet A or ultraviolet B for psoriasis. J Am Acad Dermatol 1985; 13(1):153– 155. Lebwohl M. Acitretin in combination with UVB or PUVA. J Am Acad Dermatol 1999; 41(3, pt 2):S22–S24. Moy RL, Kingston TP, Lowe NJ. Isotretinoin vs. etretinate therapy in generalized pustular and chronic psoriasis. Arch Dermatol 1985; 121(10):1297–1301. Brazzelli V, Martinoli S, Prestinari F, et al. An impressive therapeutic result of nail psoriasis to acitretin. J Eur Acad Dermatol Venereol 2004; 18(2):229–230. Mahrle G, Schulze HJ, Farber L, et al. Low-dose short-term cyclosporine versus etretinate in psoriasis: Improvement of skin, nail, and joint involvement. J Am Acad Dermatol 1995; 32(1):78–88. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001; 45(5):649–661; quiz 62–64. Murdan S. Drug delivery to the nail following topical application. Int J Pharm 2002; 236(1–2):1–26. Cannavo SP, Guarneri F, Vaccaro M, et al. Treatment of psoriatic nails with topical cyclosporin: A prospective, randomized placebo-controlled study. Dermatology 2003; 206(2):153–156. Schissel DJ, Elston DM. Topical 5-fluorouracil treatment for psoriatic trachyonychia. Cutis 1998; 62(1):27–28. Fredriksson T. Psoriatic nails and 5-fluorouracil. J Am Acad Dermatol 1982; 6(1):117. de Jong EM, Menke HE, van Praag MC, et al. Dystrophic psoriatic fingernails treated with 1% 5-fluorouracil in a nail penetration-enhancing vehicle: A double-blind study. Dermatology 1999; 199(4):313–318.

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126. Schmied E, Levy PM. Transient rhabdomyolysis connected with topical use of 5fluorouracil in a patient with psoriasis of the nails. Dermatologica 1986; 173(5):257– 258. 127. Gerster JC, Hohl D. Nail lesions in psoriatic arthritis: Recovery with sulfasalazine treatment. Ann Rheum Dis 2002; 61(3):277. 128. Yamamoto T, Katayama I, Nishioka K. Topical anthralin therapy for refractory nail psoriasis. J Dermatol 1998; 25(4):231–233. 129. Marx JL, Scher RK. Response of psoriatic nails to oral photochemotherapy. Arch Dermatol 1980; 116(9):1023–1024. 130. Yu RC, King CM. A double-blind study of superficial radiotherapy in psoriatic nail dystrophy. Acta Derm Venereol 1992; 72(2):134–136. 131. Aubin F, Vigan M, Puzenat E, et al. Evaluation of a novel 308-nm monochromatic excimer light delivery system in dermatology: A pilot study in different chronic localized dermatoses. Br J Dermatol 2005; 152(1):99–103. 132. Lindelof B. Psoriasis of the nails treated with grenz rays: A double-blind bilateral trial. Acta Derm Venereol 1989; 69(1):80–82.

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Index

6-Point Target Plaque Severity (TPS) rating scale, 169–170 7-Point Global Assessment of Improvement (GAI) rating scale, 169–170 Acitretin (Soriatane) therapeutic use for nail psoriasis, 239 Active, lesional psoriasis, expression of, 13 Active medications to the scalp, 17–18 R Adalimumab (Humira ; Abbott Laboratories), 156 Advantages and disadvantages NB-UVB, 107 PDL, 121 PDT, 123 PUVA photochemotherapy, 111 targeted (localized) phototherapy, 118 Adverse events from corticosteroid use, 31 hydrogel dressing, 175 topical calcineurin inhibitors, 86–87 Adverse side effects R calcipotriene (Dovonex ), 47–48 PDL, 122 PDT, 123 PUVA photochemotherapy, 113–115 targeted (localized) phototherapy, 119 UVA1, 120 UVB phototherapy, 108–109 Alefacept (Amevive) therapeutic use for inverse psoriasis, 219 therapeutic use for nail psoriasis, 238–239 R Alefacept (Amevive ; Astellas Pharma), 153–154

Alteration of the stratum corneum by increasing its permeability, 27 Ankylosing spondylitis, 230 Annual U.S. cost estimates of treating psoriasis, 33 Anthralin/dithranol, 96–98 Arthritis mutilans, 230 Assignment of patients to treatment groups, 174f Asymmetric oligoarthritis, 230 Beau’s lines, 227 Betamethasone dipropionate/calcipotriene combination, 66 Betamethasone dipropionate/calcipotriene ointment, topical fixed-dose, 58–59 Betamethasone dipropionate/calcipotriene scalp formulation, 166 “Black box” warning, 87 Body surface area, 1, 12 amount, cost, and time/effort of topical therapy, 16 BSA. See Body surface area Calcineurin inhibitor cyclosporine, 83 Calcipotriene-containing combination agent, 66–67 R Calcipotriene (Dovonex ), 16, 34, 41, 171 and phototherapy, 46 and systemic agents, 46–47 and tazarotene, 45–46 and topical steroids, 45 application in psoriasis, 50 combination therapy, 44–45 contraindication in patients with known calcium metabolism, 50 hypercalcemia and hypercalciuria, 49 “real life” efficacy of, 131 249

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250 R Calcipotriene (Dovonex ) (Continued )  R tazarotene (Tazorac ), 71–72 T-cell apoptosis, 104 therapeutic use for nail psoriasis, 237 topical calcineurin inhibitors, 84 Calcipotriene in children, 43–44 Calcipotriene monotherapy, 43 Calcipotriene ointment, 41, 44 Calcipotriene plus narrowband UVB phototherapy (NB-UVB), 46 Calcipotriene plus PUVA phototherapy, 46 Changing corticosteroid structural elements, functional effects of, 25f Chemistry and mechanism of action calcipotriene, 42–43 Classic psoriatic plaques, 199 Clinical findings palmar and plantar psoriasis plaques, 86 tacrolimus and pimecrolimus, 84–86 topical calcineurin inhibitors, 85 Clinical morphology scalp psoriasis, 198 Clinical presentation inverse psoriasis, 210–211 R Clobetasol propionate (Olux foam), 134 R Clobetasol propionate (Olux ), foam formulation, 170–171 Clobetasol propionate 0.05% shampoo, 200–201 R Clobetasol propionate gel (Temovate scalp application), 171 Clobetasol propionate shampoo R (CLOBEX shampoo), 170–171 R Clobetasol propionate spray (CLOBEX Spray), 168–170 COBRA trial, 170 R Clobetasol Propionate lotion (CLOBEX lotion), 171 Coagulase-positive Staphylococcus, 9 Coal tar, 92–96 Coal tar efficacy, 92 Combination corticosteroid/calcipotriene therapy, 58 Combination therapy, 139–140. See also Therapeutic use acitretin, 150–151

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Index biologic agents with topical therapies and phototherapy, 151–157 cyclosporine, 148–150 guidelines, 140t methotrexate, 147–148 PDL, 121 PDT, 122 PUVA photochemotherapy, 109–110 systemic agents with topical therapies, 146–151 targeted (localized) phototherapy, 117–118 UVA1, 119–120 UVB phototherapy, 105–106 with calcipotriene ointment, 47 Combination topical therapies, 16, 19 Compliance rates measured by electronic monitors, 28–29 Concentration of the active drug within the vehicle, 26 Contraindications PDT, 122 PUVA photochemotherapy, 111 targeted (localized) phototherapy, 118 UVA1, 120 UVB therapy, 106 Corticosteroid compound, ability to traverse the stratum corneum, 26 Crude coal tar, 92 Crumbling, 227 R CuraStain , 98 Cutaneous T-cell lymphoma (CTCL), 87 Cyclosporine (Gengraf, Neoral, Sandimmune) therapeutic use for inverse psoriasis, 217–218 therapeutic use for nail psoriasis, 240 Cytoplasmic corticosteroid receptor, 30 Delayed-type hypersensitivity local T-cell activation, 14 “Dental floss effect,” 29 Differential diagnosis inverse psoriasis, 212 palmoplantar psoriasis, 184–185, 184t scalp psoriasis, 199 Discoid plaque psoriasis, 9

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Index Distal interphalangeal (DIP) bone and joint erosion/ “pencil in cup deformity,” 230 Distal matrix, 226 Distal phalanx beneath the nail structures, 227 Doctor–patient discussion of psoriasis, 16t Dose and administration NB-UVB, 107–108 PUVA photochemotherapy, 111–113 targeted (localized) phototherapy, 118–119 UVA1, 120 Duration of treatment, affect on compliance rates, 34 R Efalizumab (Raptiva ) therapeutic use for inverse psoriasis, 219 therapeutic use for nail psoriasis, 239 R Efalizumab (Raptiva ; Genentech), 152 Efficacy PDL, 121 PDT, 122 PUVA photochemotherapy, 109 targeted (localized) phototherapy, 115–117 UVA1, 119 UVB phototherapy, 104–105 Emollients, 186 Enthesopathy, 231 Epidemiology inverse psoriasis, 209–210 scalp psoriasis, 197 Erythrodermic psoriasis, 2–3, 9–11 Etanercept (Enbrel) therapeutic use for inverse psoriasis, 218 therapeutic use for nail psoriasis, 238 R Etanercept (Enbrel ; Amgen-Wyeth), 155–156 Etiology inverse psoriasis, 211 Extensive onychodystrophy with painful pustules and loss of the nail plate, 230

Fingernail psoriasis, 230 First-line topical therapies, 15–16

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251 Fixed-dose corticosteroid/calcipotriene combination therapy compliance with a long-term treatment regimen, 68 R for scalp (Taclonex Scalp ), 166–168 in combination with biologics, 67 FKBP (FK506-, or tacrolimus-binding protein), 84 Flexural psoriasis, 11 Flurandrenolide impregnated tape (Cordran), 31 Foam formulation, 134 Generalized pustular psoriasis (GPP), 86 Goa powder, 96 Goeckerman regimen, 144 Goeckerman therapy, 92–94 Grenz ray therapy, 241 Guttate psoriasis, 8–9 Hydrocolloid dressing, 172 Hydrocolloid layer, 172 Hydrogel patch, 172–179 Hypercalcemia, 50 Hyperplasia of psoriasis, 7 Hyponychium, 227 Hypothalamic-pituitary-adrenal (HPA) axis suppression, 2 Ideal phototherapy for localized psoriasis, 103 Increased risk of SCCs, 114 Indications PUVA photochemotherapy, 110 targeted (localized) phototherapy, 118 UVA1, 120 UVB therapy, 106 Individual patient preference, 28 R Infliximab (Remicade ) therapeutic use for inverse psoriasis, 218–219 R Infliximab (Remicade ; Centocor), 154 Intercellular adhesion molecute-1 (ICAM-1), 152 Inverse psoriasis, 13, 209 botulinum toxin, 215 nephrotoxicity, 218

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252 Inverse psoriasis (Continued ) targeted ultraviolet light therapy, 216 topical anthralin and tar, 215 topical corticosteroids, 212–213 topical immunomodulators, 214–215 treatment, 212–219 ultraviolet light, 215–216 Irritation from calcipotriene, 48 Keratolytics, 15 Lactic acid, 100 Leukocyte function antigen (LFA-1), 152 Leukonychia, 229 Lichen Striatus, 234 Linear verrucous epidermal nevus, 234 Liquor carbonis detergens (LCD), 92 Localized psoriasis, treatment of, 7–8 Location of psoriasis, 13 Long-term, once daily fixed-dose therapy, 62–64 Methotrexate therapeutic use for inverse psoriasis, 216–217 Mild-to-moderate psoriasis (relatively localized psoriasis), 9 Minimal erythema doses (MEDs), 115 Minimal phototoxicity dose (MPD), 113 Moderate-to-severe psoriasis multiple approaches to rotating available therapies, 21t selection of photo/systemic treatments, 18t Moderate-to-severe psoriatic patient, therapeutic challenge, 17–18 Nail bed psoriasis with hyponychial involvement, 230 Nail biopsy, diagnostic procedure, 234–235 Nail psoriasis, 78, 225 clinical manifestations, 226–230 childhood vs. adulthood, 232–233 drug reactions, 233 treatment options and complications, 236–241

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Index phototherapy, 241 steroids and steroid-like drugs, 237 Nail psoriasis severity index (NAPSI), 235–236 National Psoriasis Foundation (NPF), 1 Nonmessy preparations, 28 Occlusion, 18 extensive use of steroid, 19 Occupational trauma/Koebner phenomena, 184 Office-based localized phototherapy, 8 Once daily fixed-dose therapy, 61–62 Once daily vs. twice daily therapy, 60–61 Onycholysis, 229 Onychomadesis, 227 Onychomycosis, 233 Outpatient UVB phototherapy, 46 Palmar–plantar psoriasis, 11, 13 Palmoplantar psoriasis, 183–192 possible treatment algorithm, 191f protective measures, 186 treatment cyclosporine A (CyA), 190 directed phototherapy, 189 systemic methotrexate, 189–190 systemic retinoids, 189 topical corticosteroids, 186–187 topical methotrexate, 188 topical psoralen and ultraviolet A (topical PUVA), 188–189 topical retinoids, 187–188 topical vitamin D derivatives (calcipotriene/calcipotriol), 187 ultraviolet B therapy (UVB), 188 Parakeratosis pustulosa, 234 Patient compliance, 28, 34 Patients with palmar–plantar psoriasis, 2–3 Patients with ungual contact dermatitis, 233 PDL, 120–122 Periodically rotating the different available therapies, 20 Photodynamic therapy (PDT), 122—123, 204 Phototherapy and/or systemic therapy, 13 Phototherapy combinations, 140–142

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Index Physicians’ compliance through practical ways, 33–34 Pimecrolimus, 215 Pitting, 227 Proximal matrix, 227 Proximal nail fold plaques, 229–230 Pseudoteigne amiantac´ee, 198 Psoralens, 109 “Psoriasis Advance”, 6 Psoriasis area and severity index (PASI) 75, 1, 12–13 Psoriasis in susceptible (Koebner-responsive) patients, 13–14 Psoriasis therapy, rationale for, 24 Psoriasis treatment, general approach, 5–8 address patients’ psychosocial needs, 5–7 categorization of psoriasis, 7 Psoriasis vulgaris, calcipotriene as a class II corticosteroid, 213 Psoriatec, 96–97 Psoriatic arthritis, 11–13 classification of, types and incidence, 12t of nail, types of, 230–231 presence or absence of,14 role of the dermatologist in identification, 12t Psoriatic arthritis and nail, key genetic haplotypes associated, 232t Pulsed dye laser. See PDL PUVA combined with systemic retinoids (RePUVA), 110 “PUVA itch,” 113 PUVA lentigines, 114 PUVA photochemotherapy, 109 PUVA-induced phototoxic reactions, 113 RAR, 71 RAR, 71 Red spots in the lunula, 229 Retinoic acid receptors (RARs), 71 Retinoid X receptors (RXRs), 71 Rotational therapy, 19 Salicylic acid, 98–100 Salicylic acid gel trials, 28–29

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253 “Salmon patches”, 229 R Saran Wrap , 172 Scaling of the scalp/pityriasis amiantacea, 199 Scalp involvement, people with psoriasis, 166 Scalp psoriasis, 8, 197–205 therapeutic aspects coal tar, 201 debridement of the scalp, 201 dithranol, 201 Imidazole antifungals, 201–202 phototherapy, 204 shampoos, 200–201 tacalcitol in an emulsion, 203 topical corticosteroids, 202 treatment strategies, 204–205 vitamin D3 analogs, 203 Self-administered treatments, 8 Self-reported compliance measures, 28 Sequential therapy, 8, 19, 129 as a flexible therapeutic strategy, 134 issue of timing of each treatment phase, 133 Short-contact anthralin therapy (SCAT), 97 “Short-contact” therapy, 79t Side effects tazarotene, 79–80 Sirolimus, 84 Skin cap, 29–30 Skin cap spray, 30 Splinter hemorrhages, 229 Squamous cell carcinoma (SCC) in psoriatic nails, 234 Stoughton–Cornell classification system, 212 Subungual hyperkeratosis, 227 Sulfasalazine (Azulfidine) therapeutic use for nail psoriasis, 240–241 Superpotent topical steroids, side-effect profile, 132 Symmetric polyarthritis, 230 Systemic retinoids in combination with NB-UVB, 106 Systemic tacrolimus, 83

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254 Tachyphylaxis, 29 Tacrolimus (Protopic), 24, 35 Targeted (localized) phototherapy, 115–119 Targeted UVA and UVB phototherapy units, 116t Targeted UVB lamp (BClearTM ), 117 R Tazarotene (Tazorac ), 16, 71 and topical steroid-induced skin atrophy, 76 and topical steroids, 74–76 and vitamin D analogs, 77 application in psoriasis, 79 chemical compatibility with a topical steroid, 76 combination therapy, 73–74 therapeutic use for inverse psoriasis, 213–214 therapeutic use for nail psoriasis, 239 vs. topical steroids, 73 Tazarotene monotherapy, 72 Tazarotenic acid, 72 T-helper lymphocyte, 84 Therapeutic use. See also Combination therapy clobetasol propionate foam and calcipotriene ointment, 134 cyclosporine with methotrexate, 149–150 halobetasol propionate and calcipotriene, 130–133 NB-UVB and bath PUVA, 141 NB-UVB and cream PUVA, 141–142 PUVA and tar/anthralin, 145 Tacrolimus and pimecrolimus as topical immunomodulators, 15 tazarotene and calcipotriene, 76–77 tazarotene and nail psoriasis, 78 tazarotene and PUVA, 144 tazarotene and PUVA phototherapy, 78 tazarotene and ultraviolet B phototherapy, 77–78 UVA and topical vitamin D, 143 UVB and PUVA, 141 UVB and tar/anthralin, 144–145

Index UVB and tazarotene, 143–144 UVB and topical vitamin D, 142 Therapy-induced remission, 13 Thicker (ointment) vehicles, 17 TNF inhibitors, therapeutic use in active psoriatic arthritis, 156–157 Tolypocladium inflatum gans, 83 Topical calcineurin inhibitors, 83 Topical corticosteroids, 23 biologic and pharmacologic activity, 24–26 clinical effectiveness of, 30–31 cost considerations, 33 delivery and physiologic potency, 26–27 potency of, 32–33 potential pitfall, 35 potential side effects from, 57 practical use of, 33–34 safety, 31–32 adherence, or compliance, 27–28 steroid receptor binding, 27–28 Topical steroids, 15 Topical tazarotene in combination with NB-UVB, 77 Topical therapies appropriate vehicle, 17–18 strength of the agent, 18 techniques to enhance, 18–19 Trachyonychia, 227 Transmembrane CD3 complex, 84 Treatment, palmoplantar psoriasis, 185–190 Triamcinolone acetonide (TAC) injection therapeutic use for nail psoriasis, 237 Two-compound scalp formulation, 65 Ultraviolet (UV) spectrum, 103 UVA1, 119–120 UVB phototherapy, 104–109 Vasoconstrictor assay, 27 Vehicle preference, 28 Vitamin D3 analogs, 41–42 Zinc pyrithion shampoos, 200

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SECOND EDITION

Dermatology about the book… Using a practical and problem-focused approach, this updated, full-color Second Edition of Mild-to-Moderate Psoriasis equips dermatologists, internists, family practitioners, and residents with a state-of-the-art guide to the clinical management of mild-tomoderate psoriasis.

about the editors... JOHN Y.M. KOO is Director of the University of California at San Francisco (UCSF) Medical Center Psoriasis and Skin Treatment Center, and Professor of Dermatology and ViceChairman of Department of Dermatology, UCSF Medical Center, San Francisco, California, USA. Dr. Koo received his M.D. degree from Harvard Medical School, Boston, Massachusetts, USA. Dr. Koo has been named on the list, “Best Doctors in America.” Dr. Koo is Board Certified in Psychiatry and Dermatology. He has published more than 300 articles and book chapters in the field of psoriasis. He is co-editor of the first edition of Mild-to-Moderate Psoriasis and the upcoming Moderate-to-Severe Psoriasis, Third Edition. CHAI SUE LEE is Director of the Psoriasis and Phototherapy Treatment Center in the Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA. Dr. Lee received her M.S. and M.D. degrees from the University of California, San Francisco, and the University of California, Berkeley Joint Degree Program, Berkeley, California, USA. Dr. Lee is author of numerous professional articles and book chapters, and was co-editor of the first edition of Mild-to-Moderate Psoriasis and Moderateto-Severe Psoriasis, Third Edition. MARK G. LEBWOHL is Professor of Dermatology and Chairman of the Department of Dermatology, the Mount Sinai School of Medicine, New York, New York, USA, and Chairman of the Medical Board of the National Psoriasis Foundation. Dr. Lebwohl received his M.D. from Harvard Medical School, Boston, Massachusetts, USA. Dr. Lebwohl is the founding editor of Psoriasis Forum and is on the editorial board of the Journal of the American Academy of Dermatology. He has authored or co-authored over 500 publications, including the first edition of Mild-to-Moderate Psoriasis and Moderate-to-Severe Psoriasis, Third Edition. Printed in the United States of America

H8860

Mild-to-Moderate

New to the Second Edition: • updates on calcipotriene, tazarotene, tars, anthralin, salicylic acid, and phototherapy • new treatment such as innovative formulations of topical corticosteroids, laser therapy and hydrogel patches • expanded coverage on scalp psoriasis

Mild-to-Moderate

Psoriasis

Written by an international team of key opinion leaders, this resource explores new treatments for the condition and provides clinicians with up-to-date management strategies for optimal patient management.

Koo • Lee • Lebwohl

Psoriasis

S E C ON D

E DI T ION

Edited by

John Y.M. Koo Chai Sue Lee Mark G. Lebwohl

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